VERSO UN TRATTAMENTO PERSONALIZZATO DELL’ASMA
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Transcript of VERSO UN TRATTAMENTO PERSONALIZZATO DELL’ASMA
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
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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
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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!!!!