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an educational program of: Module 1: Allergic Rhinitis Updated: June 2011
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an educational program of:
Module 1: Allergic Rhinitis
Updated: June 2011
Global Resources in Allergy (GLORIA™)
Global Resources In Allergy (GLORIA™) is the flagship program of the World
Allergy Organization (WAO). Its curriculum educates medical
professionals worldwide through regional and national presentations. GLORIA modules are created from
established guidelines and recommendations to address different aspects of allergy-related patient care.
World Allergy Organization (WAO)
The World Allergy Organization is an international coalition of 89
regional and national allergy and clinical immunology societies.
WAO’s Mission
WAO’s mission is to be a global resource and advocate in the
field of allergy, advancing excellence in clinical care,
education, research and training through a world-wide alliance of allergy and clinical immunology
societies
Revised in 2007 by:
Omer Kalayci, MDAnkara, Turkey
Alkis Togias, MDBethesda, MD, USA
Module 1: Allergic Rhinitis
The full GLORIA Module on Allergic Rhinitis
consists of 105 slides.
The WAO GLORIA presenter will select slides
from this set for presentation today.
These slides will be available for
download foryour own teaching
at: www.worldallergy.org/gloria
GLORIA resource documents
• Allergic Rhinitis and Its Impact on Asthma (ARIA): JACI 2001:56: 813-824
• Contemporary Approaches to Ocular Allergy Management: American College of Allergy, Asthma and Immunology, 1998.
• Consensus Statement on the Treatment of Allergic Rhinitis. Allergy 2000: 55: 116-134
• World Allergy Forum program series: WAO 2000-2003
• Rhinitis: Symptomatic disorder of the nose characterized by itching, nasal discharge, sneezing and nasal airway obstruction
• Allergic rhinitis: Induction of rhinitis symptoms after allergen exposure by an IgE-mediated immune reaction; accompanied by inflammation of the nasal mucosa and nasal airway hyperreactivity.
Rhinitis phenotypes most common forms
• Allergic
• Infectious: Viral (acute), bacterial, fungal
• Non-Allergic, Non-Infectious, Rhinitis
• Non-Allergic Rhinitis with Eosinophilia
Syndrome (NARES)
• Chronic Rhinosinusitis with or without Polyps:
Hypertrophic, inflammatory disorder that can
affect allergic or non-allergic individuals
• Occupational: May be allergic or non-allergic
• Drug-induced: Aspirin, some vasodilators
• Hormonal: Pregnancy, menstruation, hormonal
contraceptives, thyroid disorders
• Food-induced (gustatory)
• Cold air-induced (skier’s nose)
• Atrophic (rhinitis of the elderly)
Rhinitis phenotypes less common forms
• Cystic fibrosis
• Mucociliary defects
• Cerebrospinal rhinorrhoea
• Anatomic abnormalities
• Foreign bodies
• Tumors
• Granulomas: Sarcoid, Wegener’s, Midline
Granuloma
Conditions that mimic rhinitis
Non-allergic, non-infectious rhinitis
(a poorly-defined phenotype)
Pathophysiologic hypotheses
• Non-inflammatory (vasomotor)– Sensorineural hyperresponsiveness– Hyperesthesia– Dysautonomia
• Local allergic reaction
Non-inflammatory rhinitis
0
0.25
0.5
0.75
1
HealthyControlsN = 25
AllergicRhinitisN = 25
Non-allergicRhinitisN = 18
Numata T et al:Int Arch Allergy Immunol 1999;119:304-313S. Karger AG, Basel
*
Ratio ofeosinophi
ls/epithelial
cellsin
mucosalscrapings
Local allergic reaction(nasal challenges with allergen in non-allergic rhinitics)
Carney et al. Clin Exp Allergy 2002;32:1436
