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Transcript of “Linee Guida Internazionali su Asma e Rinite” Prof. Leonardo M. Fabbri Department of Pulmonary...
“Linee Guida Internazionali su Asma e Rinite”
Prof. Leonardo M. Fabbri
Department of Pulmonary DiseasesUniversity of Modena & Reggio Emilia, Italy
http//pneumologia.unimo.it
Università degli Studi di Modena e Reggio Emilia
Modena 07/05/2004
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
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
Management of asthma:Management of asthma:updating the GINA guidelinesupdating the GINA guidelines
Systemic Systemic steroidssteroids
Ast
hm
a se
veri
tyA
sth
ma
seve
rity
MildMildIntermittentIntermittent
Mild Mild PersistentPersistent
Moderate Moderate PersistentPersistent
ModerateModeratePersistentPersistent
SevereSeverePersistentPersistent
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
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
BDPBDPTriamcinoloneTriamcinolone
FlunisolideFlunisolideBudesonideBudesonideFluticasoneFluticasoneMometasoneMometasone
Systemic circulation
Lung metabolism(esterases)
““Soft steroids”Soft steroids”ButixicortButixicortTipredaneTipredane
ProdrugProdrugCiclesonideCiclesonide
Active drugreleased in the
airways
REDUCING SYSTEMIC EFFECTS REDUCING SYSTEMIC EFFECTS OF CORTICOSTEROIDSOF CORTICOSTEROIDS
EFFECTIVE
NOT EFFECTIVE
NEW BRONCHODILATORSNEW BRONCHODILATORS
Improvement in existing drugsImprovement in existing drugs
• Long-acting ßLong-acting ß22-agonists: -agonists: salmeterol, formoterolsalmeterol, formoterol once dailyonce daily
• Anticholinergics: Anticholinergics: tiotropium bromidetiotropium bromide (once daily, COPD) (once daily, COPD)
Novel classesNovel classes
• Potassium channel openers Potassium channel openers (levcromakalim)(levcromakalim)
• VIP analogues VIP analogues (Ro 25-1553)(Ro 25-1553)
• NitrovasodilatorsNitrovasodilators
PDE4INHIBITORS
PHOSPHODIESTERASE 4 INHIBITORSPHOSPHODIESTERASE 4 INHIBITORS
Cilomilast Cilomilast RoflumilastRoflumilastCP 80633CP 80633CDP-840CDP-840etcetc
Mast cell
Eosinophil
T-cell
Macrophage
Neutrophil
NANC nerves
Epithelial cells
Airway smooth muscle cells
PDE 4 INHIBITORS: SIDE EFFECTSPDE 4 INHIBITORS: SIDE EFFECTS • NauseaNausea and vomiting and vomiting• DiarrhoeaDiarrhoea• HeadachesHeadaches (N.B. side effects of theophylline)(N.B. side effects of theophylline)
• Central or peripheral effect?Central or peripheral effect? • Subtype selective inhibitors?Subtype selective inhibitors? - human PDE4A, 4B, 4C, 4D- human PDE4A, 4B, 4C, 4D
Anti-inflammatoryAnti-inflammatory NauseaNausea
2,43
0,86
2,69
0,86
0
1
2
3
4
(Med
ian
Pu
ffs
Sal
bu
tam
ol)
Roflumilast BDP
******
Roflumilast vs low-dose Beclomethasone (BDP) in moderate persistent asthma
T0 Roflumilast
Tlast Roflumilast
T0 BDP Tlast BDP
Rescue Medication – Diary
Roflumilast in Asthma
• Roflumilast 250µg / 500µg is safe and well tolerated
• Roflumilast may have antiflammatory properties- dose-dependent reduction of early and late asthmatic reactions
- ongoing sputum and biopsy studies
• In Phase II/III clinical trials Roflumilast showed – A dose response effect, with 250µg and 500µg being effective doses– Superiority over Montelukast– Equivalence to 400 µg BDP
• Efficacy already after 1 week of treatment
• Constant efficacy over at least 1 year
• Clinically relevant improvement of lung function
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 ?
