Transcript Slide 1

Module 1:
Allergic Rhinitis
an educational program of:
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.
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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
Module 1: Allergic Rhinitis
Revised in 2007 by:
Omer Kalayci, MD
Ankara, Turkey
Alkis Togias, MD
Bethesda, MD, USA
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 for
your 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
Rhinitis phenotypes
less common forms
• 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)
Conditions that mimic rhinitis
• Cystic fibrosis
• Mucociliary defects
• Cerebrospinal rhinorrhoea
• Anatomic abnormalities
• Foreign bodies
• Tumors
• Granulomas: Sarcoid, Wegener’s, Midline Granuloma
Non-allergic,
non-infectious rhinitis
(a poorly-defined phenotype)
Pathophysiologic hypotheses
• Non-inflammatory (vasomotor)
– Sensorineural hyperresponsiveness
– Hyperesthesia
– Dysautonomia
• Local allergic reaction
Non-inflammatory rhinitis
1
*
0.75
Ratio of
eosinophils/
epithelial
cells
in mucosal
scrapings
0.5
0.25
0
Healthy
Controls
N = 25
Numata T et al:Int Arch Allergy Immunol 1999;119:304-313
S. Karger AG, Basel
Non-allergic
Rhinitis
N = 18
Allergic
Rhinitis
N = 25
Local allergic reaction
(nasal challenges with allergen in non-allergic rhinitics)
Copyright permission for reproduction pending
Carney et al. Clin Exp Allergy 2002;32:1436
IgE can be produced in the nasal mucosa
In situ hybridization for I mRNA - tissue obtained from subjects with alleric rhinitis
Not exposed to
ragweed
I RNA+ cells
(germline
transcript)
Cameron et al J Immunol 2003;171:3816
Exposed to
ragweed
Prevalence of rhinitis in adults
AUTHOR
YEAR
AGE RANGE
NUMBER OF
SUBJECTS
COUNTRY
PREVALENCE
Droste
1996
20-70
2,167
Netherlands
29.5%
Sakurai
1998
19-65 (males)
2,307
Japan
35.5%
Ng
1994
20-74
2,868
Singapore
10.8%
Bachert
2006
> 15
4,959
Belgium
39.3%
Dinmezel
2005
20-44
995
Turkey
27.7%
Sibbald
1991
16-65
2,969
United
Kingdom
24%
Turkeltaub
1991
12-74
12,742
United States
30.5%
Allergic vs. nonallergic rhinitis
N = 10,854; >12 years old; NHANES II data (USA, 1976-80)
Positive skin tests
AGE
Seasonal symptoms
or
Diagnosis of “hay fever”
(9.8%)
12-24
25-49
Perennial symptoms
and no
Diagnosis of “hay fever”
(20.4%)
12-24
25-49
Negative (or equivocal) skin tests
50-74
50-74
0
25
Adapted from Gergen and Turkeltaub Arch Int Med 1991;151:487
Copyright © 1991, American Medical Association
50
75
% of subjects in each group
100
Current Prevalence of Allergic
Rhinoconjunctivitis
ISAAC phase 1 & 3 (7 years apart)
Age: 6-7 years
Copyright permission for reproduction pending
Adapted from Lancet 2006;368:733-743
Current Prevalence of Allergic
Rhinoconjunctivitis
ISAAC phase 1 & 3 (7 years apart)
Age: 13-14 years
Copyright permission for reproduction pending
Adapted from Lancet 2006;368:733-743
Allergic rhinitis: impact
•
•
•
•
•
•
High prevalence
Impaired quality of life
Work and school absence
Impaired learning
Impaired sleeping
Associated asthma, sinusitis, otitis
Short form health survey (SF-36)
profiles of patients with allergic rhinitis
controls (n=139)
90
allergic rhinitis (n=312)
85
*
†
scale: 0 to 100
80
Declining
health
status
*
75
*
70
*
*
65
60
*
55
50
Physical
Functioning
Role–
Physical
Bodily
Pain
General
Health
Vitality
Domains
Adapted from Meltzer EO et al. J Allergy Clin Immunol. 1997;99:S815
Social
Functioning
Role–
Emotional
Mental
Health
Change in
Health
Impairment due to allergic rhinitis:
work productivity and activity impairment questionnaire
Copyright permission for reproduction pending
Tanner LA et al. Am J Managed Care 1999;5(Suppl):S235
Allergic rhinitis co-morbidities
•
•
•
•
•
Conjunctivitis
Sinusitis
Otitis Media
Cough
Asthma
Co-existence of allergic conjunctivitis
with other allergic diseases
p=0.006
45
40
35
30
% with
conjunctivitis
25
20
15
10
5
0
All rhinitis
n=316
Asthma
n= 324
Eczema
n=149
Adapted from Gradman J and Wolthers OD Pediatr Allergy Immunol. 2006;17:524-6
All rhinitis + asthma
n=203
Presence of sinus disease based on CT findings in
patients with allergic rhinitis and controls
Total
With positive sinus CT
40
p=0.017
35
30
25
Number of subjects
67.5%
20
15
10
33.4%
5
0
Allergic rhinitis
Berrettini et al., Allergy. 1999;54:242-8.
