View
5
Download
0
Category
Preview:
Citation preview
Theerasuk Kawamatawong MD, FCCP
Assistant Professor of Medicine
Division of Pulmonary and Critical Care Medicine
Department of Medicine
Ramathibodi Hospital Mahidol University
Lecture Asthma Foundation of Thailand Saturday July 19th, 2018 Miracle Grand Hotel 09.00-09.45
What is New in AsthmaLecture Asthma and COPD for HCW 2018
Conflict of Interests Disclosures
Theerasuk Kawamatwong MD, FCCP
Department of Medicine Ramathibodi Hospital
Mahidol University Bangkok Thailand
Position: Assistant Professor of Medicine Consultant Chest Physician
Medical Advisory Board: Pfizer, Boehringer Ingelheim, Novartis, Astra Zeneca , MSD and Oxford Immunotech
Speaker Bureau: Glaxo Smith Kline, Astra Zeneca, MSD, Novartis, Pfizer, Takeda, OtsukaTravel grant : Astra Zeneca and Novartis Research funding : Novartis and Otsuka
There is no discussion in off labelled use of medications in my talk
Outline of presentation
• Asthma diagnosis (lung function)
• Asthma assessment (ACT, ACQ)
• Asthma biomarker (FeNo)
• GINA treatment steps
• Treatment for mild asthma (ICS vs ICS/FABA)
• Management of severe asthma
(drugs and non drug treatments: SLIT and BT)
• Biologics and FDA approval
Diagnosis of asthma symptoms
Features are increase the possibility that patient has asthma
More than one symptom (wheeze, shortness of breath, cough , chest tightness)
Symptoms worse at night or in the early morning
Symptoms vary over time and in intensity
Symptoms are triggered by viral infection (cold), exercise, allergen exposure,change in weather, irritant such as care exhaust fume, smoke, strong smell
Global Strategies for Asthma Management and Prevention GINA report 2018
Features decrease the possibility that the patient has asthma
Isolated cough without other respiratory symptoms
Chronic production of sputum
Shortness of breath associated with dizziness, light-headedness, peripheral tingling
Chest pain
Exercise induced dyspnea with noisy inspiration
Diagnosis of asthma Variable airflow limitation
• Confirm presence of airflow limitationDocument that FEV1/FVC is reduced (at least once when FEV1 is low)
(Normal FEV1/ FVC >0.75- 0.80 in healthy adults)
• Confirm variation in lung function is greater than in healthy individualsThe greater the variation, or the more times variation is seen, the greater probability that diagnosis is asthma
• Excessive bronchodilator reversibility (adults: ↑ in FEV1 >12% and >200 mL
• Excessive diurnal variability from 1-2 weeks’ twice-daily PEF monitoring (daily amplitude x 100/daily mean, averaged)
• Significant increase in FEV1 (12%) or PEF (20%) after 4 wks of controller
Summary: role of lung function in asthma
Diagnosis• Demonstrate variable expiratory airflow limitation• Reconsider diagnosis if symptoms and lung function are discordant
Frequent symptoms but normal FEV1: cardiac disease; lack of fitness? Few symptoms but low FEV1: poor perception; restriction of lifestyle?
Risk assessment• Low FEV1 is an independent predictor of exacerbation risk
Adjusting treatment?Utility for adjusting treatment is limited by between-visit variability of FEV1
Measure lung function to monitor progress• At diagnosis and 3-6 m after starting treatment (to identify personal best)
• Periodically (every 1-2 y for most adults (High risk patients)
• Consider long-term PEF monitor for severe asthma/impaired perception
Global Strategies for Asthma Management and Prevention GINA report 2018
Method of measuring asthma controlEfficacy of asthma clinical trials interventions
• Diary data Diary questionsAmbulatory lung function Peak flow variability
• Lung function and AHRSpirometryPeak expiratory flow Lung volume and airway resistance Airway hyper-responsiveness
• Composite score Categorical measure ;WC,PC,UC
(Asthma free days, well control weeks) Continuous measure (numeric)
(ACT, ATAQ, ACSS, ACQ)
• Biomarkers of T2 phenotypeInduces sputum FENO and EBC Serum ECP
