“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

http://www.policlinico.mo.it/

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

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 ?

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

“Linee Guida Internazionali su Asma e Rinite” Prof. Leonardo M. Fabbri Department of Pulmonary...

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