气喘治疗新趋势

Gene?environment?interactions in?asthma 氣喘治療新趨勢
Allergen
Macrophage Th2?cell Eosinophil
Nerve?activation
哮 喘 發 作
Mast?cell Neutrophil
Mucus?plug
Epithelium?sloughing
? 陣發性支氣管收縮 ? 可逆性的支氣管收縮 自行緩解 或 經支氣管擴張劑治療 後緩解
Subepithelial fibrosis
Plasma?exudation edema Mucus hypersecretion Sensory?nerve activation Cholinergic reflex
經常會在半夜發作 早晚肺功能差異大
Vasodilatation angiogenesis
Bronchoconstriction Muscle?hyperplasia
Immune?cells?and?the?inflammatory?cascade?in?asthma
Th2?effector?cells?and?asthma?pathogenes

Molecular and cellular control
Anti‐IgE Anti‐ Anti‐IgE antibodies
Airway?remodelling?in?asthma
Inhaled Corticosteroids
Long‐acting Long‐ beta‐2 beta‐ agonist
Clin?Chest?Med?2006;27:?133
Asthma?and?Airway?Remodeling
Airway Remodeling Chronic airway inflammation
哮喘與臨床特徵
Or
? Acute inflammation Chronic inflammation Airway remodeling
Mischief-makers
Symptoms (bronchoconstriction ）
Recurrent nonspecific airway hyperresponsivenss
Persistent airflow obstruction
Structural changes
Airway hyperresponsiveness
Effect?of?Glucocorticoid?on?Airway?Inflammation?
Corticosteroids
number Eosinophil
Apoptosis recruitment
Epithelial cell Damage cytokines
The molecular mechanism of action of Corticosteroids
Corticostero ids receptor
Vascular leakage cytokine Lymphocyte number Mast cell
?Cytokines ?Inducible NOS ?Inducible COX-2 ?Phospholipase A2 ?NK2-receptors ?Endothelin-1
?Lipocortin ?β-adrenoceptors ?Endonucleases ?Neutral endopeptidase
Gluocorticoids
Smooth muscle β2-receptor
cytokine Macrophage number Dendritic cell Mucus secretion
Steroid-responsive target Steroidgene
J Biol Chem 1996

Allergens
Asthma?Symptoms?and?Signs
Cold air
Exercise Inflammatory cells
PAF
Aspirin
Eosinophils, Mast cells
5’-Lipoxygenase
5-LO inhibitors
Cys-LT2 Receptors
Cysteinyl-Leukotrienes LTC4, LTD4, LTE4
?
Steroid Responsive
Steroid insensitive Plasma exudation 1. 2. 3. 4. Residual inflammation Specific triggers Leukotriene mediated Mechanical factors Smooth muscle proliferation Cys-LT1 Receptors
LT- antagonists
Bronchoconstriction
Mucus secretion
Eosinophil recruitment
Cellular origin and effects of Cysteiny-leukotrienes
Leukotrienes?in?Asthma
? Exercise?induced?asthma ? Aspirin?sensitive?asthma ? Sinusitis?complicated?asthma ? Pre‐menstruation?asthma
? ? ? ?
Residual?Airway?Inflammation
Cells:
Neutrophil Cytotoxic?T?cells?(CD8,?Tc2?cells) Th1?cells Structural?cells
Pro‐Inflammatory?mediators:
? ? ? ? Leukotrienes Neuropeptides Growth?factors ROS?
Triggers (refractory?to?corticosteroids)
? ? ? ? ? ? Virus?infection Exercise?induced?bronchoconstriction Emotional?stress Physical?stimulation Premenstruation?stress?(progesterone,?LT) Drugs?(Aspirin,?NSAIDs)
Lipophilicity
Fromoterol
Salmeterol
Trapped in bilayer Depot in cell membrane of SMC
Gs cAMP