• Health related QOL Generic HRQOL questionnaire (SF-36)Specific asthma related questionnaire (AQLQ, mini-AQLQ, LWAQ, AQ-20)
• Worsening of asthma or exacerbation
Primary care consultation Un-scheduled of secondary healthcare utilization ER visit or hospitalization Systemic corticosteroid usage
Helen K Raddel ATS/ERS task force et al. AJRCCM 2009
Cu
rren
t co
ntr
ol
Futu
re r
isk
Question topics ACT(4 weeks)
ACQ (1 week)
Limits daily activities
Shortness of breath
Disrupts sleep
SABA use
Effect of global control
Frequency of wheeze
Pre-bronchodilator FEV1
Asthma composite scores (ACT and ACQ)
Asthma Control Test (ACT) Asthma Control Questionnaire (ACQ)-7 (With FEV1)
Short form ACQ-5 or ACQ-6 (Without FEV1)
ACQ (Juniper et al., 1999)
ACT (Nathan et al., 2004) Schatz M. J Allergy Clin Immunol 2006
r = - 0.89(p<0.001)
ACQ score at baseline
ACTscore at baseline
5
10
15
20
25
0 1 2 3 4 5 6
Good control
Poor controlGood control
Poor control
0.75 1.5
ACT ≥ 20
Correlation between ACT and Asthma Control Questionnaire (ACQ-6)
Numeric data
MCID (Minimal Clinical Important Difference)
• Symptom score (Patient perceived improvement ) = -0.31 point(0-6 points baseline 3)
• Reliever use (Patient perceived improvement ) = -0.83 puffs/day (5.4 puffs/day baseline)
• PEF (Patient perceived improvement )= 18.8 L/min • ACQ score change =0.5
(0-6 point baseline 1.5)
• Clinically relevant MCID of morning PEF = 15-20 L/min
Helen K Raddel ATS/ERS task force et al. AJRCCM 2009
Risk factor of poor outcome (Future risk)
Risk factors of exacerbation
• Uncontrolled symptoms
• High SABA use (≥3 canisters/yr)
• ≥1 exacerbation in last 12 mo
• Low FEV1; high BD reversibility
• Incorrect inhaler technique and/or poor adherence
• Smoking
• Obesity, chronic rhinosinusitis,
• pregnancy
• Blood eosinophilia
• Elevated FeNO in adults with allergic asthma taking ICS
• Ever intubated for asthma
Risk factors for developing fixed AO
•No ICS treatment
•Smoking
•Occupational exposure
•Mucus hypersecretion
•Blood eosinophilia
•Pre-term birth, low BW
Risk factors of medication side effect
•Frequent oral steroids
•High dose/potent ICS
•P450 inhibitors
GINA 2018
Poor asthma outcome
Having 1 or more risk factors increase risk of exacerbation •even if symptoms are well controlled
Additional risk factors, even if the patient has few symptoms
L-Arginine
Arginase
L-Ornithine Polyamine
L–proline
Agonists
Ca2+Ep
ith
eliu
m
Epith
elium
in
flamm
atory cells
L citruline
cNOS
NO
Ca2+
NA
NC
ner
ve
iNOS
Reductase Oxygenase
O2 O2- NO O2 L citruline
nNOS
L citruline
ONOO-
ASM
cGMPAgonists Ca2+
NO
Airway contraction Airway relaxation
AHR
AHR Inflammation Cytotoxicities
Th2 cytokines Airway remodeling
Pro-inflammatory cytokineNF-kB
Factors affecting FeNO level
Elevated FeNO Reduced FeNO
Airway infection Spirometric maneuver
Allergic rhinitis Exercise
Nitrate-rich diet Alcohol consumption
Bronchodilator Bronchoconstriction
Ciliary dyskinesia
Pulmonary hypertension
Smoking
ICS therapy
FeNO modestly associated with levels of blood & sputum eosinophils
Am J of Respir Crit Care Med 2011; 184(5):602-15.
Parameters FENO < 25 ppb (<20 ppb in children)
FENO 25-50 ppb(20-35 in children)
FENO > 50 ppb (>35 in children )
Diagnosis
Symptoms present during past 6 wk
Eo inflammation unlikely Alternative DXUnlikely to benefit from ICS
Be cautiousEvaluate clinical context Monitor FeNO change over time
Eosinophilic inflammation likely
Likely to benefit from ICS
Monitoring in patient with diagnosed asthma
Symptomspresent
Probable alternative DXUnlikely to benefit from ICS
Persistent allergen exposure Inadequate ICS dose Poor adherence Steroid resistance
Persistent allergen exposure Poor adherence or device technique Inadequate ICS dose Risk for exacerbation Steroid resistance
Symptomabsent
Adequate ICS dose Good adherence ICS taper
Adequate ICS doseGood adherenceMonitoring in FENO
ICS withdrawal or dose reduction may result in relapse Poor adherence or device technique
FeNO guidance diagnosis & treatmentAm J of Respir Crit Care Med 2011; 184(5):602-15.