Controls
Allergic rhinitis as a risk factor for chronic sinusitis
Ear Nose Throat-related flight disqualifying events that developed over a 5year period in Naval Flight Personnel with only allergic rhinitis (N=465)
versus controls (N=12,628)
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)
Walker C. et al. Aviat Space Environ Med. 1998; 69:952
Allergic rhinitis: the basis of
co-morbidity with otitis media
with effusion
Copyright permission for reproduction pending
Adapted from Sobotta, Atlas der Anatomie des Menschen. Bd. 1, 21; 2000.
Risk factors for otitis media in children
O: otitis media with effusion (N=172)
C: controls (N=200 )
Copyright permission for reproduction pending
Adapted form Caffarelli et al., Clin Exp Allergy 1998;28:591-596
Risk factors for otitis media in children
Multivariate logistic regression for risk of OME
Case-control study in children 1-7 years (N=88 cases, N=88 controls)
Chantzi FM et al. Allergy 2006;61:332
Nasal treatment improves cough
in patients with seasonal allergic rhinitis
(15-day treatment)
1.0
0.8
Mean improvement
from baseline
in the cough
symptom score
0.6
0.4
0.2
0.0
Adapted from Gawchik S et al. Ann Allergy Asthma Immunol 2003;90:416
*
Mean baseline score: 2.3
Mometasone, N=122
Placebo, N=123
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)
25
20
OR=11
no rhinitis, N=5198
rhinitis, N=1412
15
Asthma (%)
OR=17
10
5
0
Atopic
Adapted from Leynaert B et al. J Allergy Clin Immunol 1999; 104:301
Non atopic
Association of rhinitis with incident asthma
in an adult cohort
(173 incident cases and 2,177 controls; approx. 10-yr follow-up)
9
odds ratio
for the
association
with asthma
Test for trend, p < 0.001
6
3
1
rhinitis
Guerra S et al. J Allergy Clin Immunol 2002;109:419
Test for trend, p < 0.001
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
Allergic rhinitis classification
Intermittent
Symptoms
• < 4 days / week
• or < 4 weeks
Mild
• Sleep: normal
• Daily activities (incl. sports):
normal
• Work-school activities: normal
• Severe symptoms: no
Persistent
•
•
Symptoms
> 4 days / week
or > 4 weeks
Moderate- severe
• Sleep: disturbed
• Daily activities: Restricted
• Work and school activities:
disrupted
• Severe symptoms: yes
Seasonal allergic rhinitis ≠ intermittent
perennial allergic rhinitis ≠ persistent
Intermittent
Persistent
Seasonal
Allergic
Rhinitis (n=193)
133
60
Perennial
Allergic
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
Concept of In Vitro IgE assays
Substrate
Enzyme
Secondary Ab
Sample to be
measured
Primary Ab
In Vitro specific IgE assay (standard curve)
spectrophotometric outcome (OD)
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
0
200
400
600
IgE IU/ml
800
1000
1200
Immunoassay vs skin test for diagnosis
of allergy
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
Other diagnostic tests
•
•
•
•
Nasal secretion / scraping cytology
Nasal allergen challenge
Nasal endoscopy
CT scan
– anatomic abnormalities
– concomitant presence of sinusitis
The nasal allergic response
allergen
IgE
preformed &
newly formed
mediators/cytokines
cytokines
chemokines
Endothelial
cell activation
mast cell
allergen
dendritic cell
Leukocyte
infiltration and activation
(lymphocytes, eosinophils, basophils)
IL-4
IL-13
T-lymphocyte
B-lymphocyte
IMMEDIATE (early)
RESPONSE
Sneezing
Pruritus
Rhinorrhea
Nasal obstruction
Ocular symptoms
LATE-PHASE
RESPONSES
Nasal obstruction
Rhinorrhea
Nasal
hyperresponsiveness
To allergens
(priming)
To irritants and to
atmospheric changes
IgE
The immediate (early phase) allergic
reaction in the nose
brain
PRURITUS
sensory
nerves
epithelium
glands (mucous)
SNEEZING
blood vessels
OBSTRUCTION
RHINORRHEA
histamine
sulfidopeptide leukotrienes
Cellular infiltration and activation at the site of
an allergic reaction
Busse WW, Lemanske RF Jr. N Engl J Med. 2001;344:350-62.