Fluticasone?and?Salmeterol
virus? exercise smoke
Synergistic?interaction?between?budesonide?and formoterol
Fluticasone
Sensory nerves
Salmeterol
Sameterol
Plasma exudation Mast cells bronchoconstriction
Macrophages Eosinophils
?2-adrenoceptor Glucocorticoid receptor
Ag
Virus? Fluticasone
Airway hyperresponsiveness
T-lymphocytes
Anti-inflammatory effect
Bronchodilatation
Modified from P J Barnes
Effect?of?formoterol?on?glucocorticoid receptors
Fluticaseone Salmeterol ?2 adrenoceptor
哮喘的控制
Death Severe exacerbation
↑ cyclic AMP +
Glucocorticoid receptor
Moderate exacerbations
protein
↑ PKA MAPK
Days with poor control Puffs?of?rescue No of nights awakenings
mRNA
Nucleus
Impairment – Quality of life Remodeling & progression
– Decline in Lung Function – Increase in BHR – Airway inflammation
GRE
Modified from P J Barnes
Steroid-responsive gene
Combination?therapy
Control?of?Asthma
Rescue?bronchodilators Level of control
Total Well
Many?patients?without Treatment exacerbations?still?have poor?asthma?control
Poor
Severe
moderate
mild persistent
mild intermittent
Exacerbation
Therefore,?the?main?focus?should?be on?control?of?other?outcomes ie?GINA?2006 Time (months)
Systemic?steroids Inhaled?steroids

REDUCE
LEVEL OF CONTROL
controlled partly?controlled uncontrolled exacerbation
TREATMENT OF ACTION
Reduce
GINA 2006: Treatment steps
Step 2 Step 3 Step 4
Increase
maintain?and?find?lowest?controlling step consider?stepping?up?to gain?control INCREASE step?up?until?controlled treat?as?exacerbation
Step 1
As-needed rapidacting β2-agonist
Step 5
Asthma education
Environmental control
As-needed rapid-acting β-agonist Select one Low-dose ICS Leukotriene modifier Select one Low-dose ICS plus LABA Medium- or high-dose ICS Low-dose ICS plus leukotriene modifier Low-dose ICS plus sustained release theophylline Add one or more Medium- or highdose ICS plus LABA Leukotriene modifier Sustained release theophylline Add one or both High-dose ICS plus LABA Oral glucocorticosteroid (lowest dose) Anti-IgE treatment
Change?the?level?of?treatment,?at?least?for 3‐ month adequate?treatment
REDUCE STEP STEP INCREASE
Controller options
TREATMENT?STEPS
STEP
STEP
STEP
1
2
3
4
5
ICS: inhaled glucocorticosteroid LABA: long-acting β2-agonist
Regular dosing with short- and long-acting β2-agonist is not advised unless accompanied by regular use of inhaled glucocorticosterid
慢性氣喘患者長期使用吸入型類固醇一停藥 慢性氣喘患者長期使用吸入型類固醇一停藥 ---呼吸道敏感度明顯增加-----呼吸道敏感度明顯增加--4 Change in PC20 histamine doubling dilutions Theophylline Budesonide 800 μg bd 3 Budesonide 200 μg bd
停用吸入型類固醇，一個月後呼吸道敏感性增加 停用吸入型類固醇，一個月後呼吸道敏感性增加
p<0.001 12 vs 3 months 1 p=0.30 Log10 PD20 (mg) 0 p<0.001 p<0.01
2
1
-1
0
-2 Fluticasone 750 μg bd 3 6 Time (months) 9 12
0
1
2
3
4
5
7
9
10
11
12
0
Placebo
Time (months)
After?9‐month?treatment,?inhaled?steroids?were?withdrawal.
Dahl?et?al.?Respir?Med?2002
Ward?et?al.?Thorax?2002;?57:309.
GOAL:?GINA?Control?in?80%
AIRE:?only?5%?achieving guideline‐defined?control Aiming?for?Total?Control
Patients?(%)
80
Well?controlled?asthma achieved?with?sustained?treatment
FP?Phase?II 78%* 70% 60 60% 47% FP?Phase I 75%** Seretide?Phase?II Seretide?Phase I
62%**
~40% 5% Total?Control
40
20
~40%?Well?Controlled ~20%?Improved?control
Bateman?et?al?AJRCCM?2004,?Rabe?et?al?Eur?Respir?J?2000
0 Steroid-naive (S1)
* P =?0.003 ** P Phase I, dose escalation phase, treatment was "stepped up" every 12 weeks until totally controlled asthma was achieved or GOAL?Study the highest dose of study drug was achieved Phase II, after achieving totally controlled asthma or after 12 weeks on the maximum dose of study medication, maintaining 1 year
Low‐dose?ICS?(S2)
Moderate‐dose?ICS?(S3)

