addressing the unmet needs in asthma patients with allergic...

Addressing the Unmet Needs in ASTHMA Patients

with Allergic Rhinitis

Dr.Budhi Antariksa, Sp.P(K), Ph.D

Dept Pulmonologi dan Ilmu Kedokteran Respirasi

FKUI – RS Persahabatan, Jakarta

ASMA: DEFINISI

Asma adalah penyakit pernapasan berupa inflamasi

kronik dengan ciri:

• Riwayat gangguan pernapasan seperti

wheezing (mengi), tarikan napas yang

singkat, sesak di dada dan disertai batuk yang

bervariasi waktu dan intensitasnya.

• Hambatan laju aliran pernapasan.

(GINA, 2019)

BRONKOKONTRIKSI

2019 GINA Pocket guide for Asthma Management and Prevention, Global Initiative for Asthma, 2019. Available from: https://ginasthma.org/gina-reports/. Accessed July 2019.

Nature Reviews Immunology 2, 132-138 (February 2002)

ASMA = INFLAMASI & REMODELING

3

ASMA: PATOFISIOLOGI

• Melibatkan banyak sel:

– Mast cell

– Eosinophil

– B lymphocyte

– T lymphocyte

– Macrophage

– Neutrophil

– Epithelial cell

– Dendritic Cell

• Melibatkan pelepasan cytokine / chemokine:

– IL4, IL5, IL8, IL9, IL13

– Histamine

– Leukotriene

© PDPI. Asma. 2006

ASMA = INFLAMASI & REMODELING

ASMA: TATALAKSANA

TUJUAN Tatalaksana Asma yaitu:

• Mengontrol asma

• Menurunkan risiko eksaserbasi

[Penilaian– Penyesuaian Terapi – Review Respon]

2019 GINA Pocket guide for Asthma Management and Prevention, Global Initiative for Asthma, 2019. Available from: https://ginasthma.org/gina-reports/. Accessed July 2019.

ASMA: TATALAKSANA

* Off-label; data only with budesonide-formoterol (bud-form)

† Off-label; separate or combination ICS and SABA inhalers

PREFERRED

CONTROLLER

to prevent exacerbations

and control symptoms

Other reliever option

PREFERRED

RELIEVER

STEP 2

Daily low dose inhaled corticosteroid (ICS),

or as-needed low dose ICS-formoterol *

STEP 3

Low dose

ICS-LABA

STEP 4

Medium dose

ICS-LABA

Leukotriene receptor antagonist (LTRA),

or low dose ICS taken whenever SABA

taken †

As-needed low dose ICS-formoterol *

As-needed short-acting β2 -agonist (SABA)

Medium dose

ICS, or low dose

ICS+LTRA #

High dose

ICS, add-on

tiotropium, or

add-on LTRA #

Add low dose

OCS, but

consider

side-effects

As-needed low dose ICS-formoterol ‡

Box 3-5A

Dewasa & remaja > 12 tahun

Tatalaksana asma bersifat personal: Penilaian, Penyesuaian Terapi dan Review respon

Asthma medication options:

Adjust treatment up and down for

individual patient needs

STEP 5

High dose

ICS-LABA

Refer for

phenotypic

assessment

± add-on

therapy,

e.g.tiotropium,

anti-IgE,

anti-IL5/5R,

anti-IL4R

Symptoms

Exacerbations

Side-effects

Lung function

Patient satisfaction

Confirmation of diagnosis if necessary

Symptom control & modifiable

risk factors (including lung function)

Comorbidities

Inhaler technique & adherence

Patient goals

Treatment of modifiable risk factors & comorbidities Non-pharmacological strategies

Education & skills training

Asthma medications

1 © Global Initiative for Asthma, www.ginasthma.org

STEP 1

As-needed

low dose

ICS-formoterol *

Low dose ICS

taken whenever

SABA is taken †

‡ Low-dose ICS-form is the reliever for patients prescribed

bud-form or BDP-form maintenance and reliever therapy

# Consider adding HDM SLIT for sensitized patients with

allergic rhinitis and FEV >70% predicted

GINA 2019

Other controller options

Haughney J, Price D, Kaplan A, et al. Achieving asthma control in practice: understanding the reasons for poor control. Respir Med 2008;102:1681-93

Diagnosis yang tidak tepat

Pemilihan atau penggunaan inhaler yang tidak tepat.

Riwayat merokok

- Perokok asma relatif resisten terhadap terapi kortikosteroid

Komorbid (penyakit penyerta): Rhinitis

Kepatuhan pasien

Respon individual terhadap variasi terapi.