• In steroid-naïve adult with non-specific respiratory symptom, FeNO >50ppb was associated with good short-term response to ICS
• No long-term studies examining the safety of withholding ICS if FENO is low• FeNO cannot be recommended for deciding against treatment with ICS
FeNO guidance in management of Asthma
Study design Dose ICS based on Main results
Smith et al 2005 FeNO > 15 vs.Asthma control
NS reduction exacerbation Sig reduction cumulative dose
ICS
Pijnenburg et al 2005
FeNO >30 plus symptom vs.Symptom only
AHR improve FeNO groupNS reduction exacerbation
Fritsch et al 2005 FeNO> 20 plus symptom vs. FEV1 vs.Symptom plus FEV1
NS outcomeImprove MEF in FeNO group
Shaw et al 2007 FeNO >26 ppb plus ACQ vs.ACQ
NS outcomeReduced ICS dose FeNO group
Szefler et al 2008 FeNO + AC vs. AC NS exacerbationIncreased dose in FeNO group
No significant difference in exacerbation with FENO-guided treatment compared with treatment based on current guidelinesFeNO-guided therapy is not recommended for general asthma population at present
Controller medications
Inhaled glucocorticosteroids
Leukotriene modifiers
Long-acting inhaled β2-agonists
Theophylline
Cromones
Long-acting oral β2-agonists
Anti-IgE, Anti-IL-5, Anti-IL-5R
Systemic glucocorticosteroids
Rapid-acting inhaled β2-agonist
Inhaled anticholinergics
Short-acting oral β2-agonists
Theophylline
Systemic glucocorticosteroids(for exacerbation)
Reliever medications
STEP1
Consider low dose
ICS
As needed short-acting β2 agonist (SABA)
STEP 2Low dose ICS
Leukotriene receptor antagonist Intermittent ICS
Add titropiumHigh dose ICS
+LTRA (or + Theophylline)
Add low dose OCS
Step 5 Refer to add-on
RX STEP 3 Low dose ICS-LABA
Preferred controller choice
Other controller choice
Reliever
Mod/high dose ICS Low dose ICS
+LTRA(or + Theophylline)
As needed SABA or low dose ICS/fomoterol
STEP 5
Refer to add-on treatment Tiotropium
OmalizumabMepolizumab
STEP 4
Med/ high ICS /LABA
Global Strategies for Asthma Management and Prevention GINA report 2018
Recommendation for starting ICS in asthma
Presenting symptoms Preferred initial controller
Asthma symptoms or SABA less than twice a monthNo waking up due to asthma in the last month No risk factor for exacerbation & exacerbation in last year
No controller (Evidence D)
Infrequent asthma symptoms, but 1 or more risk factor for exacerbation
Low dose ICS (Evidence D)
Asthma symptoms or SABA between 2/m and 2 /w, or patients wake due to asthma 1 or more /mo
Low dose ICS (Evidence B)
Asthma symptoms or need for SABA more than 2/week Low dose ICS (Evidence A)
Troublesome asthma symptoms most day: or waking due to asthma 1/wk or more, especially if any risk factor exist
Medium ICS (Evidence A) or Low ICS/LABA (Evidence A)
Initial presentation is with severely uncontrolled asthma or with an acute exacerbation
Short course oral CS High dose ICS (Evidence A) or Mod ICS/LABA (Evidence D)
Global Strategies for Asthma Management and Prevention GINA report 2018
STEP1
Consider low dose
ICS
STEP 2Low dose ICS
Leukotriene receptor antagonist Intermittent ICS
Add tiotropium High dose ICS
+LTRA (or + Theophylline)
Add low dose OCS
Step 5 Refer to add-on
RX STEP 3 Low dose ICS-LABA
Preferred controller choice
Other controller choice
Reliever
Mod/high dose ICS Low dose ICS
+LTRA(or + Theophylline)
As needed SABA or low dose ICS/fomoterol
STEP 5
Refer to add-on treatment Tiotropium
OmalizumabMepolizumab
STEP 4
Med/ high ICS /LABA
Global Strategies for Asthma Management and Prevention GINA report 2018
Step 1
As-needed inhaled short-acting beta2-agonist (SABA) (very few patients)
Consider adding regular low dose ICS to reduce the risk of serious exacerbations
As needed short-acting β2 agonist (SABA)
Equivalent dose of inhaled corticosteroidAdult and adolescents (12 y and older)
Estimated equivalent daily dose inhaled corticosteroid (g)
Drug Low Medium High
Beclomethasone dipropionate (CFC) 200-500 >500-1000 >1000
Beclomethasone dipropionate (HFA) 100-200 >200-400 >400
Budesonide (DPI) 200-400 >400-800 >800
Ciclesonide (HFA) 80-160 160-320 >320
Fluticasone propionate (DPI) 100-250 250-500 >500
Fluticasone propionate (HFA) 100-250 250-500 >500
Mometasone fuorate 110-220 220-440 >440
Triamcinolone 400-1000 >1000-2000 >2000
STEP1
Consider low dose
ICS
STEP 2Low dose ICS
Leukotriene receptor antagonist Intermittent ICS
Add tiotropium High dose ICS
+LTRA (or + Theophylline)
Add low dose OCS
Step 5 Refer to add-on
RX STEP 3 Low dose ICS-LABA
Preferred controller choice
Other controller choice
Reliever
Mod/high dose ICS Low dose ICS
+LTRA(or + Theophylline)
As needed SABA or low dose ICS/fomoterol
STEP 5
Refer to add-on treatment Tiotropium
OmalizumabMepolizumab
STEP 4
Med/ high ICS /LABA
Global Strategies for Asthma Management and Prevention GINA report 2018
Step 2
Preferred option: regular low dose ICS with as-needed SABAOther options
Leukotriene receptor antagonists (LTRA) with as-needed SABAIntermittent ICS with as-needed SABA for purely seasonal
allergic asthma with no interval symptoms
As needed short-acting β2 agonist (SABA)
Stepwise approach for asthma treatmentBefore adjusting treatments by adding LABA or increasing ICS/LABA
Check …..
