CURRICULUM VITAE Dr.

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 RHINITIS and

Nina Irawati Allergy-Immunology Division ENT Department Fac 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 <4 days per week Or <4 weeks Persistent 4 days per week And >4 weeks

Mild Normal sleep and No impairment of daily activities, sport, leisure Normal work and school No troublesome symptoms

Moderate-Severe 1 or more items Abnormal sleep Impairment of daily activities, sport, leisure Abnormal work and school Troublesome symptoms

ARIA = Allergic Rhinitis and its Impact on Asthma.

Bousquet et al. J Allergy Clin Immunol. 2001;108 (5 suppl):S147. Bousquet et al. Allergy. 2002;57:841.

Nasal Inflammation: An underlying mechanism in Allergic Rhinitis

Early-Phase Response Mast Cell Allergen
Histamine Proteases

Late-Phase Response Cellular Infiltration/Inflammation

Eosinophil

Basophil
Chemotactic factors

Mast cell
Other Inflam. mediators

Monocyte

Lymphocyte

Other Inflammatory Mediators

Nasal Mucosa in Patients with PAR

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.

Major Inflammatory Cells and Associated Mediators in Upper Respiratory Disease

Ag
Histamine (H1) Enzymes (eg, tryptase, chymase, etc.) PGD2 LTC4 (LTD4, LTE4) PAF TNF-, MIP-1

Vascular permeability, stimulates SMCs, itch Tissue damage/remodelling Vasodilation, neutrophil chemotaxis Mucus secretion, vascular permeability Chemotaxis/activation of leukocytes, vascular permeability Promote inflammation

Mast cells
(and Basophils)

IL-3, IL-5
IL-4, IL-13 Major basic protein, ECP Enzymes (eg, peroxidases, etc.) LTC4 (LTD4, LTE4) IL-3, IL-5, GM-CSF IL-8, IL-10, RANTES, MIP-1, eotaxin

Mast cell proliferation, eosinophil production/activation

TH2 differentiation Cell damage Tissue damage/remodelling

Mucus secretion, vascular permeability Mast cell proliferation, eosinophil production/activation Inflammation, chemotaxis of leukocytes
6

Eosinophil

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 & cost Medications 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 WHO-ARIA & experts advise continuous treatment

Control MPI Prevent the appearance of symptoms Continuous 2nd H1-antihistamines and INS : good clinical and safety profile

The most reasonable approach

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

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

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 Guidelines: Recommendations for Management of Allergic Rhinitis

Moderate severe intermittent Mild intermittent Mild persistent

Moderate severe persistent

Intra-nasal steroid
Local cromone
Leukotriene receptor antagonists

Second-generation nonsedating H1 antihistamine Intranasal decongestant (<10 days) or oral decongestant Allergen and irritant avoidance Immunotherapy
ARIA = Allergic Rhinitis and its Impact on Asthma.
Bousquet et al. J Allergy Clin Immunol. 2001;108 (5 suppl):S147.

Diagnosis of allergic rhinitis

Intermittent symptoms Persistent symptoms

Check for asthma especially in patients with severe and/or persistent rhinitis

Mild
Not in preferred order Oral H1 blocker or intranasal H1 blocker and/or decongestant or LTRA*

Moderate- Mild severe

Moderatesevere
In preferred order Intranasal CS H1 blocker or LTRA* Review the patient after 2-4 wks

Not in preferred order Oral H1 blocker or intranasal H1 blocker and/or decongestant or intranasal CS or LTRA* (or chromone)

Improved In persistent rhinitis review the patient after 2-4 wks If failure: step-up If improved: continue for 1 month Add or increase intranasal CS dose Step-down and continue treatment for >1 month

ALGORITHM FOR DIAGNOSIS AND MANAGEMENT OF ALLERGIC RHINITS ARIA UPDATE 2007
Blockage: add decongestant or oral CS (short term)

Failure Review diagnosis Review compliance Query infections or other causes

Rhinorrhea: add ipratropium

Failure: referral to specialist

Allergen and irritant avoidance may be appropriate

If conjunctivitis
Add: Oral H1 blocker or intraocular H1 blocker or intraocular chromone (or saline)

*In particular in patients with asthma.

Consider specific immunotherapy

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 A

Oral Antihistamine

+/++

++

12-24 hrs

Intra nasal Steroid Intranasal Decongestan

Intranasal Cromones Anticholinergic CysLTRA

+++ ++++
+ ++

+++ + ++ +

++/+++ -/+/+ -/-/-

12-48 hrs 3-6 hrs

2-6 hrs 4-12 hrs Not reported

A A A

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

INS: Anti-Inflammatory Effects

Allergic Rhinitis 1. Symptoms 2. Consequences 3. Co-morbidities

Rhinosinusitis 1. Symptoms 2. Consequences

Inflammation
Nasal Polyposis 1. Symptoms 2. Consequences

Adenoid Hypertrophy 1. Symptoms 2. Consequences

18

 Corticosteroid

inflammation

acts on many stages of

APC Eosinophyls & products Basophyls & mast cells influx T cells IL 3,4,5,& 13 Histamine, tryptase, leukotrienes release

