CURRICULUM VITAEDr. Nina Irawati SpTHT

Pendidikan : FKUI 1985 Sp THT FKUI 1996

Kursus &Pelatihan Alergi Imunologi : ARSR Mumbai Kuala Lumpur, NUH and SGH Siriraj Hospital Bangkok, EAACI London, AAOA & Asean Rhinology Society Singapura

Instruktur Kursus Alergi Imunologi pada PIT & KONAS PERHATI

Ketua KODI Alergi Imunologi PP PERHATI Kepala Divisi Alergi Imunologi Departemen THT FKUI/RS

CM

ALLERGIC RHINITISand

Nina IrawatiAllergy-Immunology Division

ENT DepartmentFac of Medicine University of Indonesia/Ciptomangunkusumo Hospital, JAKARTA

Allergic Rhinitis :

Important public health problem : Increasing prevalence

Economic impact

Asthma and rhinitis often coexist in the same patient

Symptoms of AR: detrimental effects on

QOL, emotional wellbeing, sleep and daytime performance and productivity

ARIA Guidelines: Classification of Allergic Rhinitis

Intermittent

Nasal Inflammation: An underlying mechanism in Allergic Rhinitis

Pearlman. J Allergy Clin Immunol. 1999;104:S132. Bascom et al. Am Rev Respir Dis. 1988;138:406. Bascom et al. J Allergy Clin Immunol.

1988;81:580. Quraishi et al. J Am Osteopath Assoc. 2004;104(suppl 5):S7. Minshall et al. Otolaryngol Head Neck Surg. 1998;118:648.

Late-Phase Response

Cellular Infiltration/Inflammation

Eosinophil

Monocyte

Lymphocyte

Mast cell

Allergen

Chemotactic

factors

Histamine

Proteases

Other

Inflam.

mediators

Early-Phase Response

Mast Cell

Basophil

Nasal Mucosa in Patients

with PAR

Oth

er

Infl

am

ma

tory

Me

dia

tors

6Eosinophil

Mast cells (and Basophils)

Histamine (H1)

Enzymes (eg, tryptase,

chymase, etc.)Ag

Vascular permeability, stimulates SMCs, itch

Tissue damage/remodelling

PGD2 Vasodilation, neutrophil chemotaxis

LTC4 (LTD4, LTE4) Mucus secretion, vascular permeability

PAF Chemotaxis/activation of leukocytes,

vascular permeability

IL-3, IL-5 Mast cell proliferation, eosinophil

production/activation

TNF-, MIP-1 Promote inflammation

IL-4, IL-13 TH2 differentiation

Major basic protein, ECP Cell damage

Enzymes (eg,

peroxidases, etc.)Tissue damage/remodelling

IL-8, IL-10, RANTES,

MIP-1, eotaxinInflammation, chemotaxis of leukocytes

LTC4 (LTD4, LTE4) Mucus secretion, vascular permeability

IL-3, IL-5, GM-CSF Mast cell proliferation, eosinophil

production/activation

Major Inflammatory Cells and Associated

Mediators in Upper Respiratory Disease

Neurogenic inflammation in Allergic Rhinitis

Sarin S, Undem B, Sanico A, Togias A. The Role of the Nervous System in Rhinitis. JACI

2006:118:999-1014

Treatment Selection: ARIA Guidelines Update (08)

EBM is an increasingly important concept, new paradigm in medicine a strategy combining the treatment of both upper & lower airway disease in terms of efficacy & safety The treatment : consider

- severity & duration- patients preference as well as efficacy,

availibility & costMedications have no longer effect when stopped,

PER maintenance th/ is required

Persistent AR : should be evaluated for asthma : medical history, chest examination, assessment of airflow obstr.