• Incorrect diagnosis
• Incorrect inhaler technique
• Poor adherence
• Persistent exposure at home/work to agents such as allergen, tobacco smoke, indoor or outdoor air pollution, or to medications (β-blocker or NSAIDs)
Global Strategies for Asthma Management and Prevention GINA report
Co-morbidities
Global airway disease conceptFrom noses and mouth to lungs
Peter W. Hellings et al Curr Allergy Asthma Rep (2010) 10:143–149
Oral candidiasis :local side effect
Malampatti score (OSAHS) :co-morbidities
Allergic Rhinitis : co-morbidities
Vasomotor rhinitis: co-morbidities
Allergic rhino-conjunctivitis Allergic shiners co-morbidities
รปนไดรบอนญาตจากผปวยในการถายเพอใชในการเรยนการสอนและการบรรยายทางวชาการ
Pulmonary drug deposition Highly variable from inhaler devices to devices
Rau JL Jr. Respiratory care pharmacology. 2002
10% As
benchmark
Exhaled
Device
Oropharynx
Lungs
100
90
80
70
60
50
40
30
20
10
0
Lun
g d
epo
siti
on
(%
do
se)
pMDI pMDISpacer
pMDIVHC
Electrostatic
pMDIVHC
Nonelectrostatic
SVNNB
DPI
Inhaler devices in asthma and COPD
Dry powder inhaler (Lactose carrier) Aerosol generator (w or w/o propellant)
Multiple dose DPI-blister
Single dose DPI capsule
Reservoirmulti-dose DPI
Metered dose inhaler
Breath actuate MDI
Soft mist inhaler
Acc
uh
aler
Bre
ezh
aler
Ellip
ta
Turb
uh
aler
Easy
hal
er
Han
dih
aler
Pre
ssu
rize
dM
DI
Res
pim
at
Au
toh
aler
Pre
ssai
r(G
enu
air)
NEX
Thal
er
Twis
thal
er
Optichamber
ACE spacer
Aerochamber
Inhale FAST and DEEP Inhale SLOW and STEADY
Propellant(HFA)
High speed aerosol MDI
Propellant free
Low speed aerosol SMI
Lactose Drug Sp
inh
aler
Physical and mental impairment Pressurized MDI Pressurized MDI with chamber
Dry Powderinhaler (DPI)
Decreased peakinspiratory flow rate
Impaired cognition
Impaired manual dexteritory
Impaired press and breath coordination
? ?? ??
P Gibson. Asthma in Elderly Lancet Respiratory 2009
4C for correct inhaler technique in asthma
Choose• Choose an appropriate device before prescribing. Consider medication options,
arthritis, patient skills and cost. For ICS by pMDI, prescribe a spacer
• Avoid multiple different inhaler types if possible
Check• Check technique at every opportunity – “Can you show me how you use your
inhaler at present?”
• Identify errors with a device-specific checklist
Correct• Give a physical demonstration to show how to use the inhaler correctly
• Check again (up to 2-3 times)
• Re-check inhaler technique frequently, as errors often recur within 4-6 weeks
Confirm• Can you demonstrate correct technique for the inhalers you prescribe?
• Brief inhaler technique training improves asthma control
Global Strategies for Asthma Management and Prevention GINA report 2017
Role of healthcare professional (nurses and pharmacists)in improving patient inhaler skill and technique
STEP1
Consider low dose
ICS
STEP 2Low dose ICS
Leukotriene receptor antagonist Intermittent ICS
Add tiotropium High dose ICS
+LTRA (or + Theophylline)
Add low dose OCS
Step 5 Refer to add-on
RX STEP 3 Low dose ICS-LABA
Preferred controller choice
Other controller choice
Reliever
Mod/high dose ICS Low dose ICS
+LTRA(or + Theophylline)
As needed SABA or low dose ICS/fomoterol
STEP 5
Refer to add-on treatment Tiotropium
OmalizumabMepolizumab
STEP 4
Med/ high ICS /LABA
Global Strategies for Asthma Management and Prevention GINA report 2018
Step 3
Adults/adolescents: preferred options are either Combination low dose ICS/LABA maintenance with as-needed SABA OR
Combination low dose ICS/formoterol maintenance and reliever regimen*
As needed short-acting β2 agonist (SABA)
Approved only for beclometasone/formoterol and budesonide/formoterol
HN
OH
OH
Olodaterol
OH
NH O
OH
O
NH
Procaterol
OH
NH
OH
OH
OH
NH
HN
OH
OH
Indacaterol
OH
NH
HN
OH
OH
NHCHO
OMe
Formoterol
Catechol nucleus
Side chain (B2 selectivity)
Salbutamol OH
OH
OH
NH
Terbutaline
Β2 sympathomimetics basic structure
Pharmacology of β2 agonists(onset and duration)
Properties Salbutamol Formoterol Salmeterol Indacaterol
Selectivity for b2-adrenoceptors Moderate High High High
Affinity for b2-adrenoceptors (pKi) Low
(6.12 ± 0.09)
High
(7.84 ± 0.05)
High
(9.19 ± 0.12)
High
(7.36 ± 0.06)
Onset of bronchodilator action (min) Quick
(11.0 ± 4.0)
Quick
(5.8 ± 0.7)
Slow
(19.4 ± 4.3)
Quick
(7.8 ± 0.7)
Duration of bronchodilator action (hours) Short
(3–6)
Long
(12 )
Long
(12)
Longer
(24)
Efficacy (agonist) Partial Complete Partial Complete
Potency (EC50) High
(8.43 ± 0.22)
High
(9.84 ± 0.22)
High
(8.36 ± 0.16)
High
(8.82 ± 0.41)
Intrinsic efficacy
(Emax % of isoprenaline)
High
(47 ± 1)
High
(90 ± 1)
Low
(38 ± 1)
High
(73 ± 1)