Aiming?for?TOTAL?CONTROL reduces?exacerbations?
Mean?exacerbation?rate per?patient?per?year 0.7 0.6 0.5 0.4 0.3 0.2 0.12 0.1 0 * 0.07 0.17 * 0.12 0.37 * 0.27 Baseline Baseline FP Seretide
Stability?of?asthma?control?with?regular treatment
Totally controlled Well controlled
81.2 53.7 32.2
13.1
5.7 14.1
Steroid-na?ve (S1)
Totally controlled Well controlled
81.0 49.2 36.9
13.1
5.9 13.9
Low‐dose?ICS (S2)
Steroid‐naive?(S1)
Low‐dose?ICS?(S2)
Moderate‐dose?ICS?(S3)
Totally controlled Well controlled
82.1 53.6 32.8
10.6
7.3 13.4
*P < 0.01
? Requiring?oral?steroids?and/or?antibiotics,?or?hospitalisations documented?in?12?months?before?study?entry;?Requiring?either?oral?steroids?or hospitalisation/emergency?visit GOAL?Study
Moderate‐ dose?ICS (S3)
Bateman, et al. Allergy 2008; 63:923
Airway?remodeling?as?reflected?by?FEV1
Change?in?post‐bronchodilator?FEV1
FEV1 100%
Interplay?severity,?management?and?level?of control?in?asthma?
氣 喘 治 療 優良 輕微 不好
Reduction?in?decline %?reduction?of?decline seemed?dose?dependent Normal
50 40
完全控制
96%
Placebo
Long‐term?treatment?required 30 to?reduce?decline
20 10 0
嚴 重 度
200?μg?BUD/day 400?μg?BUD/day
嚴重
不良控制
1
2 Time?(Years)
3
200 μg
400 μg
Pauwels?et?al.?Lancet.?2003
好的氣喘照護
? 自我監控症狀
– 尖峰流速 – Asthma?control?test
Mobile?phone?for Asthma?Care
早晚至少 各一次記錄
AM 07:30
AM 10:10
? 遵從氣喘治療計畫
PM 14:10 PM 19:10
? 定期回診與追蹤

Anti‐IgE?therapy?improve?variation?of?PEF and?clinical?symptoms
Start omalizumab
關閉程式並上傳 資料 (自動發出簡訊)
18.5%
Baseline Characteristics of subjects
Study Design
Patients?with?Moderate?to?Severe?asthma N=90 Randomization
Control?group: n=?45 Action?plan Specialist?
Asthma Education, Self-management plan, Standard Treatment
Study?group N=?45 Mobile‐assisted Suggestion
Records?of?clinical?information:
Follow-up for 6 months
Monthly Peak?expiratory?flow?rate Quality?of?life:?Short?form‐12?questionnaire Medications:?Inhaled/systemic?corticosteroids,?anti‐leukotriene,?beta‐agonist Every?3?months Pulmonary?function?test?including?FVC,?FEV1?and?FEV1/FVC?
Exacerbation:?Times?of?unscheduled?visit?and?hospitalization
Mobile phone-assisted monitoring system improving phonepulmonary function: FEV1 and PEFR
PEFR
425
Mobile phone-assisted monitoring system improving phoneQuality of Life
SF-12 PCS
55 60
FEV1, % predicted
75
SF-12 MCS
Control Mobile phone
SF-12 PCS
PEFR (L/min)
400
#
375
#
* **
#
#
45 40 35 1st 2nd 3rd 4th
##
##
SF-12 MCS
##
FEV1, % Predicted
70 65
#
Control Mobile phone
50
##
55
350
*
**
*
*
*
60 55 50
**
* ** * **
5th 6th
*
50 45 40
**
325 Baseline 1M 2M 3M 4M 5M 6M
Month
1st
2nd
3rd
4th
5th
6th
Month
Baseline
3M
6M
Control vs. Mobile phone:
#
Control vs. Mobile phone:
#
Control vs. Mobile phone:
#
p<0.05
##
Control vs. Mobile phone:
p<0.01
p<0.05
##
p<0.001
p<0.05
*p<0.001 **p<0.05
6th vs. 1st
Comparing with the baseline
Comparing with the baseline
*p<0.001 ** p=0.002
*p<0.01 **p<0.001
*p<0.01 **p<0.001