Patients with asthma should be appropriately evaluated for AR

Treatment of Allergic Rhinitis

Aim improve QOL by eliminating symptoms

Current concept :

MPI as therapeutic target

Prophylactic approach to prevent or reduce exacerbations

Long term vs symptomatic on demand

Maintenance vs on-demand

Continuous basis is better than treatment on demand ? currently no evident

1. Bousquet, J, et al. J Allergy Clin Immunol 2001;108(Suppl5)

2. Montoro J, et al. J Investig Allergol Clin Immunol 2007;17: Suppl 2

The most reasonable approachindividualization of treatment : characteristics of patient, specific conditions involved (type of sensitization, continuous or discontinuous exposure, and geographical setting)

WHO-ARIA & experts advise continuous treatment Control MPI Prevent the appearance of symptoms Continuous 2nd H1-antihistamines and INS : good clinical and

safety profile

TREATMENT GOALS

Unimpaired sleep

Ability to undertake normal daily activities, including work and school attendance,without limitation or impairment and the ability to participate fully in sport and leisure activities

No troublesome symptoms

No or minimal side effects and fast therapeutic effect of AR treatment

ARIA = Allergic Rhinitis and its Impact on Asthma.

Bousquet et al. J Allergy Clin Immunol. 2001;108 (5 suppl):S147.

ARIA Guidelines: Recommendations for Management of Allergic Rhinitis

Mild

intermittent

Moderate

severe

intermittent

Mild

persistent

Moderate

severe

persistent

Immunotherapy

Allergen and irritant avoidance

Intranasal decongestant (

Allergen and irritant avoidance may be appropriate

Diagnosis of allergic rhinitis

If conjunctivitisAdd:Oral H1 blockeror intraocular H1 blockeror intraocular chromone(or saline)

Consider specific immunotherapy

Not in preferred orderOral H1 blockeror intranasal H1 blockerand/or decongestant

or LTRA*

Mild

Intermittent

symptoms

Not in preferred orderOral H1 blockeror intranasal H1 blockerand/or decongestantor intranasal CSor LTRA*

(or chromone)

In persistent rhinitis

review the patient

after 2-4 wks

If failure: step-upIf improved: continuefor 1 month

MildModerate-severe

Failure:

referral to specialist

Moderate-severe

Failure

Review diagnosisReview complianceQuery infectionsor other causes

Add or increaseintranasal CS

dose

Rhinorrhea:add ipratropium

Blockage:add

decongestantor oral CS

(short term)

Improved

Step-downand continuetreatmentfor >1 month

Review the patientafter 2-4 wks

In preferred order

Intranasal CS

H1 blocker or LTRA*

Check for asthma

especially in patients

with severe and/or

persistent rhinitisPersistent

symptoms

*In particular in patients with asthma.

ALGORITHM

FOR DIAGNOSIS

AND

MANAGEMENT

OF

ALLERGIC

RHINITS

ARIA UPDATE

2007

ARIA Guidelines 2010 Revision Recommendations for the prevention and treatment of AR

and Asthma+AR : GRADE approach ( strong/we recommended, conditional/we suggest, high,moderate,low,very low)

No special avoidance of pets exposure ( low ev)

Multifaceted intervention to reduce early life exp to HDM (low ev)

Do not use oral H1 AH for the prevention of wheezing in infants with AD and/or family history of allergy/asthma(very low ev)

LTRA : do not use in adult persistent AR (high ev )

use in adults and children seasonal AR and preschool child with persisten AR (high ev)

Do not use oral H1 AH in children with AR to treat asthma, but to treat AR

Inhaled CS : first choice in treatment of chronic asthma

AR+Asthma : inhaled CS over LTRA ( single controlling of asthma)

Drugs efficacy to symptoms

Congestion Rhinorrhea Itching/sneezing

duration Grade recommendatio

n

Oral Antihistamine

+/++ ++ +++/++ 12-24 hrs A

Intra nasal

Steroid

+++ +++ ++/+++ 12-48 hrs A

Intranasal Decongestan

++++ - -/- 3-6 hrs

Intranasal Cromones

+ + +/+ 2-6 hrs A

Anti-cholinergic

- ++ -/- 4-12 hrs A

CysLTRA ++ + -/- Not reported

A

Bousquet et al. Allergy. 2002;57:841.

