Dal convegno "Novità diagnostico-terapeutiche in Allergologia e Immunologia Clinica" dell'11 Novembre 2017, Torino

1. Caterina Bucca
S.C. Pneumologia U ,
Città della Salute e della Scienza, Torino
Dipartimento di Scienze Mediche,
Università di Torino

2. International ERS/ATS Guidelines on Definition,
Evaluation and Treatment of Severe Asthma
Kian Fan Chung; Sally E Wenzel; Jan L Brozek; Andrew Bush; Mario Castro; Peter J Sterk ;
Ian M Adcock; Eric D Bateman; Elisabeth H Bel; Eugene R Bleecker; Louis‐Philippe Boulet;
Christopher Brightling; Pascal Chanez; Sven‐Erik Dahlen; Ratko Djukanovic; Urs Frey; Mina Gaga;
Peter Gibson; Qutayba Hamid; Nizar N Jajour; Thais Mauad; Ronald L Sorkness; W Gerald Teague.
SEVERE ASTHMA
Asthma that requires treatment with high dose inhaled
corticosteroids plus a second controller and/or systemic
corticosteroids to prevent it from becoming “uncontrolled” or
that remains “uncontrolled“ despite this therapy.
Severe asthma is a heterogeneous condition, consisting of multiple
phenotypes.
Studies are beginning to define phenotypic biomarkers, and phenotype
targeted biologic therapies are increasingly showing efficacy.
Eur Respir J. 2014 Feb;43(2):343-73

3. © Global Initiative for Asthma
Stepwise approach to control
asthma symptoms and reduce risk
GINA 2017, Box 3-5 (1/8)
Symptoms
Exacerbations
Side-effects
Patient satisfaction
Lung function
Other
controller
options
RELIEVER
REMEMBER
TO...
• Provide guided self-management education (self-monitoring + written action plan + regular review)
• Treat modifiable risk factors and comorbidities, e.g. smoking, obesity, anxiety
• Advise about non-pharmacological therapies and strategies, e.g. physical activity, weight loss, avoidance of
sensitizers where appropriate
• Consider stepping up if … uncontrolled symptoms, exacerbations or risks, but check diagnosis, inhaler
technique and adherence first
• Consider adding SLIT in adult HDM-sensitive patients with allergic rhinitis who have exacerbations despite
ICS treatment, provided FEV1 is >70% predicted
• Consider stepping down if … symptoms controlled for 3 months + low risk for exacerbations.
Ceasing ICS is not advised.
STEP 1 STEP 2
STEP 3
STEP 4
STEP 5
Low dose ICS
Consider low
dose ICS
Leukotriene receptor antagonists (LTRA)
Low dose theophylline*
Med/high dose ICS
Low dose ICS+LTRA
(or + theoph*)
As-needed short-acting beta2-agonist (SABA) As-needed SABA or
low dose ICS/formoterol#
Low dose
ICS/LABA**
Med/high
ICS/LABA
Diagnosis
Symptom control & risk factors
(including lung function)
Inhaler technique & adherence
Patient preference
Asthma medications
Non-pharmacological strategies
Treat modifiable risk factors
PREFERRED
CONTROLLER
CHOICE
Add tiotropium*
High dose ICS
+ LTRA
(or + theoph*)
Add low dose
OCS
Refer for
add-on
treatment
e.g.
tiotropium,*
anti-IgE,
anti-IL5*
SLIT added
as an option

4. Identifying new biological treatments
to target molecular mechanisms of
severe asthma
MONOCLONAL ANTIBODIES (MOA)
IgE, TNFalpha, IL5, IL13, IL4R, IL-17
NOVEL MOLECULES
GATA-3-mRNA-specific DNAzyme
CXCR2 antagonist
PHARMACOLOGIC AGENTS
Roflumilast, Tiotropium, Macrolides

5. Studio TENOR*: IgE elevate nell’asma
moderata e grave
n=38 n=435 n=253 n=19 n=228 n=228 n=81 n=1529n=1690
137
108
84
146
224
82
280
238
88
0
50
100
150
200
250
300
Children Adolescents Adults
MeanIgElevels(IU/mL)
Mild
Moderate
Severe
Dolan CM et al. Ann Allergy Asthma Immunol. 2004;92:32-39.
*TENOR: The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens Study

6. Elevati livelli locali di IgE in
pazienti con asma fatale
302328
Fatal Asthma
(n=10)
Non-Pulmonary
Deaths
(n=9)
FceRIreceptorexpressionin
laminapropria(+cells/mm2)
Mild Intermittent
Asthma†
(n=16)
1200
1000
800
600
400
200
0
1085*
*P<0.05 vs other groups.
†Biopsy
Fregonese L, et al. Am J Respir Crit Care Med. 2004;169:A297.