Patients using mobile phone-assisted monitoring system phoneIncreased dosage of Corticosteroids for asthma control
Clinical Outcomes for 6 months
Mobile?phone
(N=?45)
Control
(N?=?45)
Systemic Corticosteroids Dosage
750
Inhaled Corticosteroids Dosage
Unscheduled?visits?(ER) Number?of?patients?(%) 2?(4.4%) 2 0.044 9 (20%)* 12 0.267
Prednisolone (mg/day)
Fluticasone ( μg/day)
3
2
*
700 650
*
*
1
*
600 550
*
** **
Control Mobile phone
Number?of?visits Number?of?visit?per?patient Hospitalization, Number?of?patients?(%)
**
0 1st 2nd 3rd 4th 5th 6th
0 0 0 0 0
1 (2.2%) 1 0.022 0 0
Month
1st
2nd
3rd
4th
5th
6th
Month
Number?of?hospitalization Number?of?hospitalization?per?patient Number?of?respiratory?failure Number?of?mortality
Comparing with the 1st month
Comparing with the 1st month
*p<0.05
*p<0.05 **p<0.01
Prednisolone: 1.11
2.22 mg/day
Fluticasone: 594
678 mcg/day
*p<0.05 compared with corresponding mobile phone group
Residual?inflammation Exercise‐induced?asthma Rhinosinusitis Environmental?factors
Cause pred
Cause?of?Not‐Well?Controlled?Asthma after?proper?treatment
Number?(%) 12 (14.9%) 10 (12.3%) 32 (39.5%) 10 (12.3%) 9 (11.19%) 10 (12.3%) 4 (4.9%) 1 (1.2%) 1 (1.2%)
Irregular?use Aggravated?inflammation Nasal?blockade/post‐nasal?drip Sinusitis
Long-acting β2-agonist
Inhaled steroids Gastroesophageal?reflux Fixed?airway?disease
mild intermittent mild persistent moderate severe
Environment/weather Menstruation Bronchiectasis
Thinking of asthma treatment
Treatment for 3 months according to asthma severity
Good?response?to Inhaled?Steroid?or combination?therapy?
Improved
Totally Controlled
Thinking of asthma treatment
Treatment for 3 months according to asthma severity
Partial?response?to Inhaled?Steroid or combination?therapy
Partly Controlled or Uncontrolled
No?response?or little?effect of combination?therapy
Uncontrolled
Good?response?to Inhaled?Steroid?or combination?therapy?
Improved
Totally Controlled
Maintain?and find?lowest controlling?step
Residual Inflammatory?cells
No effect
Structural?change Upper?airway?problems Gastroesophageal?reflux Specific?condition Environmental?factors
Subepithelial fibrosis Hypersecretion Mast?cells?related
Maintain?and find?lowest controlling?step
Increased?dose?of?inhaled Steroids?or?Combination?therapy Or?Add‐on?therapy
Improved
Treat underling Add-on therapy
Improved
Maintain?and find?lowest controlling?step
High?dose?of combination?therapy?or Add‐on?therapy Physical?therapy Pulmonary?rehabilitation New?therapy?of?asthma
Montelukast (5 or 10 mg each night); Fluticasone 100 μg?twice?per?day Fluticasone?100?μg?+?Salmeterol 50μg NEJM,?2007;?356:2027‐2039?