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
MEDIATOR ANTAGONISTSMEDIATOR ANTAGONISTS
MEDIATOR ANTAGONIST/INHIBITOR HistamineProstaglandinsThromboxaneLeukotriene B4
cys-LeukotrienesPAFBradykininTachykininsAdenosineReactive oxygen speciesEndothelin-1Nitric oxide
loratadine, cetirizineindomethacinozagrelLY293111montelukast, zileutonapafant, modipafanticatibantCP 999994theophyllineN-acetyl cysteinebosentaniNOS inhibitors
NEW ANTI-INFLAMMATORYNEW ANTI-INFLAMMATORYTREATMENTS FOR ALLERGIC DISEASESTREATMENTS FOR ALLERGIC DISEASES
New steroidsNew steroids ‘‘Soft steroids’Soft steroids’ ‘‘Dissociated steroids’Dissociated steroids’
Anti-eosinophil drugsAnti-eosinophil drugs IL-5 inhibitionIL-5 inhibition VLA4 inhibitorsVLA4 inhibitors CCR3 antagonistsCCR3 antagonists
Non-steroidal Non-steroidal anti-inflammatory agentsanti-inflammatory agents PDE4 inhibitorsPDE4 inhibitors NF-NF-B inhibitorsB inhibitors p38 MAP kinase inhibitorsp38 MAP kinase inhibitors
Anti-allergic drugsAnti-allergic drugs Anti-IgEAnti-IgE Anti-IL-4Anti-IL-4 IL-12, IL-18, IFN-IL-12, IL-18, IFN-
W. Busse and R. Lemanske. Immunology of asthma NEJM 2001: 344:350W. Busse and R. Lemanske. Immunology of asthma NEJM 2001: 344:350
Th1 and Th2 balanceTh1 and Th2 balance
Preferential expression of chemokine Preferential expression of chemokine receptors in Th1 vs Th2 cellsreceptors in Th1 vs Th2 cells
Sinigaglia et al, Am J Respir Crit Care Med 2001; 164: 1266-1275Sinigaglia et al, Am J Respir Crit Care Med 2001; 164: 1266-1275
CCR4 expression in asthma
normal control non-challenged allergen-challenged
0
5000
NON CHALLENGEDALLERGEN CHALLENGED
1000
2000
3000
4000
CC
R4+
T c
ells
/mm
2
P<0.05
CD
3/C
CR
4
P. Panina-Bordignon, A. Papi et al. J Clin Invest 107:1357, 2001
Up-regulation of MDC and TARC after allergen challenge
control non-challenge allergen-challenge
MD
CT
AR
C
P. Panina-Bordignon et al. J Clin Invest 107:1357, 2001
CCR3 is not expressed by lung T cells but only by eosinophils in asthma
allergen-challenged
Normal control Non-challenged
allergen-challenged
CD
3/C
CR
3C
D3/
CC
R3
CD
3/CC
R3
EG
2/CC
R3
Chemokines-cytokines expression in T cells Chemokines-cytokines expression in T cells infiltratinginfiltrating
the central airways of asthmatics the central airways of asthmatics vsvs COPD COPD patientspatients
CCR4CCR4//IL-4IL-4
CCR4CCR4//IL-4IL-4
CXCR3CXCR3//IFN-IFN-
CXCR3CXCR3//IFN-IFN-
ee
ee
eeee
LL
LL
LL
LLLL
AS
TH
MA
AS
TH
MA
CO
PD
CO
PD
CO
PD
CO
PD
AS
TH
MA
AS
TH
MA
Panina Bordignon, Papi A et al J Clin Invest 2001; 107:1357Panina Bordignon, Papi A et al J Clin Invest 2001; 107:1357
Differences between asthma and COPDDifferences between asthma and COPD
ASTHMAASTHMASensitizing agentSensitizing agent
COPDCOPDSmokingSmoking
Asthmatic airwayAsthmatic airwayinflammationinflammation
CD4+ T-lymphocytesCD4+ T-lymphocytes
EosinophilsEosinophils
COPD airway inflammationCOPD airway inflammationCD8+ T-lymphocytesCD8+ T-lymphocytes
MarcrophagesMarcrophages
NeutrophilsNeutrophils
CompletelyCompletelyreversiblereversible
CompletelyCompletelyirreversibleirreversibleAirflow limitationAirflow limitation
CHEMOKINE ANTAGONISTS IN ALLERGYCHEMOKINE ANTAGONISTS IN ALLERGY
Eosinophil Th2 cell Mast cell
Eotaxin, Eotaxin-2Eotaxin, Eotaxin-2RANTESRANTESMCP-4MCP-4
CCR3 antagonistsCCR3 antagonistsMet-RANTES Met-RANTES
UCB35625UCB35625SB-328437SB-328437
CCR3
Monocyte Mast cell T cell
MCP1-5MCP1-5
CCR2 antagonistsCCR2 antagonists
CCR2
Th2 cell
MDCMDCTARCTARC
CCR4 antagonistsCCR4 antagonists
CCR4
CCR8CCR8CXCR4CXCR4
Chemokine receptors in the Chemokine receptors in the clinicclinic
Chemokine receptor
Indication Company Phase Compound
CCR1 RA Astra Zeneca
I AZD8309
CCR1 MS Berlex I BX471
CCR3 Allergy Asthma BMS I DPC-168
CCR5 HIV Pfizer I UK-427857
CCR5 HIV Shering Plough
I SCH-C
