Kenji Izuhara
Saga Medical School, Japan
Periostin: Update on Clinical Use
WISC2014 Biomarkers in Asthma: Helping Diagnosis and Treatment
12/8/2014
Heterogeneity of bronchial asthma
Age of onset (Early onset vs. Late onset)
Existence of obesity
Inflammatory cells (Eosinophil-dominant vs. Neutrophil-dominant)
IgE-dependency (Atopic vs. Non-atopic)
Responsiveness to ICS (Good vs. Poor)
The status and the problems of the treatment
using ICS or anti-IgE antibody (Omalizumab)
・ICS is effective and has significantly decreased deaths from asthma
・But 5-10% of the patients are resistant or hypo-responsive
Adcock, J Endocrinol, 2003
・61% of severe asthma patients show improvement of QOL
・Serum IgE cannot predict the responsiveness
Bousquet, Respr Med, 2007
・Expensive cost
ICS
Anti-IgE antibody (Omalizumab)
T cell subsets and innate lymphoid cells
important for immune responses
Helper T cells
Innate lymphoid cells
IFN-g
Th1
ILC1
IL-17
IL-22
Th17
ILC3
IL-4
IL-13
IL-5
Th2
ILC2
Yuyama, Cytokine, 2002
Identification of periostin as a novel mediator in bronchial asthma
± IL-13
Airway epithelial cell
DNA microarray Periostin
+IL
-13
- IL-13
Periostin stainingH&E staining
PeriostinThickened Basement Membrane
Takayama, J Allergy Clin Immunol, 2006
Two faces of periostin
A conventional extracellular matrix (ECM) protein
periostin
collagen I/fibronectin tenascin Cmaintenance of tissue/organ structure
and fibrosis
A matricellular protein
PeriostinaVb3 integrin (periostin receptor)
cell activation
Fasciclin 1 domainsEMI domain
signal
Izuhara, Allergol Int, 2014
Characteristics pf periostin in bronchial asthma
1. A novel component of thickened basement membrane downstream
of IL-13 signals
2. A surrogate biomarker of type 2 immune responses
3. A companion diagnostic for antagonists against type 2 immune responses
Takayama, J Allergy Clin Immunol, 2006, Hayashi, Proc Natl Acad Sci USA, 2007
Woodruff, Am J Respir Crit Care Med, 2009
Corren, N Engl J Med, 2011, Hanania, Am J Respir Crit Care Med, 2013
Sehra, J Immunol, 2011, Gordon, Clin Exp Allergy, 2011
Blanchard, Mucosal Immunol, 2008, Bentley, J Allergy Clin Immunol, in press
4. Still controversial whether it is a good guy or a bad guy
Periostin deposition
in bronchial subepithelium (%)
-150
-100
-50
0
50
0
ΔF
EV
1(m
L/y
ear)
10 20 30 40
Kanemitsu, Am J Respir Crit Care Med, 2014
Periostin deposition is associated with 20-year decline of
pulmonary function in asthma patients
Periostin
Why is periostin useful as a biomarker?
Easily moves from the lesions to blood
Basal concentration in blood is appropriate (periostin: 10-90 ng/ml)
not too high (fibronectin/vitronectin: ~100 mg/ml)
not too low (cytokines: ~10 pg/ml)
A kit with low detection limit (20 pg/ml) is available
Serum periostin levels are associated
with DFEV1 decline in asthma patients
Rapid decliners
(n=52)
Non-rapid decliners
(n=172)
0
20
40
60
80
100
120
P = 0.023
89.2
Seru
m p
eriostin level (n
g/m
l)
140
89.2
104.6
Rapid decliners : DFEV1 < -30 ml/yr
Non-rapid decliners : DFEV1 ≥ -30 ml/yr
Asthma
patients
(n=224)
Healthy
donors
(n=66)
0
50
100
150
200
250
300
350
Se
rum
pe
rio
stin
le
ve
l (n
g/m
l)
SS18A X SS17B
Kanemitsu, J Allergy Clin Immunol, 2013
Asthma can be categorized into four clusters
by eosinophils and neutrophils
Cluster 1
Cluster 2
Cluster 3
Cluster 4
Late onset
Non-atopic
Early onset
Atopic
Poor control
Low FEV1
High IL-6
Late onset
Eosinophil-dominant25
30
40
50
60
65
0 1 2 3 4 5
Neutr
ophils
(✕
10
2/m
L)
Eosinophils（✕ 102/mL）
Cluster 1
Cluster 2
Cluster 3
Cluster 4
Steroid-sensitive
Steroid-insensitive
Nagasaki, J Allergy Clin Immunol, 2014
-30
-20
-10
0
DF
EV
1(m
l/yr)
10
Cluster 1 Cluster 2
Cluster 3 Cluster 4
High periostin group
Low periostin group
Serum periostin levels are well correlated
with decline of FEV1 in cluster 3
Nagasaki, J Allergy Clin Immunol, 2014
Algorithm for treatment of asthma
LowGood response to ICS
HighPoor response to ICS
Asthma patients Clusterization
Neutrophils
✕Eosinophils Cluster 3
Measurement of
serum periostin levels
Addition of type2 antagonists
Cluster 4
Cluster 2
Cluster 1Good response to ICS
Poor response to ICS
Characteristics of periostin as a biomarker
A type 2 biomarker
Useful to predict efficacy of type 2 antagonists
A remodeling biomarker
Useful to predict hypo-responsiveness to ICS
Kyoto University
Yoshihiro Kanemitsu
Tadao Nagasaki
Hisako Matsumoto
Acknowledgment
Saga Medical School
Shoichiro Ohta
Go Takayama
Shino test Co. Ltd.
Junya Ono
Genox Co. Ltd.
Noriko Yuyama