Thinking of asthma treatment
Treatment for 3 months according to asthma severity
Partial?response?to Inhaled?Steroid or combination?therapy
Partly Controlled or Uncontrolled
Evaluate?the?uncontrolled?airway?inflammation
肺功能檢查
Good?response?to bronchodilators?
Residual Inflammatory?cells
No effect
Structural?change Upper?airway?problems Gastroesophageal?reflux Specific?condition Environmental?factors
早晚尖峰流速
PEFR variation?>?20‐30%
Increased?dose?of?inhaled Steroids?or?Combination?therapy Or?Add‐on?therapy
Improved
Treat underling Add-on therapy
Improved
吐氣一氧化氮檢查
Maintain?and find?lowest controlling?step
Normal
Asthma
Proposed?systemic?inflammatory?mechanisms?linking the?upper?and?lower?airways
Rhinitis?and?sinusitis?affecting?lower?airways
Relationships?between?allergic?rhinitis?and asthma
Related?to?PEFR?and?daily?asthma?symptom?
Sinusitis,?only?postnasal?drip GORD
Variation?Variation?>?20%
Antihistamine
Proton?pump?inhibitor

Record of PEFR
Treatment
300
Similar Immunological Responses between Allergic Rhinitis and Asthma
Allergen
IgE Allergic rhinitis Asthma bronchospasm mucus secretion airway edema
Histamine
Surgery
Mast cells
New synthesis Leukotrienes
, PGs, PAF
sneezing rhinorrhea nasal stuff
PEFR (L/min)
200
Eosinophils
100
Cytokines
Early morning cough, aggravated by URI Summer Winter Spring
Chronic allergic responses edema Inflammatory cells hyperresponsiveness
Lymphocytes
0
CysLTs=cysteinyl leukotrienes; PGs=prostaglandins; PAF=platelet activating factor Based on and modified from Casale TB, Amin BV Clin Rev Allergy Immunol 2001;21(1):27-49; Kay AB N Engl J Med 2001;344:30-37.
Treatment with Corticosteroids
Allergic rhinitis Asthma bronchospasm mucus secretion airway edema
Anti-leukotriene concomitantly improves AntiAllergic rhinitis & Asthma
Allergic rhinitis
0 Change –0.1 from baseline –0.2 score (LS –0.3 mean) –0.4 –0.5 15 Morning FEV1 10 mean % change from 5 baseline 0
Montelukast 10 mg once daily at bedtime (n=348) Montelukast 10 mg once daily (n=408) Placebo (n=273)
Allergen
IgE
Asthma
Histamine Mast cells
New synthesis Leukotrienes
, PGs, PAF
sneezing rhinorrhea nasal stuff
Placebo (n=352)
Eosinophils Cytokines Chronic allergic responses edema Inflammatory cells hyperresponsiveness
0
3
6 9 Weeks
12
15
*p<0.001 montelukast vs. placebo
Adapted from Reiss TF et al Arch Intern Med 1998;158:1213-1220 Multicenter, randomized, 12-week double-blind trial of montelukast vs. placebo in patients 15 years and older with asthma
*p<0.001 montelukast vs. placebo
Adapted from Malmstrom K et al. Poster presentation at the 57th AAAAI Annual Meeting, March 16–21, 2001. Multicenter, 12-week double-blind, randomized trial in patients 15 to 81 years with seasonal allergic rhinitis.
Lymphocytes
CysLTs=cysteinyl leukotrienes; PGs=prostaglandins; PAF=platelet activating factor Based on and modified from Casale TB, Amin BV Clin Rev Allergy Immunol 2001;21(1):27-49; Kay AB N Engl J Med 2001;344:30-37.
Other?factors?of?upper?airway?disease
? Dryness of mucosa
? Nasal blockade ? Upper airway resistance syndrome ? Malocclusion ? Sleep apnea syndrome
治療慢性鼻炎
? Atrophy of mucosa ? Hypertrophy of mucosa
較嚴重時在睡覺時 使用經鼻陽壓輔助器 (CPAP)
戴上牙套、舌套輔助器

