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.
 ASMA: PATOFISIOLOGI
ASMA = INFLAMASI & REMODELING
3

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

 ASMA = INFLAMASI & REMODELING

• Melibatkan banyak sel: • Melibatkan pelepasan cytokine /

chemokine:
– Mast cell
– IL4, IL5, IL8, IL9, IL13
– Eosinophil
– Histamine
– B lymphocyte
– Leukotriene
– T lymphocyte
– Macrophage
– Neutrophil
– Epithelial cell
– Dendritic Cell

© PDPI. Asma. 2006

 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.
 Box 3-5A
Dewasa & remaja > 12 tahun
Confirmation of diagnosis if necessary
Symptom control & modifiable
GINA 2019
risk factors (including lung function)

ASMA: TATALAKSANA Comorbidities

Inhaler technique & adherence
Patient goals

Tatalaksana asma bersifat personal:

Penilaian, Penyesuaian Terapi dan Review
respon Symptoms
Exacerbations
Side-effects
Lung function
Patient satisfaction

Treatment of modifiable risk

factors & comorbidities STEP 5
Non-pharmacological strategies
Education & skills training High dose
Asthma medications ICS-LABA
Asthma medication options: Refer for
Adjust treatment up and down for STEP 4
phenotypic
individual patient needs assessment
Medium dose
STEP 3 ± add-on
ICS-LABA therapy,
STEP 2 Low dose e.g.tiotropium,
PREFERRED STEP 1 ICS-LABA anti-IgE,
CONTROLLER Daily low dose inhaled corticosteroid (ICS), anti-IL5/5R,
to prevent exacerbations As-needed or as-needed low dose ICS-formoterol * anti-IL4R
and control symptoms low dose
ICS-formoterol *

Low dose ICS Leukotriene receptor antagonist (LTRA), Medium dose High dose Add low dose
Other controller taken whenever or low dose ICS taken whenever SABA ICS, or low dose ICS, add-on OCS, but
options consider
SABA is taken † taken † ICS+LTRA # tiotropium, or
add-on LTRA # side-effects

PREFERRED As-needed low dose ICS-formoterol * As-needed low dose ICS-formoterol ‡

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

* Off-label; data only with budesonide-formoterol (bud-form)
† Off-label; separate or combination ICS and SABA inhalers
© Global Initiative for Asthma, www.ginasthma.org
‡ 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
1
 ASMA: TATALAKSANA

ALASAN KONTROL ASMA BURUK

 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.

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

turunan dari asam arachidonat melalui jalur 5-lipoxygenase/leukotriene C4-
synthase. (LTC4Synthase).
5-lipoxygenase/FLAP

Phospholipase A2 5-HPETE

Phospolipid
Asam Arakhidonat
pada
(arachidonic acid)
membran sel

Prostaglandins
Cyclo-oxygenase Thromboxanes

*5-HPETE = 5-HydroPeroxyEicosaTetraenoic Acid

Leukotriene

LTB4
LTC4 synthase
LT4 hydrolase

5-HPETE LTA4 LTC4 LTD4 LTE4

5-lipoxygenase/FLAP

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.
 Perubahan Target Terapi: LEUKOTRIEN…

Kadar leukotrien pada pasien asma Sintesis & pelepasan

* leukotrien tidak
14.0 13.0
dihambat oleh
#
12.0
11.4 kortikosteroid
sputum Cys-LT concentration (ng/ml)

*
9.4
10.0

8.0
6.4
6.0
perlu anti-
leukotrien /
4.0 antagonis reseptor
2.0
leukotrien (LTRA).
* p<0.02 vs normal control
0.0 # p<0.05 vs normal control
Normal control Subjects with Treated with ICS Acute severe
(n=10) asthma (n=20) (n=10) asthma (n=6)

Diadaptasi dari: Pavord ID, et al. Induced sputum eicosanoid concentrations in asthma. AM J Respir Crit Care Med
1999;160:1905–1909.
 LT-Receptor Antagonist dan LT-Synthesis Inhibitor

Mengatasi leukotriene yang meningkat dengan menggunakan:

LEUKOTRIENE RECEPTOR ANTAGONIST: LEUKOTRIENE SYNTHESIS INHIBITOR:

● Montelukast ● 5-Lipoxygenase inhibitors

● Zafirlukast ● Zileuton
● Pranlukast ● 5-Lipoxygenase activating protein
● Verlucast 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.
 Bagaimana LTRA pada GINA 2019 ?

