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