Copyright permission for reproduction pending
Cameron et al J Immunol 2003;171:3816
In situ hybridization for I mRNA - tissue obtained from subjects with alleric rhinitis
I RNA+ cells(germline transcript)
Not exposed toragweed
Exposed toragweed
IgE can be produced in the nasal mucosa
Prevalence of rhinitis in adults
30.5%United States
12,74212-741991Turkeltaub
24%United
Kingdom2,96916-651991Sibbald
27.7%Turkey99520-442005Dinmezel
39.3%Belgium4,959> 152006Bachert
10.8%Singapore2,86820-741994Ng
35.5%Japan2,30719-65
(males)1998Sakurai
29.5%Netherland
s2,16720-701996Droste
PREVALENCE
COUNTRYNUMBER
OF SUBJECTS
AGE RANGEYEARAUTHOR
0 25 50 75 100
Seasonal symptomsor
Diagnosis of “hay fever”(9.8%)
Perennial symptomsand no
Diagnosis of “hay fever”(20.4%)
12-2425-49
50-74
12-2425-49
50-74
AGEPositive skin testsNegative (or equivocal) skin tests
Allergic vs. nonallergic rhinitisN = 10,854; >12 years old; NHANES II data (USA, 1976-80)
% of subjects in each group
Adapted from Gergen and Turkeltaub Arch Int Med 1991;151:487Copyright © 1991, American Medical Association
Current Prevalence of Allergic Rhinoconjunctivitis
ISAAC phase 1 & 3 (7 years apart) Age: 6-7 years
Adapted from Lancet 2006;368:733-743
Copyright permission for reproduction pending
Current Prevalence of Allergic Rhinoconjunctivitis
ISAAC phase 1 & 3 (7 years apart) Age: 13-14 years
Adapted from Lancet 2006;368:733-743
Copyright permission for reproduction pending
Allergic rhinitis: impact
• High prevalence
• Impaired quality of life
• Work and school absence
• Impaired learning
• Impaired sleeping
• Associated asthma, sinusitis, otitis
Adapted from Meltzer EO et al. J Allergy Clin Immunol. 1997;99:S815
Short form health survey (SF-36)
profiles of patients with allergic rhinitis
*
*
*
*
**
50
55
60
65
70
75
80
85
90
PhysicalFunctioning
Role– Physical
Bodily Pain
GeneralHealth
Vitality Social
Functioning
Role– Emotional
MentalHealth
Change inHealth
allergic rhinitis (n=312)
controls (n=139)
†
Declininghealthstatus
Domains
scale: 0 to 100
Impairment due to allergic rhinitis:
work productivity and activity impairment questionnaire
Tanner LA et al. Am J Managed Care 1999;5(Suppl):S235
Copyright permission for reproduction pending
Allergic rhinitis co-morbidities
• Conjunctivitis
• Sinusitis
• Otitis Media
• Cough
• Asthma
0
5
10
15
20
25
30
35
40
45
% with conjunctivitis
All rhinitisn=316
Asthma n= 324
Eczema n=149
All rhinitis + asthma n=203
Co-existence of allergic conjunctivitis with other
allergic diseasesp=0.006
Adapted from Gradman J and Wolthers OD Pediatr Allergy Immunol. 2006;17:524-6
Berrettini et al., Allergy. 1999;54:242-8.
Presence of sinus disease based on CT findings in
patients with allergic rhinitis and controls
67.5%
33.4%
0
5
10
15
20
25
30
35
40
Number of subjects
Allergic rhinitis Controls
Total With positive sinus CT
p=0.017
Allergic rhinitis as a risk factor for chronic sinusitis
Ear Nose Throat-related flight disqualifying events that developed over a 5-year period in Naval Flight Personnel with
only allergic rhinitis (N=465) versus controls (N=12,628)
Walker C. et al. Aviat Space Environ Med. 1998; 69:952
Relative Risk 95% CI
Chonic Sinusitis 4.5 (1.7-11.6)
Alternobaric Disease
1.6 (0.4-6.6)
Polyposis 1.2 (0.2-8.7)
Conductive Hearing Loss
0.9 (0.1-6.6)
Requirement for ENT Surgery
3.4 (0.4-27.1)
Allergic rhinitis: the basis of co-morbidity with otitis media
with effusion
Adapted from Sobotta, Atlas der Anatomie des Menschen. Bd. 1, 21; 2000.
