Inflammatory phenotypes

VERSO UN TRATTAMENTO
PERSONALIZZATO
DELL’ASMA
Valore del farmaco nell’ASMA
Controllo della malattia
panel a
first four days of treatment
panel b
four days of the following week
panel c
the last four days
before the fatal attack
mucous plug
thickening of the
basement 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
Effects of Inhaled Corticosteroids
PC20
methacholine
(mg/ml)
Asthmatic
symptoms
100
6
4
mg/ml
Severity
10
1
2
0,1
0
Pre-BD
6 wk
0,01
Pre-BD 6 wk
number of cells/mm2 of submucosa
Bronchial Function
Bronchial Submucosa
mast cells eosinophilsT lymphocytes
760
720
240
200
160
120
80
40
0
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 corticosteroids
AP 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
Controllo dell’Asma

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
Definizioni di “controllo”
Controllo Totale 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
Il CONTROLLO TOTALE dell’asma migliora con il
trattamento prolungato
% di pazienti controllati ogni settimana
= Total Control Asthma Weeks
100
Salm/FP
80
Fluticasone
60
40
20
0
-4
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Settimane
Bateman et al , GOAL study, ARJCCM 2004
La gestione del paziente asmatico
Controllo dell’asma
Nonostante la larga diffusione delle Linee Guida,
il controllo dell’asma è ancora insoddisfacente
J Allergy Clin Immunol 2007;120:1360-7
Adherence
Different Phenotypes
The aim of this study was to identify factors affecting
changes in asthma treatment adherence in an
international court
A major reason of the poor control of asthma is that patients fail to adhere to
their treatment.
 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
Traditionally asthma has been categorized as…
Atopic/Extrinsic
Nonatopic/Intrinsic
Allergen exposures,
Progressive allergic inflammation,
Hyperresponsiveness and symptoms in the airways
• Atopic asthma often starts in childhood,
• Family history
• Response to treatment against anti Thelper cell type 2 (anti-Th2)
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.
Complexity of
asthma
mechanisms
Clinical or physiological phenotypes
Severity- defined
Exacerbation-prone
Defined by chronic restriction
Treatment-resistant
Defined by age at onset
Phenotypes related to the following triggers
Aspirin or on-steroidal anti-inflammatory drugs
Enviromental allergens
Occupational allergens or irritants
Menses
Exercise
Inflammatory phenotypes
Eosinophilic
Neutrophilic
Pauci-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.
Early/childhood onset phenotypes
Fixed
obstruction
Exacerbation
prone
Severe
Exercise-induced
Eosinophilic
steroid-responsive
Allergic
Wenzel S, Lancet 2006;386:804-813
Late/adult onset
PMA
Aspirin-sensitive
Allergic
Eosinophilic corticosteroid
responsive
Severe
Occupational
Non-Allergic
Wenzel SE. Lancet 2006; 368: 804–13
Clinical or physiological phenotypes
Severity- defined
Exacerbation-prone
Defined by chronic restriction
Treatment-resistant
Defined by age at onset
Phenotypes related to the following triggers
Aspirin or on-steroidal anti-inflammatory drugs
Enviromental allergens
Occupational allergens or irritants
Menses
Exercise
Inflammatory phenotypes
Eosinophilic
Neutrophilic
Pauci-granulocytic
Inflammatory Phenotypes
Eosinophilic asthma
Neutrophilic asthma
EG2 +
Paucigranulocytic asthma
Neutrophil elastase +
Haldar e Pavord JACI 2007
Inflammatory Phenotypes
Eosinophilic asthma
Haldar e Pavord JACI 2007
EG2 +
Comparison of two methods of processing induced
sputum: selected versus entire sputum
A Spanevello et al. AJRCCM 1998; 157: 665-668
Eosinophils (%)
30
asthmatics
25
20
normals
15
10
5
0
Selected Sputum
Entire Sputum
Eos inophils ( X 1 30/g)
p <0.001
p <0.01
1 0000
p <0.001
p <0.05
1 000
1 00
10
1
Co n tro l
I nt ermi t t ent
Mi l d t o moderat e
Severe
g ro u p
ast hma
ast hma
ast hma
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
Eosinophilic asthma
Targeted therapy with anti IL-5 in asthma
Patients with sputum eosinophils > 3% despite steroid treatment
Pavord et al. 2012
Haldar et al. NEJM 2009;360:973-984
exacerbations
exacerbations
placebo
250 mg
75 mg
750 mg
Sputum eos
Sputum eos
placebo
75 mg
250 mg
750 mg
Laviolette M., et al.
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.
Wenzel S., et al
human monoclonal antibody to the alpha subunit of the interleukin-4 receptor
Patients with persistent, moderate-to-severe asthma and elevated eosinophil levels
Inflammatory Phenotypes
Neutrophilic asthma
Neutrophil elastase +
Haldar e Pavord JACI 2007
Neutrophilic Inflammation in severe persistent asthma.
A Jatakanon et al. AJRCCM 1999; 160: 1532-1539
Inflammatory Phenotypes
Paucigranulocytic asthma
Haldar e Pavord JACI 2007
Phenotypes
Clinical sputum database from January 2005
388 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 patients
Lowhagen 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
Corren J et al.
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.
TAKE HOME
MESSAGES
Where are we now?
Asthma is treated empirically
• Standard of care guidelines:
asthma is treated empirically
according to clinical severity
and response to treatment,
not according to underlying
biology
Step 6
High-dose ICS
+ LABA + oral corticosteroid
Step 5
High-dose ICS
+ LABA
Step 4
Medium-dose ICS
+ LABA
Step 3
Low-dose ICS + LABA,
or Medium-dose ICS
Step 2
Low-dose ICS
Step 1
SABA PRN
Cont. Uncont.
NHLBI Guidelines for the Diagnosis and Management of Asthma, Oct 2007
High-Need
(severe)
Asthma Treatment
Where do we need to go?
Personalized Medicine
Treatment A
Treatment B
Treatment C
Treatment D
Personalized Medicine for Asthma
Getting 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.
OK!!!!
Step 6
High-dose ICS
+ LABA + oral corticosteroid
Step 5
High-dose ICS
+ LABA
Step 4
Medium-dose ICS
+ LABA
Step 3
Low-dose ICS + LABA,
or Medium-dose ICS
Step 2
Low-dose ICS
Step 1
SABA PRN
Cont. Uncont.
NHLBI Guidelines for the Diagnosis and Management of Asthma, Oct 2007
High-Need
(severe)