Classes of β2 agonistsOnset of acting* (fast or slow) and #duration (short or long acting)
Inhaled Terbutaline
Inhaled Salbutamol
Fast onset long duration
Inhaled formoterol
Inhaled indacaterol
Oral Terbutaline
Oral Salbutamol
Oral Formoterol
Slow onset long duration
Inhaled Salmeterol
Oral Bambuterol
Fast
Slow
Short Long
Speed of action
Duration of action
Rescued medications for symptoms(Reliever)
Mai
nte
nan
ce fo
r p
reve
nti
on
(co
ntr
olle
rs)
GINA 2017Step 3-4: Fixed ICS/LABA combination
Controller option Reliever Maintenance and reliever therapy
GINA 2017Step 3-4: MART approach
Maintenance and Reliever Therapy
Optimised daily
maintenance dose
Symptom relief &
increase
anti-inflammatory
Optimised daily
maintenance doseSymptom relief
Conventional approach
ICS+LABA fixed combination
SABAICS+formoterol MART
Controller A.M. Controller P.M. Rescuer PRN Controller A.M. Controller P.M. Rescuer PRN
STEP1
Consider low dose
ICS
STEP 2Low dose ICS
Leukotriene receptor antagonist Intermittent ICS
Add tiotropium High dose ICS
+LTRA (or + Theophylline)
Add low dose OCS
Step 5 Refer to add-on
RX STEP 3 Low dose ICS-LABA
Preferred controller choice
Other controller choice
Reliever
Mod/high dose ICS Low dose ICS
+LTRA(or + Theophylline)
As needed SABA or low dose ICS/fomoterol
STEP 5
Refer to add-on treatment Tiotropium
OmalizumabMepolizumab
STEP 4
Med/ high ICS /LABA
Global Strategies for Asthma Management and Prevention GINA report 2018
Step 3
Adults/adolescents: Increase ICS dose or add LTRA or theophylline (less effective than ICS/LABA)
Adults: consider adding SLIT (see Non-pharmacological interventions)
As needed short-acting β2 agonist (SABA)
Medication changes for WAAP
ICS/FORM : BUD/FORM or BDP/FORMMaintenance ICS/FOR 4 x Maintenance ICS/FORM (<72 µg FORM/d)Maintenance & reliever ICS/FORMContinue maintenance & Reliever ICS/FORM (<72 µg/d)
ICS/SALMMaintenance ICS/SAML dose to highestConsider adding separate ICS inhaler for higher ICS
Oral prednisolone 1 mg/kg up to 50 mg/d 5-7 d
Increase frequency of SABA or low dose ICS/FORM
Increase ICS component 2 x dose to high dose (2000 mg BDP equivalent)
WAAP
Global Strategies for Asthma Management and Prevention GINA report 2015
4 puff BID
16 puff PRN
ICS/LABA in single inhaler as reliever therapy (ICS/FABA) in intermittent and mild asthma:
Proof concept study and meta-analysis (6 RCTs)
Pro
po
rtio
n o
f Ex
acer
bat
ion
1.0
0.9
0.8
0.7
0.6
0 100 200 300
FABA
ICS/FABA
ICS
Day after randomization
G Wang et al. Respiratory Research 2017, 18:203
STEP1
Consider low dose
ICS
STEP 2Low dose ICS
Leukotriene receptor antagonist Intermittent ICS
Add tiotropium High dose ICS
+LTRA (or + Theophylline)
Add low dose OCS
Step 5 Refer to add-on
RX STEP 3 Low dose ICS-LABA
Preferred controller choice
Other controller choice
Reliever
Mod/high dose ICS Low dose ICS
+LTRA(or + Theophylline)
As needed SABA or low dose ICS/fomoterol
STEP 5
Refer to add-on treatment Tiotropium
OmalizumabMepolizumab
STEP 4
Med/ high ICS /LABA
Global Strategies for Asthma Management and Prevention GINA report 2018
Step 4
Tiotropium SMI add-on (age ≥12 y) with a history of exacerbations Adults: consider adding SLIT for HDM (Non-pharmacological therapy)Trial of high dose combination ICS/LABAIncrease dosing frequency (for budesonide-containing inhalers)Add-on LTRA or low dose theophylline
As needed short-acting β2 agonist (SABA)
Step 4.5 Tiotropium bromide
Tiotropium Respimat in asthma clinical trial development program
Adult Pediatric
Kerstjens et al JACI 2011Phase II POC Add-on to ICS/LABA
Prima TinA-asthma Kerstjens et al NEJM 2012
Twin Phase III Add-on to ICS
Bateman et al JACI 2011Phase II POC Add-on to ICS
Grazia TinA-asthma Pagalaro et al AAAAI 2014
Twin Phase III Add-on to low ICS
Mezza TinA-asthma Kerstjens et al NEJM 2012
Twin Phase III Add-on to ICS
Coden TinA –asthma Japanese local registration
Add on to ICS+/-LABA
205, 424Phase II safety/ 12-17 YAdd-on to at lease ICS
205, 425Phase II safety/ 6-11 YAdd-on to at lease ICS
205, 443Phase II/III safety/ 1-5Y
Ruba Tin A-asthma Phase III in 12-17 y
Add-on to at least ICS
Pensie TinA-asthma Phase III in 12-17 y
Add-on to ICS +≥1 controller
205, 411Phase II posology
Add-on to ICS
18 trails in over 6,000 patients
Age groups 1-5 years
6-11 years 12-17 years ≥18 years
STEP1
Consider low dose
ICS
STEP 2Low dose ICS
Leukotriene receptor antagonist Intermittent ICS
Add tiotropium High dose ICS
+LTRA (or + Theophylline)
Add low dose OCS
Sputum guidance
Step 5 ReferSTEP 3 Low dose ICS-LABA
Preferred controller choice
Other controller choice
Reliever
Mod/high dose ICS Low dose ICS
+LTRA(or + Theophylline)