Copyright permission for reproduction pending
Adapted form Caffarelli et al., Clin Exp Allergy 1998;28:591-596
Risk factors for otitis media in children
O: otitis media with effusion (N=172) C: controls (N=200 )
Copyright permission for reproduction pending
Multivariate logistic regression for risk of OMECase-control study in children 1-7 years (N=88 cases, N=88 controls)
Chantzi FM et al. Allergy 2006;61:332
Risk factors for otitis media in children
Adapted from Gawchik S et al. Ann Allergy Asthma Immunol 2003;90:416
Nasal treatment improves coughin patients with seasonal allergic
rhinitis(15-day treatment)
1.0
0.8
0.6
0.4
0.2
0.0
*
Mean improvement from baselinein the cough
symptom score
Placebo, N=123
Mometasone, N=122
Mean baseline score: 2.3
ALLERGIC RHINITIS AND ITS IMPACT ON ASTHMA
ARIA
JACI 2001:56: 813-824
Perennial rhinitis: an independent risk factor for
asthma(European Community Respiratory Health Survey)
Adapted from Leynaert B et al. J Allergy Clin Immunol 1999; 104:301
Asthma (%)
Atopic Non atopic
no rhinitis, N=5198
rhinitis, N=1412
OR=11
OR=17
0
5
10
15
20
25
none
inco
nsis
tent
pers
iste
nt
rhinitis
none
mild
mod
erat
ese
vere
odds ratiofor the
associationwith asthma
1
3
6
9
Guerra S et al. J Allergy Clin Immunol 2002;109:419
Test for trend, p < 0.001 Test for trend, p < 0.001
Association of rhinitis with incident asthma
in an adult cohort(173 incident cases and 2,177 controls; approx. 10-yr follow-up)
In patients with rhinitis:
• Routinely query for symptoms suggestive of asthma
• Perform chest examination
• Consider lung function testing
• Consider tests for bronchial hyperresponsiveness in selected cases
Intermittent Symptoms• < 4 days / week• or < 4 weeks
Persistent Symptoms• > 4 days / week• or > 4 weeks
Mild• Sleep: normal• Daily activities (incl. sports): normal• Work-school activities: normal• Severe symptoms: no
Moderate- severe• Sleep: disturbed• Daily activities: Restricted• Work and school activities: disrupted• Severe symptoms: yes
Allergic rhinitis classification
Seasonal allergic rhinitis ≠ intermittent
perennial allergic rhinitis ≠ persistent
Intermittent
Persistent
SeasonalAllergic
Rhinitis (n=193)133 60
PerennialAllergic
Rhinitis (n=208)151 57
Bauchau, V. & Durham, S. R. Allergy 2005; 60 (3), 350-353.
Globally important sources of allergens
• House dust mites
• Grass, tree and weed pollen
• Pets• Cockroaches• Molds
Diagnosis of allergic rhinitis
• Detailed personal and family allergic history
• Intranasal examination – anterior rhinoscopy
• Symptoms of other allergic diseases• Allergy skin tests and/or
• In vitro specific IgE tests
Allergy skin prick testing
Skin prick test / positive result
Primary Ab
Secondary Ab
Enzyme
Sample to be measured
Substrate
Concept of In Vitro IgE assays
In Vitro specific IgE assay (standard curve)
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
0 200 400 600 800 1000 1200
IgE IU/ml
spec
troph
otom
etric
out
com
e (O
D)
Immunoassay• Not influenced by
medication• Not influenced by
skin disease• Does not require
expertise• Quality control
possible• Expensive
Skin test• Higher sensitivity• Immediate results• Requires expertise• Cheaper
Immunoassay vs skin test for diagnosis of allergy
Other diagnostic tests
• Nasal secretion / scraping cytology• Nasal allergen challenge• Nasal endoscopy • CT scan
– anatomic abnormalities – concomitant presence of sinusitis
Endothelialcell activation
Leukocyteinfiltration and
activation(lymphocytes, eosinophils,
basophils)
IMMEDIATE (early)RESPONSE
LATE-PHASERESPONSES
preformed &newly formed
mediators/cytokines
mast cell
SneezingPruritusRhinorrheaNasal obstructionOcular symptoms
Nasal obstructionRhinorrhea
Nasal hyperresponsivene
ss
To allergens(priming)
To irritants and to
atmospheric changes
IgE
allergen
dendritic cell
T-lymphocyte
cytokineschemokines
allergen
B-lymphocyte
IgE
IL-4IL-13
The nasal allergic response
brain
SNEEZING
PRURITUS
RHINORRHEA
OBSTRUCTION
sensorynerves
epithelium
glands (mucous)blood vessels
histamine
sulfidopeptide leukotrienes
The immediate (early phase) allergic reaction in the nose
Cellular infiltration and activation at the site of an allergic reaction
Busse WW, Lemanske RF Jr. N Engl J Med. 2001;344:350-62.
