VERSO UN TRATTAMENTO PERSONALIZZATO

DELL’ASMA

Valore del farmaco nell’ASMA

Controllo della malattia

panel afirst four days of treatment

panel bfour days of the following week

panel cthe last four daysbefore the fatal attack

mucous plug

thickening of thebasement membrane

Saetta M et al. ERJ 1989;2:1008-1012

Dissociation between Airway Inflammation and Airway hyperresponsiveness in Allergic Asthma

Crimi E et al. Am J Respir Crit Care Med 1998; 157:4-9

0

2

4

6

Pre-BD 6 wk

Effects of Inhaled Corticosteroids

Bronchial Function Bronchial SubmucosaAsthmaticsymptoms

Seve

rity

0,01

0,1

1

10

100

Pre-BD 6 wk

PC20 methacholine(mg/ml)m

g/m

l

num

ber o

f cel

ls/m

m2 o

f sub

muc

osa

eosinophilsT lymphocytesmast cells

04080

120160200240720760

Pre-BD6 wk Pre-BD6 wk Pre-BD6 wk

Djukanovic et al, Am Rev Respir Dis 1992;145:669-74

Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroidsAP Greening, PW Ind, M Northfield, G Shaw

Lancet 1994; 344:219-224

A substantial body of evidence from randomized controlled trials indicates that addition of a LABA to existing ICS therapy is clinically more effective than increasing the dose of ICS monotherapy

L’obiettivo principale del trattamento è ottenere il “buon controllo” dell’asma

Tale indice composito include tutte le principali misure cliniche e funzionali, ed è realisticamente raggiungibile in una alta percentuale di pazienti

Il solo controllo delle riacutizzazioni, senza tener conto dei sintomi quotidiani e del livello di funzione polmonare, non è sufficiente

La rivalutazione periodica dell’ottenuto controllo permette di adeguare la terapia sia in step-up che in step-down

Controllo dell’Asma

Sintomi diurni nessuno Uso farmaci al bisogno nessuno PEF del mattino > 80% predetto

Risvegli notturni nessuno

Riacutizzazione di qualsiasi gravità nessuna

Visite di emergenza nessuna

Eventi avversi dovuti al trattamento nessuno

Definizioni di “controllo”Controllo Totale dell’asma

Il CONTROLLO TOTALE dell’asma migliora con il trattamento prolungato

100

20

80

0

60

40

Settimane

Salm/FP Fluticasone

-4 0 4 40 44 4812 16 24 28 32 36 528 20

% d

i paz

ient

i con

trolla

ti og

ni s

ettim

ana

= To

tal C

ontro

l Ast

hma

Wee

ks

Bateman et al , GOAL study, ARJCCM 2004

Controllo dell’asma

Nonostante la larga diffusione delle Linee Guida, il controllo dell’asma è ancora insoddisfacente

La gestione del paziente asmatico

J Allergy Clin Immunol 2007;120:1360-7

Adherence

Different Phenotypes

A major reason of the poor control of asthma is that patients fail to adhere to their treatment.

The aim of this study was to identify factors affecting changes in asthma treatment adherence in an

international court

Among the 428 non-adherent subjects in ECRHS-I, the only predictors of increased adherence among the variables considered were having regular appointments for asthma or not thinking that it is bad to take medicine all the time.

Gender, age at baseline, duration of the disease, smoking habit, educational level, having written instruction from a doctor, having a personal PEF meter and having had spirometry during the previous 12 months were not significant determinants for the improvement or the persistence of adherence to antiasthmatic treatment.

Adherence

Different Phenotypes

Nonatopic/Intrinsic

Traditionally asthma has been categorized as…

Atopic/Extrinsic

Allergen exposures,

Progressive allergic inflammation,

Hyperresponsiveness and symptoms in the airways

• Adult onset form of the disease• Absence of family history.• More severe symptoms and nasal

polyps, and persistent airflow limitation in men.

• Atopic asthma often starts in childhood,• Family history• Response to treatment against anti T-

helper cell type 2 (anti-Th2) inflammation

Hyperresponsiveness and symptoms in the airways

Complexity of asthma

mechanisms

Clinical or physiological phenotypesSeverity- definedExacerbation-proneDefined by chronic restrictionTreatment-resistantDefined by age at onset

Phenotypes related to the following triggersAspirin or on-steroidal anti-inflammatory drugsEnviromental allergensOccupational allergens or irritantsMensesExercise

Inflammatory phenotypesEosinophilicNeutrophilicPauci-granulocytic

Volume 132, Issue 2 , Pages 336-341

The majority of patients with severe adult-onset asthma are nonatopic and have persistent eosinophilic airway inflammation.

Wenzel S, Lancet 2006;386:804-813

Eosinophilicsteroid-responsive

Exacerbationprone

Severe

Fixedobstruction

Allergic

Exercise-induced

Early/childhood onset phenotypes

Wenzel SE. Lancet 2006; 368: 804–13

Allergic

Severe

OccupationalNon-Allergic

Aspirin-sensitive

Eosinophilic corticosteroid responsive

PMA

Late/adult onset

Clinical or physiological phenotypesSeverity- definedExacerbation-proneDefined by chronic restrictionTreatment-resistantDefined by age at onset

Phenotypes related to the following triggersAspirin or on-steroidal anti-inflammatory drugsEnviromental allergensOccupational allergens or irritantsMensesExercise