As needed SABA or low dose ICS/fomoterol
STEP 5
Refer to add-on treatment Tiotropium
OmalizumabMepolizumab
ReslizumabBenralizumab
STEP 4
Med/ high ICS /LABA
Global Strategies for Asthma Management and Prevention GINA report 2018
Step 5 Preferred option: refer specialist investigation & consider add-on RxAdd-on tiotropium (age ≥12 y) with history of exacerbationsAdd-on anti-IgE for severe allergic asthma (omalizumab) Add-on biologics for severe eosinophilic asthma• Anti-IL5 [mepolizumab (SC, ≥12 y) or reslizumab (IV, ≥18 y)]• Anti-IL5R [benralizumab (SC, ≥12 y)]
As needed short-acting β2 agonist (SABA)
STEP1
Consider low dose
ICS
STEP 2Low dose ICS
Leukotriene receptor antagonist Intermittent ICS
Add tiotropium High dose ICS
+LTRA (or + Theophylline)
Add low dose OCS
Sputum guidance
Step 5 ReferSTEP 3 Low dose ICS-LABA
Preferred controller choice
Other controller choice
Reliever
Mod/high dose ICS Low dose ICS
+LTRA(or + Theophylline)
As needed SABA or low dose ICS/fomoterol
STEP 5
Refer to add-on treatment Tiotropium
OmalizumabMepolizumab
ReslizumabBenralizumab
STEP 4
Med/ high ICS /LABA
Global Strategies for Asthma Management and Prevention GINA report 2018
Step 5
Other add-on treatment options • Sputum-guided treatment: in specialized centers
(reduces exacerbations & corticosteroid dose• Add-on low dose oral corticosteroids
(≤7.5mg/day prednisone equivalent)
As needed short-acting β2 agonist (SABA)
Difficult to control asthma vs. severe asthma
Watch patient using their
inhaler
Discuss adherence & barriers
Confirm the diagnosis
of asthma
Remove potential risk factors.
Assess & manage comorbidities
Consider treatment
step-up
Refer to a specialist or
severe asthma clinic
Compare inhaler technique with a device-specific checklist
AND correct errors; recheck frequently
Have an empathic discussion about barriers to adherence.
If PFT normal during symptoms
Consider halving ICS dose and repeating PFT after 2–3 weeks
Check risk factors or inducers(smoking, B-blockers, NSAIDs, allergen)
Check comorbidities (rhinitis, obesity, GERD, depression/anxiety)
Consider step up to next treatment level. Share decision-making, and balance potential benefits and risks
If asthma still uncontrolled after 3–6 months on Step 4 treatment, refer for expert advice
Refer earlier if symptoms severe or doubts about diagnosis
Dif
ficu
lt t
o c
on
tro
l ast
hm
a Se
vere
as
thm
a
Bronchial thermoplastyFDA approved indication and procedural detail
• Adult severe persistent asthma (age >18 years)
• Inadequate control despite combination ICS/LABA
• Able to safely undergo bronchoscopy
Patient stable for FOB
BRONC 1 RLL
BRONC 2 LLL 3 weeks
BRONC 3 LUL RUL
3 weeks
Electrode array is contact to airway wall and RF energy is activatedAlair® delivers RF energy (65 °C) to wall for 10 s per activation
Clinical trials of bronchial thermoplasty in asthma
Feasibility trial AIR (RCT) n=108
RISA (RCT) n=32
AIR 2 (RCT) n=297
A.M. PEFR AQLQ AQLQ AQLQ
P.M. PEFR Rescue Medications Rescue Medication Severe exacerbations
Symptom free days
Symptom free day FEV1 ER visit
Exacerbation Oral steroid (NS) Day lost from workand school or activities
AJRCCM 2006 NEJM 2007 AJRCCM 2007 AJRCCM 2010
Ext 5 year AIR 2
89% rate
No AENo RS AENo EXAFEV1 NS
BDR+
JACI 2013
X 3 procedure vs. sham control
Potential phenotypes Targeted therapies in severe asthma for clinical use
Characteristics Associations Specific target treatments
Severe allergic
asthma
Blood and sputum eosinophilsHighs serum IgEHigh FeNo
Anti-IgE (Adult and children) Anti-IL-4/IL-13Anti-IL-4 receptor
Esoniophilic
asthma
Blood and sputum eosinophilsRecurrent exacecerbationHigh FeNo
Anti-IL-5 Anti-IL-4/IL-13Anti-IL-4 receptor
Neutrophilic
asthma
Corticosteroid insensitivityBacterial infection
Anti-IL-8 CXCR2 antagonists Anti-LTB4 (Adult and children) Macrolide (Adult and children)
Chronic airflow
obstruction
Airway wall remodeling as increased airway wall thickness
Anti-IL-13 Tiotropium bromide Bronchial thermoplasty
Recurrent
exacerbation
Sputum eosinophiliaReduced response to ICS/OCS
Anti-IL-5 Anti-IgE (Adult and children)
Corticosteroid
insensitivity
Increased sputum neutrophilia P38 MAPK inhibitorTheophylline (adult & children) Macrolides (adult and children)
KF Chung et al, Eur Respir J 2014; 43: 343-373
Biomarkers to identify T2 phenotypesFor personalized treatment of asthma
• Sputum eosinophils (>2% or 3%)
• Exhaled nitric oxide (>30 ppb)
• Circulating eosinophils (150-400/µl)
• Serum periostin (> 50 ng/ml)
• Serum IgE
• Allergen skin testing
What is the impact of monoclonal Ab for Th2/eosinophilic phenotype asthma?