Sanico AM et al:Int Arch Allergy Immunol 1999;118:154-158S. Karger AG, Basel
0
1
2
3
4
5
6
7
Sneezesinduced byhistamine*
Perennial AllergicRhinitis
Healthy
N = 25
N = 18
p<0.0001
* same dose in both groups
Nasal hyperresponsiveness in allergic rhinitis
Nasal priming in the naturalpresentation of seasonal allergic rhinitis
Norman P. J Allergy 1969;44:129
The ratio of symptoms to pollen counts almost
doubles between the beginning to the endof the pollen season
MANAGEMENT OF
ALLERGIC RHINITIS
mildintermittent
mildpersistentmoderate
severeintermittent
moderatesevere
persistent
avoidance of allergens, irritant and pollutants
immunotherapy
intranasal decongestant (<10 days) or oral decongestant
intranasal steroid
oral or local nonsedative H1-blocker
Management of Allergic Rhinitis: ARIA
Guidelines
Modified from Bousquet J et al. J Allergy Clin Immunol. 2001;108:S147.
leukotriene receptor antagonists
Stepwise management of allergic rhinitis
Modified from ARIA workshop, 2001
Copyright permission for reproduction pending
Environmental control
• House dust mites• Pets• Cockroaches• Molds• Pollen
1. Allergens
2. Pollutants and Irritants
Allergen avoidance• Pets
• Remove pets from bedrooms and, even better, from the entire home
• Vacuum carpets, mattresses and upholstery regularly
• Wash pets regularly (±)
• Molds
• Ensure dry indoor conditions
• Use ammonia to remove mold from bathrooms and other wet spaces
• Cockroaches
• Eradicate cockroaches with appropriate gel-type, non-volatile, insecticides
• Eliminate dampness, cracks in floors, ceilings, cover food; wash surfaces, fabrics to remove allergen
• Pollen
• Remain indoors with windows closed at peak pollen times
• Wear sunglasses
• Use air-conditioning, where possible
• Install car pollen filter
House dust mite allergen avoidance – Provide adequate ventilation to decrease humidity
– Wash bedding regularly at 60°C
– Encase pillow, mattress and quilt in allergen
impermeable covers
– Use vacuum cleaner with HEPA filter
– Dispose of feather bedding
– Remove carpets
– Remove curtains, pets and stuffed toys from
bedroom
2003;349:237
Bed covers in persistent allergic rhinitis
Terreehorst et al. N Engl J Med. 2003;349:237
Der p1 and Der f1 in mattress (µg/g of dust)
No. of patients 79 87
Base-line concentration
4.12 (2.93-5.79)
5.91 (4.00-8.73)
0.18
12-Mo concentration
1.29 (0.95-1.75)
4.84 (3.62-6.47)
<0.001
Mean change (95%Cl) P value
.31 (0.21 to 0.46)
<0.001
0.82 (0.58 to 1.15)
0.25
Difference between changes (95%Cl)§
0.38 (0.23 to 0.64)
<0.001
Bed covers in persistent allergic rhinitis
Terreehorst et al. N Engl J Med. 2003;349:237
Variable
Primary end pointRhinitis-spcific visual-analogue scale
Impermeable-Cover Group
Control Group P Valu
e
No. of patients 114 118
Base-line score 52.18+2.79 49.82+2.76 0.56
12-Mo score 42.35+2.79 38.96+2.68 0.38
Mean change (95%Cl) P value
-9.83 (-15.28 to-4.39)
<0.001
-10.86 (-16.64 to-5.09)
<0.001
Difference between changes (95%Cl)
1.03 (-6.87 to 8.94) 0.80
2004;351:1068-80
937 subjects randomized
469 assigned to environmental
intervention
468 assigned to control