CXCR4 Bone marrow transplantation
Anormed I AMD3100
BEYOND STEROIDSBEYOND STEROIDS
Non-steroidal anti-inflammatory agentsNon-steroidal anti-inflammatory agents
• Anti-eosinophil strategiesAnti-eosinophil strategies
• Anti-TNFAnti-TNF
• NF-NF-B inhibitorsB inhibitors
• p38 MAP kinase inhibitorsp38 MAP kinase inhibitors
Eosinophils
Chromosomal regions involved in the pathogenesis of asthma
IgE-receptor
(11q)
APC CD4Th
B-cell
Antigens
Class II HLAMOLECULES
(6p)
Mast cells
chronic airway inflammation-bronchoconstriction-airway hyperrsponsiveness
T-cell-receptor
(14q)
CD4Th2
Activated Tcell
Y
Y
Y
YIgE
Airway smooth muscle cell
2-receptor (5q)Inflammatory mediatorsLTC4LTD4Histamine, PAF
IL4IL13
(5q)IL5
GMCSF (5q)
Beta-2-agonists
Y
v
v
IL-4R(16p)
Y
IL-4
Modified from Parè et al, 1999
Association between genetic polymorphisms of Association between genetic polymorphisms of the the 22-adrenoreceptor and response to albuterol in -adrenoreceptor and response to albuterol in
children with and without a history of wheezingchildren with and without a history of wheezing
Martinez FD et al, J Clin Invest 1997;100:3184-3188Martinez FD et al, J Clin Invest 1997;100:3184-3188
When compared to homozygotes for Gly-16, homozygotes When compared to homozygotes for Gly-16, homozygotes for Arg-16 were 5.3 and heterozygotes for for Arg-16 were 5.3 and heterozygotes for 22AR-16 were 2.3 AR-16 were 2.3
times more likely to respond to albuterol.times more likely to respond to albuterol.
Wild typeABT-761
MutantABT-761
Wild typeplacebo
Day 8 Day 16
0
5
10
15
25
20
FE
V1 c
han
ge f
rom
bas
elin
e
Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment
Drazen J et al, Nature Genetics 1999;2:168-170
CONCLUSIONSCONCLUSIONS
Room for improvement of current treatment options
Ciclesonide, phosphodiesterase inhibitors and anti-IgE available soon
Very few new treatments likely over next 15 yearsVery few new treatments likely over next 15 years
Studies on genetics of asthma may contribute to Studies on genetics of asthma may contribute to improve characterization and treatment of asthmaimprove characterization and treatment of asthma
In collaboration with the World Health Organization
The ARIA initiative was developed
• as a state-of-the-art for the specialist, the general practitioner and for health care workers:
• to update their knowledge of allergic rhinitis,
• to highlight the impact of allergic rhinitis on asthma,
• to provide an evidence-based documented revision on the diagnosis methods,
• to provide an evidence-based revision on the treatments available,
• to propose a stepwise approach to the management of the disease,
• to assess the magnitude of the problem in developing countries and to implement guidelines (with IUATLD)
ARIA programme First phase:
• Development of evidence-based guidelines during a workshop held at WHO in December 1999 (J Allergy Clin Immunol, suppl, Nov 2001).
• Document has been endorsed by several allergy, respiratory, ENT and paediatric associations.
ARIA programme First phase: • Development of evidence-based guidelines during a
workshop held at WHO in December 1999 (J Allergy Clin Immunol, suppl, Nov 2001).
• Document has been endorsed by several allergy, respiratory, ENT and paediatric associations.
Second phase:
• To produce materials to help improve delivery of care to those with rhinitis. In particular a pocket guide
• To implement ARIA guidelines
• To update the workshop report
1- Why ARIA ?
2- New classification of rhinitis
3- Importance of nasal inflammation
4- Treatment based on evidence
5- Impact of rhinitis on asthma
Dalla Rinite all’Asma
“Linee Guida Internazionali su Asma e Rinite”
Prof. Leonardo M. Fabbri
Department of Pulmonary DiseasesUniversity of Modena & Reggio Emilia, Italy
http//pneumologia.unimo.it
Modena, 07/05/2004