Am J of Respir and Crit Care Med, 2011; 184(5):602-15.
PG Gibson et al Lancet 2011; 378: 983-991
Guiquan Jia et al. J Aller Clin Immunol. 2012; 130(3): 647–654.
Green et al, Lancet 2002; 360: 1715-21
• Eosinophilic/Th2 phenotypes (IL-4, IL-5 and IL-13)
• Non eosinophilic (sputum eosinophils< 2% or blood Eo <200/µl)
Mechanisms of IL-5 targeted treatment
IL-5Rα
IL-5Rα
IL-5
IL-5
No signaltransduction
IL-5
Differentiation & maturationEosinophil migration Mediators releaseInhibition of apoptosis
Eosinophil Eosinophil
IL-5
Mepolizumab(Anti-IL-5)
Reslizumab(Anti-IL-5)
IL-5Rα
Benralizumab(Anti-IL-5Rα)
Neutralize circulating IL-5
IL-5R receptorblock
Tan LD. J Asthma Allergy. 2016; 4;9:71-81
Mechanism of Benralizumab(Anti-IL-5R, IgG1) deplete eosinophils in blood and airways
IL-5Rα
ADCC
IL-5
IL-5 mAbMepolizumab
Reslizumab
Passive removal ofactivating interleukin
Antibody Dependent Cell mediated Cytotoxicity(ADCC: Active mode of action)
IL-5
Eosinophil
Basophil
Macrophage NK cell
FcgRIIIα
BenralizumabIL-5Rα mAb
Summary of biologics and mAb in T2 asthma
Targettherapies
Drug name(antibody)
Route of administration
Markers Development phase
IgE OmalizaumabLigelizumabQuilizumab
Subcutaneous Subcutaneous Subcutaneous
Total serum IgE, FENO, periostin, and blood Eo
Marketed Phase 2Phase 2
IL-5
IL-5Rα
MepolizumabReslizumabBenralizumab
Subcutaneous Intravenous Subcutaneous
Blood Eo (> 150-300/µl)Blood Eo (> 400/µl)Blood Eo (> 200-300/µl)
Marketed (12 y+)Marketed (18 y+)Marketed (12 y+)
IL-4Rα Dupilumab
Pitrakinra(IL-4 varient)
Subcutaneous
SubcutaneousNebulizer
Blood Eo (> 300/µl)Sputum Eo (> 3%)
Phase 3 Phase 2
IL-13 Lebrikizumab
Tralokinumab
Subcutaneous
Subcutaneous
Blood Eo (> 300/µl)Serum periostin (> 50 ng/dl)High serum periostin
Phase 3
Phase 3
TSLP AMG-157 Intravenous NA Phase 3
Eotaxin(CCL11)
Bertilimumab(CCR3 block)
Oral NA Phase 3
Diagnosis criteria of severe eosinophilic asthma
Major criteria
• Late onset
• Involvement of upper airway (chronic sinusitis, nasal polyps)
• Other biomarker (FeNO)
• Fixed airflow obstruction
• Hyperinflation or mucus plug
• Severe asthma
• Blood eosinophil
(> 2 occasions)
• Frequent exacerbation (> 2 per year)
• Need for (chronic intermittent) oral steroid
Minor criteria
Buhl R et al Eur Resp J 2017
Murano et al J Allergy Clin Immunol 2016; 137;1347-58
2003 2015 2016
Total IgEand kg BWT
(75-375 mg SC)Q 2-4 weeksUS FDA EMA
≥ 6 years
Blood EO >150-300/mm3
(100 mg SC)Q 4 weeks
US FDA ≥ 12 years
Blood EO > 400/mm3
(3 mg/Kg IV)Q 4 weeks
US FDA, EMA ≥ 18 years
Benralizumab Dupilumab Lebrikizumab
Trivedi A. Lancet Respir Med 2016;4:585-592
Blood EO > 200-300/mm3
(30 mg SC)Q 4 weeks
US FDA>12 years
Blood EO > 300/mm3
(200 mg SC)Q 2-4 weeks
US FDANot approved
Blood EO > 300/mm3
PONST >50 (150-300 SC)
Q 4 weeksNot approved
Omalizumab Mepolizumab Reslizumab
2017
Biologics in severe asthmaWhen start, continue and discontinue?