444 included in Year 2 analyses
407 included inYear 2 analyses
425 included in Year 1 analyses
414 included inYear 2 analyses
Adapted from Morgan WJ et al. New Engl J Med 2004;351:1068-80
Environmental intervention in urban US children with asthma
Environmental intervention in urban US children with
asthma
• Tailored to• Skin test profile• Environmental
exposure• Caretaker’s report
• House dust mite• Passive smoking
Adapted from Morgan WJ et al. New Engl J Med 2004;351:1068-80
• Cockroaches• Pets• Rodents• Mold
Morgan WJ et al. New Engl J Med 2004;351:1068-80
Environmental intervention in urban US children with
asthma
The difference between treatment arms wasstatistically significant (p<0.001) in bothphases of the study
Environmental control
• The most logical strategy for disease that relates to the indoor environment
• Effectiveness requires comprehensive and multifaceted measures
• More studies are needed to also address the role of indoor pollutants (e.g. NO2, PMs, tobacco smoke, endotoxin)
PHARMACOTHERAPY
OF
ALLERGIC RHINITIS
Modified from van Cauwenberge P Allergy 2000;55:116-134
Agents and actionsOral
antihistamines
Nasal antihistamines
Cys-LT1 receptor antagoni
sts
Nasal steroids
Nasal decongestants
Oral decongestants
Nasal ipratropi
um
Nasal cromon
es
Rhinorrhea + + ++ ++ +++ 0 0 +++ +
Congestion + + + +++ ++++ ++ 0 +
Sneezing ++ ++ ++ +++ 0 0 0 +
Pruritus ++ ++ + +++ 0 0 0 +
Ocular symptoms ++ 0 ++ ++ 0 0 0 0
Onset of action 1 hr 15 min 48 hr 12 hr
5-15 min
1 hr15-30 min
-
Duration12-24
hr6-12 hr 24 hr
12-48 hr
3-6 hr12-24
hr4-12 hr 2-6 hr
Oral antihistamines
• First generation
agents
Chlorpheniramine
Brompheniramine
Diphenydramine
Promethazine
Tripolidine
Hydroxyzine
Azatadine
• Newer agents
Acrivastine
Azelastine
Cetirizine
Desloratadine
Fexofenadine
Levocetirizine
Loratadine
Mizolastine
Nasal antihistamines
• Azelastine
• Levocabastine
• Olopatadine
Simons, F. E. R. N Engl J Med 2004;351:2203
Simplified two-state model of the histamine H1-receptor
Copyright permission for reproduction pending
Bachert C et al. J Allergy Clin Immunol 2004:114:838
Efficacy of an antihistamine over 6 months inpersistent allergic rhinitis
Sneezing Rhinorrhea Pruritus Nose Pruritus Eyes Congestion
*
*
*
*
*
*
*
*
*
*
*
*
*
1.0
0.8
0.6
0.4
0.2
01 wk
4 wk6 mo 1 wk
4 wk6 mo 1 wk
4 wk6 mo 1 wk
4 wk6 mo 1 wk
4 wk6 mo
meanIndividualsymptom
scoreimprovement
* P<0.05
Levocetirizine, 5 mg, N = 276Placebo, N = 271
Baseline total symptom score: 8.95
Efficacy of an antihistamine in the treatment of allergic rhinitis with perennial symptoms
(n= 337)(n= 339)
Simons FER et al., J Allergy Clin Immunol 2003;111:617
PlaceboN =201
Fexofenadine 120 mgN =211
Fexofenadine 180 mgN =202
Cetirizine 10 mgN =207
** *
Change frombaseline in
total symptomscore
(AM, instantaneous,trough)
0
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
Newer antihistamines are equally effectivein the treatment of allergic rhinitis
Howarth P et al. J Allergy Clin Immunol 1999;104:927
*: <0.05 compared to placeboBaseline symptomsStudy duration
Storms WW et al. Ear Nose Throat J. 1994;73:382.