STEP 5

High dose
ICS-LABA
Asthma medication options: Refer for
Adjust treatment up and down for STEP 4
phenotypic
individual patient needs assessment
Medium dose
STEP 3 ± add-on
ICS-LABA therapy,
STEP 2 Low dose e.g.tiotropium,
PREFERRED STEP 1 ICS-LABA anti-IgE,
CONTROLLER Daily low dose inhaled corticosteroid (ICS), anti-IL5/5R,
to prevent exacerbations As-needed or as-needed low dose ICS-formoterol * anti-IL4R
and control symptoms low dose
ICS-formoterol *

Low dose ICS Leukotriene receptor antagonist (LTRA), Medium dose High dose Add low dose
Other controller taken whenever or low dose ICS taken whenever SABA ICS, or low dose ICS, add-on OCS, but
options consider
SABA is taken † taken † ICS+LTRA # tiotropium, or
add-on LTRA # side-effects

PREFERRED As-needed low dose ICS-formoterol * As-needed low dose ICS-formoterol ‡

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

* Off-label; data only with budesonide-formoterol (bud-form)
† Off-label; separate or combination ICS and SABA inhalers
© Global Initiative for Asthma, www.ginasthma.org
‡ 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
1
 GINA 2019
STEP 3
STEP 2 Low dose ICS-
PREFERRED LABA
CONTROLLER Daily low dose inhaled corticosteroid (ICS),
to prevent exacerbations
and control symptoms or as-needed low dose ICS-formoterol *

Other Leukotriene receptor antagonist (LTRA), or Medium dose

controller ICS, or low dose
options low dose ICS taken whenever SABA taken †
ICS+LTRA #

PREFERRED
RELIEVER
As-needed low dose ICS-formoterol *

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

option

Terapi LTRA digunakan sebagai terapi pilihan untuk mengontrol ASMA

 STEP 2: Daily low dose inhaled corticosteroid (ICS)

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 3: Low dose ICS-LABA

Preferred option:

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)

Before considering Step up, check:

inhaler technique, poor adherence, & confirm diagnosis as asthma
STEP 4:

Preferred option: Medium 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
 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.
MONTELUKAST – Studi MONICA
Improvements in ACT Scores With Add-On Montelukast in ICS and ICS + LABA Subgroups

ACT Scores
25 (Completely controlled) 16–19 (Poorly controlled)
20–24 (Well controlled) <16 (Uncontrolled)
2.1 0.9
100
9.4 6.0 9.6
Patients in Each ACT Category, %

15.2 11.9 15.1

19.5 25.0
75 23.5 39.3
47.5 45.2
29.8 45.8
53.3
50
54.3
27.9
63.1 23.1
25 27.6 21.3
48.3
19.2
13.4 23.8 20.4
14.1 10.8 16.7
0 6.5
Baseline Month 3 Month 6 Month 12 Baseline Month 3 Month 6 Month 12
(n=388) (n=357) (n=318) (n=230) (n=1,163) (n=1,035) (n=911) (n=622)

ICS Subgroup ICS + LABA Subgroup

 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.
MONTELUKAST – Studi MONICA

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

Baseline ICS
Baseline ICS + LABA
Montelukast + baseline therapy
7
5.90
6 5.53 5.43
5.32
5.11
4.86
5
4.18
3.80
4
Score

0
Baseline Month 3 Month 6 Month 12 Baseline Month 3 Month 6 Month 12
(n=379) (n=345) (n=309) (n=228) (n=1,137) (n=983) (n=883) (n=613)

ICS Subgroup ICS + LABA Subgroup

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.
MONTELUKAST – Studi MONICA

Improvements in Lung Function With Add-On Montelukast

ICS or ICS + LABA Montelukast + baseline therapy

3 7
2.61a 6.20a 6.22a
2.60a
2.46 5.76
6

5
2
4

PEF, L/s
FEV1, L

3
1
2

0 0
Baseline Month 3 Month 6 Baseline Month 3 Month 6
(n=1,445) (n=1,057) (n=914) (n=967) (n=669) (n=563)
aP<0.0001 vs baseline.
Lung function measurements were performed at the investigator’s discretion; thus, not all patients had data for these
parameters.

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.
 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 vs Other LTRAs

Montelukast Zafirlukast Pranlukast

• Indicated for asthma and • Indicated for asthma and • Indicated for asthma and
rhinitis rhinitis rhinitis
• For adults and children > • For adults and children > • For adults and children >
6 months 5 years 1 year
• Administered once daily • Administered twice daily • Administered twice daily
• Adverse effects not • Adverse effects: single • Adverse effects not
observed report of hepatotoxicity observed
• Unaffected by food (with • Food reduce
or without food) bioavailability (empty
• The only FDA-approved stomach, 1 hour before or
LTRA in USA 2 hour after eat)

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 DAN ASMA PADA KEHAMILAN

Montelukast dapat diberikan pada pasien asma selama kehamilan

Kategori FDA: B
Dosis: 10 mg/hari
 SUMMARY
 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.