Eosinophils (cell/µl)
30 1500
300
Serum IgE(IU/ml)
Eosinophilic asthma Anti-IL-5
MepolizumabReslizumabAnti-IL-5R
Benralizumab
Allergic asthma Anti-IgE
Allergic asthma Eosinophilic
asthma Anti-IL-5
Anti-IL-5RAnti-IgE
No-eosinophilic asthma
Anti-IL-17Anti-CXCR2Macrolide
4 months 12 months
Nonresponders
Intermediate responders
Superresponder
Continue treatment
Continue treatment for a year
to assess response ORConsider switching if response is low
Stop treatment
Severe asthmaInflammatory phenotypes and current therapies
Induced sputum, FeNO and peripheral blood eosinophils
‘’Th2 high’’
Eosinophilic
Steroids Anti-eosinophilic
Anti-IgEAnti IL-5/IL5RAnti IL4Rα/IL-13
Anti TSLPAnti IL-33
CRTH2 antagonist
‘’Th2 low’’
Neutrophilic
Steroid resistance Anti-neutrophilic
MacrolidesCXCR2 antagonist
Anti TNFAnti IL-1
Anti IL-17/IL-23P38 MAPK inhibitor
PDE4 inhibitors
Paucigranulocytic
Steroid resistance
LAMALAMA+LABA
LABA/LAMA/ICSBronchial
thermoplasty
Barnes PJ. J Allergy Clin Immunol 2015; 136:631-645
Roadmap & milestone for anti-eosinophilic in asthmaFrom corticosteroid to biologic agents
1950
Cortisone 1949
1960 1970
IgE(Reagin)
1968
ICS1973
1980 1990 2000
Omalizumab2003
IL-5 IL-13
IL-5Rα
IL-4R
2010 2020
Mepolizumab 2015
Reslizumab 2016
Benralizumab 2017
Dupilumab
Trakolinumab
Lebrikizumab
Bertilimumab
FevipiprantmAb
BA
C D
3
2
9
45
67
8
17
10
11
1213
1
14 15
1618
CH3
18CH3OH
C 18CH3
20 O
OH
O
Corticosteroid
GINA 2018 Revised asthma treatments
ICS should be considered for mild asthma (rather than prescribing SABA alone) is to reduce their risk of serious exacerbations
Adding LABA to ICS in a combination inhaler reduces exacerbation risk and improves symptoms and PFT, compared with the same dose of ICS alone
SC benralizumab(monoclonal anti-IL5R αAb) is another add-on treatment for patients with severe eosinophilic asthma
Step 1 Step 3-4Step 5
Severe asthma management
Reddel HK et al. START study. Lancet 2017;389:157-66
Peters SP et al. N Engl J Med 2016;375:850-60Stempel DA et al. N Engl J Med 2016;374:1822-30
Castro M et al. Lancet Respir Med2:879-890.Bleecker ER. Lancet;388:2115-2127FitzGerald JM. Lancet;388:2128-2141.
Stepwise asthma management Additional components (The 7 wonders of GINA 2018)
1. Provide guided self-management education
2. Treat modifiable risk factors and comorbidities
3. Advise about non-pharmacological therapies and strategies
4. Consider adding SLIT in HDM-sensitive adults with allergic rhinitis having exacerbation despite ICS (FEV1 > 70%)
5. Consider step up if uncontrolled symptom or exacerbationBUT check diagnosis, inhaler technique and adherence
6. Consider step down if symptom controlled for 3 m and low risk for exacerbations
7. Stopping ICS is not advised
Pregnancy drug safety(US FDA drug safety in pregnancy)
Drug Pregnancysafety
Lactation
ICS
Beclomethasone C Unknown
Budesonide B Unknown
Ciclesonide C Unknown
Fluticasone C Unknown
Mometasone C Unknown
LABA
Formoterol C Unknown
Salmeterol C Unknown
Systemic corticosteroids
Dexamethasone C Probably safe
Hydrocortisone C Probably safe
Methylprednisolone C Probably safe
Prednisone C Probably safe
Drug Pregnancysafety
Lactation
SABA
Albuterol C Probably safe
Levalbuterol C Unknown
Terbutaline C Probably safe
Theophylline C Probably safe
SAMA
Ipratropium bromide B Unknown
Leukotriene inhibitors
Montelukast B Unknown
Zafirlukast B Possibly unsafe
Zileuton C Probably safe
Prednisone C Probably safe
Mast-cell stabilizers
Nedocromil B Unknown
Cromolyn B Unknown
Omalizumab B Unknown
Asthma education, environmental control, influenza vaccine and pulmonary rehabilitation
As needed rapid- acting 2-agonist
Low dose steroid
ส ำหรบผปวยทม
High Risk
exacerbation
Select one Select one Add one or more Add one or both
Low-doseinhaled ICS
Low-dose ICS pluslong-acting 2 -agonist
Medium or high-dose ICS plus long-acting 2-agonist
Oral glucocorticosteroid
(lowest dose)Leukotriene
modifierMedium or high-dose ICS Leukotriene modifier Anti - IgE
Low-dose ICS plus leukotriene modifier
Sustained release theophylline
Low dose ICS plus sustained release
theophylline
Tiotropium bromide
Step 1 Step 2 Step 3 Step 4 Step 5
Decrease IncreaseTreatment steps
แนวทางการวนจฉยและรกษาโรคหดในประเทศไทยส าหรบผใหญ พ.ศ. 2560
Thank you for your attention
Recommended