Effectiveness of a nasal antihistamine in allergic
rhinitis with seasonal symptoms
Copyright permission for reproduction pending
Newer generation oral antihistaminessomnolence/drowsiness
Active Placebo Data Source
Cetirizine10 mg qd
13.7% 6.3% www.PDR.net
Desloratadine
5 mg qd2.1% 1.8% www.PDR.net
Fexofenadine
60 mg bid1.3% 0.9% www.PDR.net
Levocetirizine
5 mg qd6.8% 1.8%
Bachert et alJACI
2004;114:838
Loratadine10 mg qd
8% 6% www.PDR.net
• First line treatment for mild allergic rhinitis
• Effective for– Rhinorrhea– Nasal pruritus– Sneezing
• Less effective for– Nasal blockage
• Possible additional anti-allergic and anti-inflammatory effect • In-vitro effect > in-vivo effect
• Minimal or no sedative effects
• Once daily administration
• Rapid onset and 24 hour duration of action
Newer generation oral antihistamines
Decongestants: alpha-2 adrenergic agonists
• Oral
Pseudoephedrine
• Nasal
Phenylephrine
Oxymetazoline
Xylometazoline
vasoconstriction
Decongestants: alpha-2 adrenergic agonists
nasal airway lumen
nasalturbinates
nasal septum
Effect of a nasal decongestant under MRI imaging
Adapted from Ng BA et al. Ear, Nose and Throat J 1999;78:159
Copyright permission for reproduction pending
0.0
1.0
0.8
0.6
0.4
0.2
Day 4 Endpoint Overall(15 days)
Pseudoephedrine 120 mg twice daily, N=211
Placebo, N=212
Mean reductionin “nasal stuffiness”
score from baseline
*
*
*
Adapted from Bronsky E. et al. J Allergy Clin Immunol 1995;96:139
Efficacy of pseudoephedrine in
seasonal allergic rhinitis
0.5
0.9
1.3
1.7
2.1
0 2 4 6 8 10 12 14 16 18 20 21
Day
Nasal obstruction
severity score
(scale: 0-3)
Cetirizine 5mg twice daily, N=70
Pseudoephedrine 120 mg twice daily , N=70
Combination, N=70
Bertrand et al. Rhinology 1996;34:91
Nasal obstruction: antihistamine vs decongestant vs vombination in allergic
rhinitis with perennial symptoms
DecongestantsEFFICACY:
• Oral decongestants: moderate
• Nasal decongestants: high
ADVERSE EFFECTS:
• Oral decongestants: insomnia, tachycardia,
hyperkinesia
tremor, increased blood pressure, stroke (?)
• Nasal decongestants: tachyphylaxis, rebound
congestion, nasal
hyperresponsiveness, rhinitis medicamentosa
Mechanism of action of ipratropium bromide
brain
RHINORRHEA
sensorynerves
epithelium
submucosal glands
vidian nerve
Acetylcholineon
muscarinic receptors
X
X
direct effect of mediators: not cholinergic
indirect effect: cholinergic
Adapted from Meltzer E at al. J Allergy Clin Immunol 1992;90:242
Efficacy of ipratropium bromide againstrhinorrhea in allergic rhinitis with perennial symptoms
6.0 3.0
5.0
4.0
3.0
2.0
1.0
0
2.5
2.0
1.5
1.0
0.5
0
**
**
* **
Mean SeverityScore
(scale: 0-5)
Mean Duration (hours/day)
Baseline Wk 4Wk 1 Wk 2 Wk 3 Baseline Wk 4Wk 1 Wk 2 Wk 3
Placebo, N=42
Ipratropium, 42 µg/nostril three times daily, N=42
Ipratropium, 21 µg/nostril three times daily, N=39
* p<0.05 against Placebo
Anticholinergic treatment: ipratropium bromide
• Nasal glands are activated by muscarinic, cholinergic
receptors
• Ipratropium bromide is a nonselective muscarinic