Thinking of asthma treatment
Myofibroblast Treatment for 3 months according to asthma severity
Good?response?to Inhaled?Steroid?or combination?therapy?
Improved
Totally Controlled
CD34‐,?Collagen?I++, α‐SMA++
Partial?response?to Inhaled?Steroid or combination?therapy
Partly Controlled or Uncontrolled
No?response?or little?effect of combination?therapy
Uncontrolled
Lesional?Fibroblast
CD34‐low,?Collagen?I+, α‐SMA+
Resident Fibroblast
Maintain?and find?lowest controlling?step
Residual Inflammatory?cells
No effect
Structural?change Upper?airway?problems Gastroesophageal?reflux Specific?condition Environmental?factors
Subepithelial fibrosis Hypersecretion Mast?cells?related
Fibrocyte
CD14+/‐ ,CD16‐ CD34+,?collagen?I+
Increased?dose?of?inhaled Steroids?or?Combination?therapy Or?Add‐on?therapy
Improved
Treat underling Add-on therapy
Improved
Maintain?and find?lowest controlling?step
High?dose?of combination?therapy?or Add‐on?therapy Physical?therapy Pulmonary?rehabilitation New?therapy?of?asthma
Fibrocyte precursor
CD14+,?CD16‐ CD34+
Increased?circulating?fibrocyte?in?chronic?obstructive?asthma
p<0.0001 p<0.0001
Percentage of fibrocyte in NANT cells, %
50
p<0.0001 p<0.0001
Chemokine gradient for fibrocyte recruitment
Immunoconfocal?images?of?bronchial?biopsy?from?healthy subjects?and?chronic?obstructive?asthmatics
40
30
20
10
0 Normal Subjects Asthma Normal PFT Chronic Asthma with AE Obstuctive asthma
Red signals represented collagen-I, green signals represented CD45 and blue signals represented cell nuclei. Panels B-D and F-H are enlarged views of the box areas indicated in panel A and E respectively. Panels B and F showed CD45 and nuclei signals only, and panels C and G showed collagen I signal only. Bar = 14 μm.
Wang et al; AJRCCM 2008 ;178:583-91. Collagen I, III, V; Fibronectin; Proteoglycan; Tenascin; Elastin
The?role?of?the?fibrocyte,?a?bone?marrow‐derived?mesenchymal?progenitor,?in reactive?and?reparative?fibroses
Anti‐IgE?therapy?improve?variation?of?PEF and?clinical?symptoms
Start omalizumab
Circulating fibrocyte 30%
18.5%
23.4%

Decrease?the?proliferation?of?fibrocytes?after anti‐IgE?therapy
Change?of?pulmonary?function?after cessation?of?Omalizumab
N=8, *p<0.05
Mechanism?of?Anti‐IgE?therapy in?IgE‐mediated?asthma
B lymphocyte Reduces Allergic mediator release inflammation:
Thinking of asthma treatment
Treatment for 3 months according to asthma severity
Good?response?to Inhaled?Steroid?or combination?therapy?
Improved
Totally Controlled
ε-switch
Plasma cell Release of IgE
Allergic mediators
eosinophils and lymphocytes
Partial?response?to Inhaled?Steroid or combination?therapy
Partly Controlled or Uncontrolled
No?response?or little?effect of combination?therapy
Uncontrolled
Anti‐IgE (Omalizumab)
Perennial aeroallergens
Asthma exacerbation
Binds to free IgE, reducing cell-bound IgE
Reduces high-affinity receptors Mast cells Basophils
Maintain?and find?lowest controlling?step
Residual Inflammatory?cells
No effect
Structural?change Upper?airway?problems Gastroesophageal?reflux Specific?condition Environmental?factors
Subepithelial fibrosis Hypersecretion Mast?cells?related
Reduces asthma exacerbations and symptoms
Increased?dose?of?inhaled Steroids?or?Combination?therapy Or?Add‐on?therapy
Improved
Treat underling Add-on therapy
Improved
Maintain?and find?lowest controlling?step
High?dose?of combination?therapy?or Add‐on?therapy Physical?therapy Pulmonary?rehabilitation New?therapy?of?asthma
Molecular and cellular control
Anti‐IgE monoclonal antibodies
Long‐acting?β2 agonist
Inhaled steroids
Clin?Chest?Med?2006;27:?133