18

INS: Anti-Inflammatory Effects

Adenoid Hypertrophy1. Symptoms2. Consequences

Rhinosinusitis1. Symptoms2. Consequences

Nasal Polyposis1. Symptoms2. Consequences

Allergic Rhinitis1. Symptoms2. Consequences3. Co-morbidities

Inflammation

Corticosteroid acts on many stages of inflammation

APC

Eosinophyls & products

Basophyls & mast cells influx

T cells

IL 3,4,5,& 13

Histamine, tryptase, leukotrienes release

20

INS Have Multiple Anti-Inflammatory Activities

La

te-P

ha

se

Re

sp

on

se

Eosinophil

Mast cells (and Basophils)

Histamine (H1)

Ea

rly-P

ha

se

Re

sp

on

se

Enzymes (eg. Tryptase,

Chymase, etc.)Ag

Vascular permeability, stimulates SMCs

Tissue damage/remodeling

PGD2 Vasodilation, neutrophil chemotaxis

LTC4 (LTD4, LTE4) Mucus secretion, vascular permeability

PAF Chemotaxis/activation of leukocytes,

vascular permeability

IL-3, IL-5 Mast cell proliferation, eosinophil

production/activation

TNF-, MIP-1 Promote inflammation

IL-4, IL-13 TH2 differentiation

Major basic protein, ECP Cell damage

Enzymes (eg.

Peroxidases, etc.)Tissue damage/remodeling

IL-8, IL-10, RANTES,

MIP-1, eotaxinInflammation, chemotaxis of leukocytes

LTC4 (LTD4, LTE4) Mucus secretion, vascular permeability

IL-3, IL-5, GM-GSF Mast cell proliferation, eosinophil

production/activation

X

XXX X

X X X

X X

X

X

X

X X

X

X X

X

X

A pharmacological study rank orders of potency mometasone furoate,

fluticasone propionate, & fluticasone furoate

furoate & propionate ester highly lipophilic :facilitate their absorption through nasal

mucosa & uptake across phospholipid cell membranes

one - year studies INS in children :

mometasone furoate, fluticasone furoate & budesonide no adverse effects on HPA axis function or growth

Derendorf H, Meltzer EO.Molecular & clinical pharmacology of INS corticosteroids: clinical & therapeutic implications. Allergy. 2008 Oct;63(10):1292-300

22

INS: Improvement in Symptoms

Associated With AR

Desired attributes for a new INS

Treats bothersome nasal and ocular symptoms

Strong affinity for the GRProvides 24-hour efficacyHighly selective for the glucocorticoid

receptor (GR)Good safety and tolerability profile Fast onset of action Comfortable and easy to use device

New device: comparison to traditional

devices

Berger WE et al. Expert Opin Drug Deliv 2007;4:689701.

Short delivery nozzle and improved

overall ergonomic design

The rationale: high drug concentrations can be achieved at receptor sites in nasal mucosa, minimal risk of systemic adverse effect

The onset of action : the 1st 2 hours

Low bioavailability ,the best tolerated

Long term used , atrophy (-)

Fluticasone furoate is highly selective for GR relative to the mineralocorticoid receptor and progesterone receptor-b

Selectivity of all compounds for androgen receptor >1700 and for oestrogen receptor >22,000

Salter M et al. Am J Physiol Lung Cell Mol Physiol 2007;293:L660L667.

0 10 20 30 40 50 500 600 700

Fluticasone propionate

Fluticasone furoate

Human steroid hormone receptor selectivity

Mometasone furoate

Ciclesonide active principle

Budesonide

800 900

High selectivitySelectivity for the GR

Low selectivity

800/11/1

Mineralocorticoid receptor

Progesterone receptor-b

27

TNSS Relief in AR: INS vs Oral Antihistamines

Weiner et al. BMJ. 1998;317:1624.