receptor antagonist
• Ipratropium bromide applied intranasally blocks
rhinorrhea induced by
cholinergic stimulation
• Ipratropium bromide has negligent systemic
anticholinergic activity
• Topical adverse effects: excessive dryness, epistaxis
Anti-leukotriene agents
CysLT1 Receptor
Antagonists
Montelukast *
Pranlukast *
Zafirlukast
5-Lipoxygenase
Inhibitors
Zileuton
* Approved for allergic rhinitis
nucleus
cytosolicphospholipase A2
arachidonicacid
5-lipoxygenaseactivating
protein
leukotriene A4
5-lipoxygenase leukotriene C4
synthase
leukotriene C4
leukotriene C4
leukotriene D4
leukotriene E4
CysLT1receptor
mast cellsbasophilseosinophilsmacrophages
+
Cysteinyl-leukotriene production and the CysLT1
receptor
Daytime Nasal Symptoms Score (0-3 point scale)
-0.6
-0.4
-0.2
0
Adapted from Nayak, et al. Ann Allergy Asthma Immunol. 2002;88: 592
Change frombaseline
(mean, 95% CI)
mean baseline=2.0
* *placebo, N=149
montelukast, N=155
loratadine, N=301*p<0.01 vs placebo
Efficacy of a CysLT1 receptor antagonistin allergic rhinitis with seasonal symptoms
0
10
20
30
40
50
60
70
% ofsubjects
* **
*
Adapted from Meltzer EO, et al. J Allergy Clin Immunol. 2000;105:917
Additive effects of CysLT1 receptor antagonists and H1 receptor antagonists in allergic rhinitis ?
improvement no change worsening
placebo montelukast10 mg
montelukast20 mg
loratadine10 mg
montelukast10 mg
+loratadine
10 mg
150
160
170
180
190
200
210
220
230
B 1 2 3 4 5 6 7 8 9 10 11 12
Liters/min
Fexofenadine/Pseudoephedrine, N = 34
Loratadine/Montelukast, N = 34
Treatment Days
Equipotency of CysLT1 receptor antagonist/antihistamine and decongestant/antihistamine
on nasal peak inspiratory flow
Adapted from Moinuddin R et al. Ann Allergy Asthma Immunol 2004;92:73
Anti-leukotriene treatment in allergic rhinitis
Efficacy
• Equipotent to H1 receptor antagonists but with onset of action after 2 days
• Reduce nasal and systemic eosinophilia• May be used for simultaneous treatment of
allergic rhinitis and asthma
Safety
• Dyspepsia (approx. 2%)
Nasal vorticosteroids Beclomethasone dipropionate
Budesonide
Ciclesonide*
Flunisolide
Fluticasone propionate
Mometasone furoate
Triamcinolone acetonide
* Currently only approved for asthma
Molecular effects of corticosteroids
Adapted from Barnes PJ. Eur J Pharmacol. 2006;533:2
Copyright permission for reproduction pending
Nasal corticosteroids
reduction ofsymptoms and exacerbations
reduction ofmucosal inflammation
reduction oflate phase reactions
primingnasal hyperresponsiveness
1
reduction ofmucosal mast cells
reduction ofacute allergic reactions
2
• suppression ofglandular activityand vascular leakage• induction ofvasoconstriction
3
Meltzer E. et al. J Allergy Clin Immunol. 1999;104:107.
Efficacy of nasal corticosteroid sprays in children with allergic rhinitis and seasonal symptoms
Onset of action of intranasal budesonide Against allergen
exposure(controlled environmental exposure - peak nasal
inspiratory flow)
Day JH. et al. J Allergy Clin Immunol. 2000;105:489.
