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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
Nina Irawati Allergy-Immunology Division ENT Department Fac of Medicine University of Indonesia/ Ciptomangunkusumo Hospital, JAKARTA
Allergic
Symptoms
of AR: detrimental effects on QOL, emotional wellbeing, sleep and daytime performance and productivity
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
Basophil
Chemotactic factors
Mast cell
Other Inflam. mediators
Monocyte
Lymphocyte
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.
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
Mucus secretion, vascular permeability Mast cell proliferation, eosinophil production/activation Inflammation, chemotaxis of leukocytes
6
Eosinophil
Sarin S, Undem B, Sanico A, Togias A. The Role of the Nervous System in Rhinitis. JACI 2006:118:999-1014
Persistent
AR : should be evaluated for asthma : medical history, chest examination, assessment of airflow obstr. Patients with asthma should be appropriately evaluated for AR
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
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
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.
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*
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)
If conjunctivitis
Add: Oral H1 blocker or intraocular H1 blocker or intraocular chromone (or saline)
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)
Oral Antihistamine
+/++
++
12-24 hrs
+++ ++++
+ ++
+++ + ++ +
A A A
Inflammation
Nasal Polyposis 1. Symptoms 2. Consequences
Corticosteroid
inflammation
APC Eosinophyls & products Basophyls & mast cells influx T cells IL 3,4,5,& 13 Histamine, tryptase, leukotrienes release
Ag
X LTC X
(LTD4, LTE4)
PAF
Mast cells
(and Basophils)
X X IL-3, X IL-5 X
IL-4, IL-13
TNF-, MIP-1
Late-Phase Response
Eosinophil
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
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
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
800/1
High selectivity
Selectivity of all compounds for androgen receptor >1700 and for oestrogen receptor >22,000
TNSS
Weight (%) 8.1 15.4 4.3 19.7 11.0 15.4 2.9 17.8 5.4 100
27
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
Placebo
FFNS 110 g
Global (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
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
1.5 2.0
2.5 3.0 3.5 4.0
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
Non-nose symptoms
Nose symptoms
Eye symptoms
Overall
Sleep
Emotional problems
Practical problems
Activities
1.5
2 2.5
* P<0.001
* *
* Global (PAR)
Placebo 3.3 1.21 151
1.85 *P<0.001
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