FavorsINS

Favorsantihistamine

Weight (%)

8.1

15.4

4.3

19.7

11.0

15.4

2.9

17.8

5.4

100

-1.5 -1.0 -0.5 0 0.5 1.0

Ghanno

Bronsky

Munch

Schoenwetter

Van Bavek

Bernstein

Beswick

Vervloet

Wood

StudyTNSS

Total

28

Congestion Relief in AR: INS vs Intranasal Antihistamines

INS included beclomethasone dipropionate, fluticasone propionate, and budesonide.

Topical antihistamines included azelastine and levocabastine.Yez and Rodrigo. Ann Allergy Asthma Immunol. 2002;89:479.

Study

Davies 14.5 -1.87 (-2.43, -1.31)

Ortolani 53.3 -0.80 (-1.10, -0.51)

Di Lorenzo 4.4 -0.67 (-1.69, 0.34)

Stern 27.8 -0.47 (-0.87, -0.06)

100.0 -0.86 (-1.07, -0.64)

Total

-4 -2 0 2 4

Favors

INS

Favors

antihistamine

Weight SMD (95% CI)

Nasal Blockage

0 42352821147

-

6.5

-

6.0

-

5.5

-

5.0

-

4.5

-

4.0

-

3.5

-

3.0

-

2.5

-

2.0

-

1.5

-

1.0

-

0.5

0

EP 0 2821147

-

6.5

-

6.0

-

5.5

-

5.0

-

4.5

-

4.0

-

3.5

-

3.0

-

2.5

-

2.0

-

1.5

-

1.0

-

0.5

0

EP

Me

an

ch

an

ge

in

da

ily

rTN

SS

North American (PAR)Global (PAR)

Global (PAR) North American (PAR)

FFNS 110 g Placebo FFNS 110 g Placebo

Baseline mean daily rTNSS 8.8 8.5 8.6 8.7

LS mean change FFNS 110

g

vs placebo over 2-week

treatment period*

3.95

*P

Ocular efficacy (rTOSS)M

ea

n c

ha

ng

e in

da

ily

rTO

SS

EP14131211109876543210

-

4.0

-

3.5

-

3.0

-

2.5

-

2.0

-

1.5

-

1.0

-

0.5

0

EP14131211109876543210

-

4.0

-

3.5

-

3.0

-

2.5

-

2.0

-

1.5

-

1.0

-

0.5

0

EP14131211109876543210

-

4.0

-

3.5

-

3.0

-

2.5

-

2.0

-

1.5

-

1.0

-

0.5

0

Placebo

FFNS 110 g

European Grass (SAR) US Ragweed (SAR) US Mountain Cedar (SAR)

FFNS 110 g Placebo FFNS 110 g Placebo FFNS 110 g Placebo

Baseline mean daily rTOSS 5.4 5.3 6.6 6.5 6.6 6.5

LS mean change FFNS 110 g

vs placebo over 2-week

treatment period*

3.00

*P

Global (PAR)

FFNS 110 g Placebo

Baseline mean daily rTNSS 3.4 3.3

LS mean change FFNS 110 g

vs placebo over 2-week

treatment period*

1.85

*P

FUTURE TREATMENT OF AR

Soluble IL4 receptors

Inhibitors of chemokines : RANTES and eotaxin

Chemokine receptor inhibitors : ICAM 1

Recombinant allergens, peptide vaccines, IL12, plasmid DNA encoding of Ag

Conclusion

Allergic rhinitis is characterized by nasal inflammation which leads to congestion

Intranasal corticosteroids are first-line therapy when congestion is a major component of rhinitis

Persistent AR : should be evaluated for asthma

Patients with asthma should be appropriately evaluated for AR

Aim improve QOL by eliminating symptoms

WHO-ARIA & experts advise continuous treatment

Provides 24-hour efficacy

Good safety and tolerability profile

Fast onset of action

Comfortable and easy to use device