Mandl M. et al. Ann Allergy Asthma Immunol 1997;79:370
Comparative efficacy of nasal corticosteroids
Adapted from Di Lorenzo et al. Clin Exp Allergy 2004;934:259
Various treatment combinations in seasonal allergic rhinitisNasal congestion score, Scale: 0-3
Copyright permission for reproduction pending
Adapted from Di Lorenzo et al. Clin Exp Allergy 2004;934:259
Various treatment combinations in
seasonal allergic rhinitistotal symptom score
Scale: 0-12Copyright permission for
reproduction pending
Nasal corticosteroids
• Most potent anti-inflammatory agents
• Effective in treatment of all nasal symptoms including obstruction
• Superior to anti-histamines and anti-leukotienes
• First line pharmacotherapy for persistent allergic rhinitis
Nasal corticosteroids
• Overall safe to use
• Adverse Effects– Nasal irritation– Epistaxis– Septal perforation (extremely rare)– HPA axis suppression (inconsistent and not
clinically significant)– Suppressed growth (only in one study with
beclomethasone)
Adapted from Galant, S. P. et al. Pediatrics 2003;112:96
Nasal corticosteroid vs placebo: effects on 12-hour urinary free Cortisol in 2-3
year-old children6-week treatment
0.98SE=1.14
N=31
0.94SE=1.15
N=29
Adjusted Geometric Meanof the Change from Baseline
1.0
0.8
0.6
0.4
0.2
0FluticasoneProprionateNasal Spray200 µg daily
Placebo
Value of 1 indicatesno change from baseline
Allergen immunotherapy (vaccines)
• Subcutaneous
• Sublingual
• Nasal
DCTh0-
lymphocyte
Treg-lymphocyte
Possible mechanisms of immune response regulation by allergen
immunotherapy
Th1
Th2
Possible mechanism: allergen immunotherapy induces regulatory T-lymphocytes
TH2lymphocyte
Treg
lymphocyte
Blymphocyte
interleukin 10TGF
interleukin 10TGF
IgG4
Subcutaneous immunotherapy: effect on serum specific IgE
10
20
30
40
50
60
70
Anti - ragweedIgE
(ng/ml)
Initiation ofimmunotherapy
AugustNovember
baseline year 1 year 2 year 6 year 7 year 8
Adapted from: Peng et al. J Allergy Clin Immunol 1992;89:519
Long-term efficacy of subcutaneous immunotherapy
Durham et al. N Eng J Med 1999;341:468
Copyright permission for reproduction pending
Dahl R et al., J Allergy Clin Immunol. 2006;118:434.
Sublingual immunotherapy in grass pollen-induced allergic rhinitis
Need:Overall p value Treatment: grass allergen
tabletsDose?Frequency?Started how long before season?
SLIT, N=316Placebo, N=318
Omalizumab
IgE
Humanized monoclonalanti-IgE antibody:
omalizumab
C3region
Placebo, N=136
Omalizumab
50mg, N=137 150mg, N=134 300mg. N=129
Efficacy of omalizumab in seasonal allergic rhinitis
(ragweed pollen season)
Averageweekly
symptomscore
4 13 20 27 3Aug
10 17 24 1Sep Oct
8 15 22 29
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
Casale T, et al. JAMA 2001;286:2956Copyright © 2001 American Medical Association. All Rights reserved
• SQ treatments every 3-4 weeks x 3-4• First dose prior to the pollen season
Omalizumab and subcutaneous immunotherapy in children: study
design
Week 0 Week 12 Week 36
SIT titration SIT maintenance + study drug
Prescreening
SIT (grass) + omalizumab
SIT (birch) + omalizumab
SIT (birch) + placebo
SIT (grass) + placebo
n = 55
n = 54
n = 59
n = 53
Randomization
Kuehr J et al. J Allergy Clin Immunol 2002;109:274
Omalizumab and subcutaneous immunotherapy in children:
symptom load (rescue medications + symptom severity scores)
grass pollen season
Kuehr J et al. J Allergy Clin Immunol 2002;109:274
Copyright permission for reproduction pending
Anti IgE - omalizumab
• Not licensed to treat allergic rhinitis
• Could be considered in severe cases
unresponsive to conventional treatment
• Could be an adjunct to immunotherapy in
severe cases
World Allergy Organization (WAO)For more information on the World Allergy
Organization (WAO), please visit www.worldallery.org or contact the:
WAO Secretariat555 East Wells Street, Suite 1100
Milwaukee, WI 53202United States
Tel: +1 414 276 1791Fax: +1 414 276 3349
Email: [email protected]