ALASAN KONTROL ASMA BURUK

ASMA: TATALAKSANA

ASMA: Studi INSPIRE

• Subjek: 3,415 pasien asma dewasa ≥16 thn dari 11 negara yang diresepkan

ICS atau ICS+LABA

• Hasil:

– 74% masih menggunakan SABA setiap hari;

– 51% pasien memiliki asma yang tidak terkontrol;

– 21% pasien memiliki asma yang tidak terkontrol dengan baik; dan

– hanya 28% pasien yang diklasifikasikan memiliki asma yang terkontrol dengan baik.

Partridge MR, et al. Attitudes and actions of asthma patients on regular maintenance therapy: the INSPIRE study. BMC

Pulmonary Medicine 2006;6:13.

ASMA: Studi AIRIAP

• Metode interview: 2.323 dewasa dan 884 anak-anak • Tingkat derajat asma:

o Intermittent-ringan o Persitent-ringan o Persistent-sedang o Persistent-berat

• Terapi yang diberikan bronkodilator; teofilin, ICS dan terapi pencegahan lainnya.

• Hasil: • Kontrol asma masih kurang, 51,4% responden

masih gejala asma pada siang hari. • 44,3% responden mengalami terbangung

karena asma dalam 4 mingu terakhir.

Studi INSPIRE + Studi AIRIAP II

“Perlu perubahan dalam manajemen terapi asma”

=

• Diproduksi oleh leukosit dan memiliki struktur tiga rantai ganda (triena)

• Mediator pro-inflamasi, hasil dari aktivasi sel-sel imun pada membran sel akibat adanya alergen

• Vora AC. Montelukast – place in therapy. Supplement to Journal of The Association of Physicians of India 2014(62):46-50. • Benninger MS & Waters H. Montelukast: Pharmacology, safety, tolerability and efficacy. Therapeutics 2009(1):1253-61.

Leukotriene

Leukotriene

Leukotriene atau Cysteinyl leukotrine (Cys-LTs) adalah mediator inflamasi

turunan dari asam arachidonat melalui jalur 5-lipoxygenase/leukotriene C4-

synthase. (LTC4Synthase).

Phospolipid pada

membran sel

Asam Arakhidonat (arachidonic acid)

Phospholipase A2 5-HPETE

Prostaglandins Thromboxanes

5-lipoxygenase/FLAP

Cyclo-oxygenase

*5-HPETE = 5-HydroPeroxyEicosaTetraenoic Acid

5-HPETE

LTB4

LTC4 LTA4 LTD4 LTE4

5-lipoxygenase/FLAP

LT4 hydrolase

Cysteinyl Leukotriene Receptor

LTC4 dan LTD4 pada reseptor Cyst-LTs menginduksi bronkokontriksi.

LTE4 bronkokonstriktor lemah, tetapi paling potent karena mengakumulasi eosinofil dan basofil pada

bronchial submucosa dan kadar LTE4 ditemukan tinggi pada urine pada saat eksaserbasi asma.

• Dempsey, O. J. Leukotriene receptor antagonist therapy. Postgrad Med J. 2000; 76:767-773. • Kanaoka, Y., et. al., Cysteinyl leukotrienes and their receptors; Emerging Concepts. Allergy Asthma Immunol Res. 2014; 6(4):288-295.

LTC4 synthase

Leukotriene

Sintesis & pelepasan leukotrien tidak dihambat oleh kortikosteroid

perlu anti-leukotrien /

antagonis reseptor leukotrien (LTRA).

Diadaptasi dari: Pavord ID, et al. Induced sputum eicosanoid concentrations in asthma. AM J Respir Crit Care Med 1999;160:1905–1909.

Perubahan Target Terapi: LEUKOTRIEN…

0.0

2.0

4.0

6.0

8.0

10.0

12.0

14.0

Normal control(n=10)

Subjects withasthma (n=20)

Treated with ICS(n=10)

Acute severeasthma (n=6)

6.4

9.4

11.4

13.0

spu

tum

Cys

-LT

con

cen

trat

ion

(n

g/m

l)

Kadar leukotrien pada pasien asma

* p<0.02 vs normal control # p<0.05 vs normal control

#

*

*

LT-Receptor Antagonist dan LT-Synthesis Inhibitor

Mengatasi leukotriene yang meningkat dengan menggunakan:

LEUKOTRIENE RECEPTOR ANTAGONIST:

● Montelukast

● Zafirlukast

● Pranlukast

● Verlucast

LEUKOTRIENE SYNTHESIS INHIBITOR:

● 5-Lipoxygenase inhibitors ● Zileuton ● 5-Lipoxygenase activating protein

inhibitors ● BAYx1005 ● MK-0591

LTRA (leukotriene receptor antagonist) bekerja dengan menghambat reseptor CysLT LTC4; LTD4; dan LTE4.