INS Have Multiple AntiInflammatory Activities

Early-Phase Response
Histamine (H1)

Vascular permeability, stimulates SMCs

Ag

Enzymes (eg. Tryptase, Chymase, etc.) PGD2

4

Tissue damage/remodeling Vasodilation, neutrophil chemotaxis

X LTC X

(LTD4, LTE4)

Mucus secretion, vascular permeability

Chemotaxis/activation of leukocytes, vascular permeability Promote inflammation Mast cell proliferation, eosinophil production/activation TH2 differentiation

PAF

Mast cells
(and Basophils)

X X IL-3, X IL-5 X
IL-4, IL-13

TNF-, MIP-1

Late-Phase Response

Major basic protein, ECP Enzymes (eg. Peroxidases, etc.)

Cell damage Tissue damage/remodeling

LTC4 (LTD4, LTE4)

Mucus secretion, vascular permeability

Eosinophil

X X X IL-8, RANTES, X IL-10, X MIP-1 , eotaxin X X

IL-3, IL-5, GM-GSF

Mast cell proliferation, eosinophil production/activation

Inflammation, chemotaxis of leukocytes
20

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

INS: Improvement in Symptoms Associated With AR

22

Desired attributes for a new INS

Treats

bothersome nasal and ocular symptoms Strong affinity for the GR Provides 24-hour efficacy Highly 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 Short delivery nozzle and improved
overall ergonomic design

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

 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
Human steroid hormone receptor selectivity
0 Fluticasone furoate Fluticasone propionate Mometasone furoate Ciclesonide active principle Budesonide 1/1 Low selectivity Mineralocorticoid receptor Progesterone receptor-b 10 20 30 40 50 500 600 700 800 900

Selectivity for the GR

800/1
High selectivity

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.

TNSS Relief in AR: INS vs Oral Antihistamines

Study
Ghanno Bronsky Munch Schoenwetter Van Bavek Bernstein Beswick Vervloet Wood Total
-1.5 -1.0 -0.5 Favors INS 0 0.5 Favors antihistamine 1.0

TNSS

Weight (%) 8.1 15.4 4.3 19.7 11.0 15.4 2.9 17.8 5.4 100

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

27

Congestion Relief in AR: INS vs Intranasal Antihistamines

Nasal Blockage
Study
Weight SMD (95% CI)

Davies Ortolani Di Lorenzo Stern

Total

14.5 53.3 4.4 27.8

-1.87 -0.80 -0.67 -0.47

(-2.43, -1.31) (-1.10, -0.51) (-1.69, 0.34) (-0.87, -0.06) (-1.07, -

100.0 -0.86 0.64)

-4
-2 0 2 4

Favors INS

Favors antihistamine

INS included beclomethasone dipropionate, fluticasone propionate, and budesonide. Topical antihistamines included azelastine and levocabastine.
Yez and Rodrigo. Ann Allergy Asthma Immunol. 2002;89:479.
28

Global (PAR)
0 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7 14 21 28 35 42 EP 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 0

North American (PAR)

7 14 21 28 EP

Mean change in daily rTNSS

Placebo

FFNS 110 g

Global (PAR)

North American (PAR)

FFNS 110 g
8.8 3.95 *P<0.001 151

Placebo
8.5 2.69

FFNS 110 g
8.6 2.78 *P=0.005 149

Placebo
8.7 2.08

Baseline mean daily rTNSS LS mean change FFNS 110 g vs placebo over 2-week treatment period* Patients, n

151

153

Significant and consistent improvement of nasal symptoms

Ocular efficacy (rTOSS)

European Grass (SAR)
0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 EP 0 0.5 1.0 0 1 2

US Ragweed (SAR)
3 4 5 6 7 8 9 10 11 12 13 14 EP 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

US Mountain Cedar (SAR)

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 EP

Mean change in daily rTOSS

0.5 1.0 1.5 2.0 2.5 3.0 3.5

1.5 2.0
2.5 3.0 3.5 4.0

Placebo FFNS 110 g

4.0

European Grass (SAR) FFNS 110 g Baseline mean daily rTOSS LS mean change FFNS 110 g vs placebo over 2-week treatment period* Patients, n 5.4 3.00 *P<0.001 141 Placebo 5.3

US Ragweed (SAR) FFNS 110 g 6.6 2.23 *P=0.004 151 Placebo 6.5

US Mountain Cedar (SAR) FFNS 110 g 6.6 2.15 *P=0.008 152 Placebo 6.5

2.26
144

1.63
148

1.60
150

Proven and consistent efficacy for ocular symptoms

Non-nose symptoms

Nose symptoms

Eye symptoms

Overall

0 0.5 1 RQLQ score

Sleep

Emotional problems

Practical problems

Activities

Placebo FFNS 110 g data from Global PAR study

aGraph

1.5
2 2.5

* P<0.001

* *

* *FFNS * 110 g 3.4

* Global (PAR)
Placebo 3.3 1.21 151

Baseline mean daily rTNSS

LS mean change FFNS 110 g vs placebo over 2-week treatment period*

Patients, n

1.85 *P<0.001

151 Significant improvements in QoL

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