Inflammatory phenotypesEosinophilicNeutrophilicPauci-granulocytic

Eosinophilic asthmaNeutrophilic asthma

Paucigranulocytic asthma

EG2 +

Neutrophil elastase +

Haldar e Pavord JACI 2007

Inflammatory Phenotypes

Eosinophilic asthma

EG2 +Haldar e Pavord JACI 2007

Inflammatory Phenotypes

Comparison of two methods of processing induced sputum: selected versus entire sputum

A Spanevello et al. AJRCCM 1998; 157: 665-668

30

25

20

15

10

5

0

Selected Sputum Entire Sputum

Eos

inop

hils

(%) asthmatics

normals

1

10

100

1000

10000

Eosin

ophi

ls (X

10

3 /g)

p<0.05

p<0.001

p<0.01

Controlgroup

Intermittentasthma

Mild to moderateasthma

Severeasthma

p<0.001

Sputum eosinophils are higher in asthmatics than in controls and their amount in sputum increases with the severity of the disease

Sputum eosinophil count predicts response to corticosteroids

Meijer et al Clin Exp Med 2002;32:1096-1103

Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial 

Ruth H Green, Christopher E Brightling, Susan McKenna, Beverley Hargadon, Debbie Parker, Peter Bradding, Andrew J Wardlaw, lan D Pavord

Lancet 2002;360: 1715-21

Effects of Anti-IgE Omalizumab on Inflammation in Asthma

Djukanovic et al Am J Respir Crit Care Med 2004:170 p583-593

Targeted therapy with anti IL-5 in asthmaPatients with sputum eosinophils > 3% despite steroid treatment

Haldar et al. NEJM 2009;360:973-984

placebo

250 mg

75 mg

750 mg

Eosinophilic asthma

placebo

75 mg

250 mg

750 mg

exacerbations exacerbations

Sputum eos Sputum eos

Pavord et al. 2012

Benralizumab targets eosinophils by binding IL-5 receptor α, inducing apoptosis through antibody-dependent cell-mediated cytotoxicity.

Single-dose intravenous and multiple-dose subcutaneous benralizumab reduced eosinophil counts in airway

mucosa/submucosa and sputum and suppressed eosinophil counts in bone marrow and peripheral blood.

Laviolette M., et al.

Wenzel S., et al

Patients with persistent, moderate-to-severe asthma and elevated eosinophil levels

human monoclonal antibody to the alpha subunit of the interleukin-4 receptor

Neutrophilic asthma

Neutrophil elastase +

Haldar e Pavord JACI 2007

Inflammatory Phenotypes

Neutrophilic Inflammation in severe persistent asthma. A Jatakanon et al. AJRCCM 1999; 160: 1532-1539

Paucigranulocytic asthma

Haldar e Pavord JACI 2007

Inflammatory Phenotypes

Phenotypes

Clinical sputum database from January 2005388 samples 297 patients

• AO + AHR + Eosinophils • AO + AHR + Neutrophils (infective) • AO + AHR + Neutrophils (non-infective)• AO + AHR + Eosinophils + Neutrophils

• no AO + AHR + eosinophils • no AO + AHR, no cellular inflammation• no AO + no AHR + eosinophils

Data submitted

Paucigranulocytic asthma

Severe asthma

No inflammatory cells

No biological markers identified

Steroid-resistant

Assessment of Airway Inflammation

Indirect Indices

Blood inflammatory cells

The inflammatory marker serum eosinophil cationic protein (ECP) compared with PEF as a tool to decide inhaled corticosteroid dose in asthmatic patientsLowhagen O et al.

Respir Med 2002; 96:95-101

The objective of this study was to compare the inflammatory marker eosinophil cationic protein (ECP) with peak expiratory flow (PEF) in

determining the therapeutic needs of inhaled corticosteroids in asthma patients assessed as asthma symptoms

None of the used algorithms for ECP and PEF led to improvement in symptom scores, in spite of increased doses of inhaled corticosteroids. In

the respect, both methods were equivalent and insufficient

AJRCC 2009

AJRCC 2009

AJRCC 2009

Lebrikizumab IgG4 humanized monoclonal antibody that binds to IL-13

Stratifying patients into a high Th2 phenotype using serum periostin, which is upregulated in lung epithelial cells by IL-13, may identify individuals responsive to blockade of IL-13.

Corren J et al.

TAKE HOME MESSAGES

Where are we now? Asthma is treated empirically

Cont. Uncont.

Step 1SABA PRN

Step 2Low-dose ICS

Step 3Low-dose ICS + LABA,

or Medium-dose ICS

Step 4Medium-dose ICS

+ LABA

Step 5High-dose ICS

+ LABA

Step 6High-dose ICS

+ LABA + oral corticosteroid

High-Need (severe)

NHLBI Guidelines for the Diagnosis and Management of Asthma, Oct 2007

• Standard of care guidelines:asthma is treated empirically

according to clinical severity and response to treatment,

not according to underlying biology

Treatment A

Treatment B

Treatment C

Treatment D

Asthma TreatmentWhere do we need to go?

Personalized Medicine

Personalized Medicine for AsthmaGetting there

Improved understanding of the molecular mechanism of different clinical phenotypes of

asthma.

Non-invasive (preferably blood-based) biomarkers that identify molecular phenotypes to guide

treatment.

Cont. Uncont.

Step 1SABA PRN

Step 2Low-dose ICS

Step 3Low-dose ICS + LABA,

or Medium-dose ICS

Step 4Medium-dose ICS

+ LABA

Step 5High-dose ICS

+ LABA

Step 6High-dose ICS

+ LABA + oral corticosteroid

High-Need (severe)

NHLBI Guidelines for the Diagnosis and Management of Asthma, Oct 2007

OK!!!!