1 yaitu: CysLT1R dan CysLT2R

• Drakatos, et. al., Targeting Leukotrienes for the teratment COPD?. Inflammation & Allergy – Drugs Targets, 2009;8:297-306.

* Off-label; data only with budesonide-formoterol (bud-form)

† Off-label; separate or combination ICS and SABA inhalers

PREFERRED

CONTROLLER



Other reliever option

PREFERRED

RELIEVER

STEP 2



STEP 3

Low dose

ICS-LABA

STEP 4

Medium dose

ICS-LABA

Leukotriene receptor antagonist (LTRA),

or low dose ICS taken whenever SABA

taken †


As-needed short-acting β2 -agonist (SABA)

Medium dose

ICS, or low dose

ICS+LTRA #

High dose

ICS, add-on

tiotropium, or

add-on LTRA #

Add low dose

OCS, but

consider

side-effects

As-needed low dose ICS-formoterol ‡

Asthma medication options:

Adjust treatment up and down for

individual patient needs

STEP 5

High dose

ICS-LABA

Refer for

phenotypic

assessment

± add-on

therapy,

e.g.tiotropium,

anti-IgE,

anti-IL5/5R,

anti-IL4R

1 © Global Initiative for Asthma, www.ginasthma.org

STEP 1

As-needed

low dose

ICS-formoterol *

Low dose ICS

taken whenever

SABA is taken †

‡ Low-dose ICS-form is the reliever for patients prescribed

bud-form or BDP-form maintenance and reliever therapy

# Consider adding HDM SLIT for sensitized patients with

allergic rhinitis and FEV >70% predicted


Bagaimana LTRA pada GINA 2019 ?

STEP 2



Leukotriene receptor antagonist (LTRA), or

low dose ICS taken whenever SABA taken †

PREFERRED

CONTROLLER



PREFERRED

RELIEVER


As-needed short-acting β2 -agonist (SABA) Other reliever option


Medium dose

ICS, or low dose

ICS+LTRA #

STEP 3

Low dose ICS-

LABA

Terapi LTRA digunakan sebagai terapi pilihan untuk mengontrol ASMA

GINA 2019

Preferred option: Daily Low-dose ICS + or as-needed low dose ICS-formoterol *

ICS at low doses : ↓ asthma symptoms ↓ risk of exacerbations & asthma-related hospitalizations & death Other controller options: Leukotriene (LTRA) + or low dose ICS taken whenever SABA taken

STEP 2: Daily low dose inhaled corticosteroid (ICS)

Preferred option:

Before considering Step up, check: inhaler technique, poor adherence, & confirm diagnosis as asthma

Combination low dose ICS/LABA as maintenance + as-needed SABA, OR combination low dose ICS/formoterol maintenance & reliever regimen (budesonide/formoterol).

Other options: Medium dose ICS, or low dose ICS + Leukotriene (LTRA)

STEP 3: Low dose ICS-LABA

Other options: High dose ICS, add-on tiotropium, or add-on LTRA

Before considering Step up, check: inhaler technique, poor adherence, &

confirm diagnosis as asthma

STEP 4:

Preferred option: Medium dose ICS-LABA

MONTELUKAST

• Montelukast: LTRA paling poten dan spesifik

• Sebagai pengontrol pada alergi, asma, maupun asma akibat olahraga (exercise-induced)

• Berikatan dengan kuat dan selektif pada reseptor CysLTR1 untuk menghambat pengikatan leukotrien LTD4 antagonis leukotrien

anti-inflamasi

• Aman & ditoleransi dengan baik tidak ada perbedaan bermakna dengan plasebo

• Vora AC. Montelukast – place in therapy. Supplement to Journal of The Association of Physicians of India 2014(62):46-50. • Benninger MS & Waters H. Montelukast: Pharmacology, safety, tolerability and efficacy. Therapeutics 2009(1):1253-61.

MONTELUKAST – Studi MONICA

• Subjek: ≥18thn dengan asma ringan-sedang diberikan MON 10 mg 1x1 sebagai add-on ICS atau ICS+LABA selama 6 bulan

• Hasil: Terjadi perbaikan klinis ketika montelukast ditambahkan pada terapi ICS atau ICS+LABA. Perbaikan tersebut mencakup kontrol asma, kualitas hidup, fungsi paru, serta status asma, dengan profil keamanan yang baik.

Virchow JC, et al. Add-on montelukast in inadequately controlled asthma patients in a 6-month open-label study: the montelukast in chronic asthma (MONICA) study. Respiratory Medicine 2010;104:644-51.


ACT scores: LS mean ACT score improved from baseline to Month 12 of add-on montelukast by 6.6 in the ICS subgroup and 5.4 in the ICS + LABA subgroup.