7. omalizumab
IgE
C3
Binding site of omalizumab to IgE

11. Targetting
INTERLEUKINS/CYTOKINES
Th2 (ILC2) T2
IL-17
TSLP
TNFαIL-5
IL-5Rα
IL-13 IL-4Rα
Mepolizumab
Reslizumab
Benralizumab
GSK679586
Lebrikizumab
Tralokinumab
AMG317
Dupilumab CXCR2
Antagonist
(SCH527123)
IL-4
IL-13
Non-T2
CXCR8
Brodalumab
Etanercept
GolimumabOmalizumab
QGE031
Quilizumab
IgE
AMG157

12. Regime di rimborsabilita' e
prezzo di vendita della specialita'
medicinale «Xolair»
(omalizumab), autorizzata con
procedura centralizzata europea
dalla Commissione europea con la
decisione del 25 ottobre 2005 ed
inserita nel registro comunitario
dei medicinali con il numero:
EU/1/05/319/002-150 mg polvere e
solvente per soluzione iniettabile
uso so...

13. Indicazioni approvate per l’uso di omazulimab (Xolair), come
terapia aggiuntiva:
migliorare il controllo dell’asma in pazienti adulti e adolescenti
(a partire dai dodici anni di età) con le seguenti caratteristiche
➢ asma allergico grave e persistente
➢ positività ai test cutanei o al test di reattività in vitro per un
aeroallergene perenne
➢ funzionalità polmonare ridotta (FEV1 <80%)
➢ frequenti sintomi diurni e risvegli notturni
➢ numerosi e documentati episodi di riacutizzazione di asma
grave, nonostante assunzione giornaliera di corticosteroidi
inalatori ad alto dosaggio, + b2-agonista a lunga durata
d’azione per via inalatoria
➢ Il trattamento con omalizumab dovrebbe essere
considerato solo per i pazienti con asma di accertata di
natura IgE mediata

14. Benefits of omalizumab as add-on therapy in patients with
severe persistent asthma who are inadequately controlled
despite best available therapy
(GINA step 4 treatment): INNOVATE
0.48
0.24
omalizumab
omalizumab
placebo
placebo
Clinicallysignificant
Asthmaexacerbationsrate
Severeasthma
exacerbationsrate
0
0
0.2
0.4
0.6
0.8
1.0
0.2
0.4
0.6
0.68
0.91P=0.042
P=0.002
Humbert M et al; Allergy 2005; 60:309-316
419 pazienti con
asma grave
persistente, allergia
ad aero-allergene
perenne,
scarsamente
controllati
nonostante terapia
secondo linee guida
GINA , IgE 30-
700 IU/ml
FEV1 tra 40% e 80%
del teorico
omalizumab x 28 sett.
➢ Riduzione del 26%
delle esacerbazioni
dell’asma
clinicamente
significative e del
50% delle
esacerbazioni gravi
➢ Miglioramento
della qualità della
vita

16. Riduzione degli
eosinofili nello
sputo indotto e
nella sottomucosa
bronchiale dopo 16
settimane di
terapia con
omalizumab
(Djukanovic R. Am J Respir
Crit Care Med 2004)

24. ICS decrease remodeling?

27. Il rimodellamento è reversibile?

28. During treatment: significant increase in ACT, and decrease in AE in both groups,
already evident after 6 months. By contrast,
FENO and FEV1 and improved only in G1.
Omalizumab attenuates airway inflammation and remodeling, acting in the first few
months of therapy. This effect can be expected in patients with high FENO and
eosinophilia before treatment.
Bucca et al. ERS Congress 2016

29. Forty-five patients [mean age 44.9 years
(range 19e69), females 37/45 (82%), mean
duration of omalizumab treatment 60.7 ±
30.9 months (range 23-121) were included in
the analysis.
Efficacia mantenuta dopo 5 anni di
trattamento

30. Maggior efficacia per trattamento
superiore a 60 mesi

31. Meno efficace
nell’anziano a causa delle
comorbilità

32. .

33. Andamento dopo
sospensione
dell’omalizumab
Nopp A, Allergy 2007

35. I pz. che continuarono la terapia: miglior ACT e ACQ

39. OMALIZUMAB NON SOLO NELL’ASMA

40. Kaplan outlined 7 potential mechanisms that may contribute to
the efficacy of omalizumab in CSU:
1. Decreased free IgE and IgE receptors;
2. Reduced mast cell releasability;
3. Reversal of basopenia and improved basophil IgE receptor
function;
4. Reduced activity of IgE autoantibodies against IgE and IgE
receptors;
5. Reduced activity of intrinsically ‘abnormal’ IgE;
6. Reduced activity of IgE autoantibodies against and unknown
autoantigen;
7. Decreased role of coagulation involvement.
No single theory or combination of theories was found to fully
explain the pattern of response seen with omalizumab for CSU
patients .

41. UAS7: urticaria activity score
calculated over 7 days

44. Omalizumab treatment in patients with chronic inducible urticaria: A systematic review of published
evidenceJournal of Allergy and Clinical Immunology [0091-6749] Maurer, Marcus anno:2017

48. Caterina Bucca
S.C. Pneumologia U ,
Città della Salute e della Scienza, Torino
Dipartimento di Scienze Mediche,
Università di Torino