ICS or ICS + LABA at baseline; add-on montelukast at Months 3, 6, and 12.

Improvements in ACT Scores With Add-On Montelukast in ICS and ICS + LABA Subgroups

Pa

tien

ts i

n E

ach

AC

T C

ate

go

ry, %

ACT Scores 25 (Completely controlled) 16–19 (Poorly controlled) 20–24 (Well controlled) <16 (Uncontrolled)

0

100

75

50

25

Month 3

(n=357)

47.5

14.1

9.4

27.6

Month 6

(n=318)

53.3

10.8

15.2

19.2

Month 12

(n=230)

54.3

6.5

25.0

13.4

Month 3

(n=1,035)

39.3

23.8

6.0

27.9

Month 6

(n=911)

45.2

20.4

9.6

23.1

Month 12

(n=622)

45.8

16.7

15.1

21.3

Baseline

(n=388)

19.5

48.3

29.8

2.1

Baseline

(n=1,163)

11.9

63.1

23.5

0.9

ICS Subgroup ICS + LABA Subgroup


Improvements in Mini AQLQ With Add-On Montelukast in ICS and ICS + LABA Subgroups S

core

0

7

4

3

2

4.18

1

6 5.32

5.53 5.90

3.80

4.86 5.11

5.43

5

ICS Subgroup ICS + LABA Subgroup

Baseline ICS Baseline ICS + LABA Montelukast + baseline therapy

Month 3

(n=345)

Month 6

(n=309)

Month 12

(n=228) Month 3

(n=983)

Month 6

(n=883)

Month 12

(n=613)

Baseline

(n=379) Baseline

(n=1,137)


aP<0.0001 vs baseline.

Lung function measurements were performed at the investigator’s discretion; thus, not all patients had data for these parameters.

Improvements in Lung Function With Add-On Montelukast F

EV

1, L

PE

F, L

/s

0

3

2

1

0

7

3

2

1

5

4

6 2.46

Baseline

(n=1,445)

2.61a

Month 3

(n=1,057)

2.60a

Month 6

(n=914)

5.76

Baseline

(n=967)

6.20a

Month 3

(n=669)

6.22a

Month 6

(n=563)

ICS or ICS + LABA Montelukast + baseline therapy



Conclusion:

The efficacy of 12-week treatment with MON-400BUD in older asthmatics was comparable to that

of 800BUD on asthma control but associated with reduced frequency of asthma

exacerbations requiring oral steroids and sore throat events.

Changes in ACT and PFS can be useful predictors of asthma control status in older patients.

Montelukast

• Indicated for asthma and rhinitis

• For adults and children > 6 months

• Administered once daily

• Adverse effects not observed

• Unaffected by food (with or without food)

• The only FDA-approved LTRA in USA

Zafirlukast


• For adults and children > 5 years

• Administered twice daily

• Adverse effects: single report of hepatotoxicity

• Food reduce bioavailability (empty stomach, 1 hour before or 2 hour after eat)

Pranlukast


• For adults and children > 1 year

• Administered twice daily

• Adverse effects not observed

Sanak M. Antileukotrienes in the treatment of allergic rhinitis. Global Atlas Of Allergic Rhinitis and Chronic Rhinosinusitis. In: Akdis CA, Hellings P, Agache I, editors.

Published by the European Academy of Allergy and Clinical Immunology; 2015, pp 197–199. http://eaaci.org/globalatlas/ENT_Atlas_web.pdf.

Seidman MD, Gurgel RK, Lin SY, Schwartz SR, Baroody FM, Bonner JR, et al. Clinical practice guideline: allergic rhinitis. Otolaryngol Head Neck Surg. 2015;152(1)

Suppl;S1–43

MONTELUKAST vs Other LTRAs

MONTELUKAST DAN ASMA PADA KEHAMILAN

Montelukast dapat diberikan pada pasien asma selama kehamilan Kategori FDA: B Dosis: 10 mg/hari

Studi INSPIRE & AIRIAP menunjukkan bahwa terapi terkini belum mengontrol asma dengan optimal.

Reaksi asma melibatkan peranan mediator pro-inflamasi leukotrien yang tidak bisa dihambat dengan terapi kortikosteroid, sehingga dibutuhkan antagonis reseptor leukotrien (LTRA), seperti montelukast.

LTRA direkomendasikan dalam guideline GINA.

Dari uji klinis, montelukast efektif digunakan sebagai monoterapi maupun kombinasi dengan ICS

Montelukast aman untuk diberikan sebagai terapi kontroler pada masa kehamilan.

SUMMARY

addressing the unmet needs in asthma patients with allergic...

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