Nasal hyperresponsiveness in allergic rhinitis
7
6
5
Sneezes
induced by
histamine*
4
3
p<0.0001
N = 25
2
1
* same dose in both groups
N = 18
0
Perennial
Allergic
Rhinitis
Sanico AM et al:Int Arch Allergy Immunol 1999;118:154-158
S. Karger AG, Basel
Healthy
Nasal priming in the natural
presentation of seasonal allergic rhinitis
The ratio of symptoms
to pollen counts almost
doubles between the
beginning to the end
of the pollen season
Norman P. J Allergy 1969;44:129
MANAGEMENT OF
ALLERGIC RHINITIS
Management of
Allergic Rhinitis: ARIA Guidelines
mild
intermittent
moderate
severe
intermittent
mild
persistent
moderate
severe
persistent
intranasal steroid
oral or local nonsedative H1-blocker
intranasal decongestant (<10 days) or oral decongestant
leukotriene receptor antagonists
avoidance of allergens, irritant and pollutants
immunotherapy
Modified from Bousquet J et al. J Allergy Clin Immunol. 2001;108:S147.
Stepwise management of allergic rhinitis
Copyright permission for reproduction pending
Modified from ARIA workshop, 2001
Environmental control
1. Allergens
• House dust mites
• Pets
• Cockroaches
• Molds
• Pollen
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
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)§
Terreehorst et al. N Engl J Med. 2003;349:237
0.38 (0.23 to 0.64)
<0.001
Bed covers in persistent allergic rhinitis
Variable
Impermeable-Cover
Group
Control Group
P
Value
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
-9.83 (-15.28 to-4.39)
<0.001
-10.86 (-16.64 to-5.09)
<0.001
Primary end point
Rhinitis-spcific visual-analogue scale
Mean change (95%Cl)
P value
Difference between changes (95%Cl)
Terreehorst et al. N Engl J Med. 2003;349:237
1.03 (-6.87 to 8.94)
0.80
2004;351:1068-80
Environmental intervention in urban US
children with asthma
937 subjects
randomized
469 assigned
to environmental
intervention
444 included in
Year 2 analyses
407 included in
Year 2 analyses
Adapted from Morgan WJ et al. New Engl J Med 2004;351:1068-80
468 assigned
to control
425 included in
Year 1 analyses
414 included in
Year 2 analyses
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
Environmental intervention in urban
US children with asthma
The difference
between treatment
arms was
statistically
significant
(p<0.001) in both
phases of the study
Morgan WJ et al. New Engl J Med 2004;351:1068-80
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
Agents and actions
Oral
antihistam
ines
Nasal
antihistam
ines
Cys-LT1
receptor
antagonists
Nasal
steroids
Nasal
decongest
ants
Oral
decongest
ants
Nasal
ipratropium
Nasal
cromones
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 hr
15-30 min
-
Duration
12-24 hr
6-12 hr
24 hr
12-48 hr
3-6 hr
12-24 hr
4-12 hr
2-6 hr
Modified from van Cauwenberge P Allergy 2000;55:116-134
Oral antihistamines
• First generation agents
• Newer agents
Chlorpheniramine
Acrivastine
Brompheniramine
Azelastine
Diphenydramine
Cetirizine
Promethazine
Desloratadine Fexofenadine
Tripolidine
Levocetirizine Loratadine
Hydroxyzine
Mizolastine
Azatadine
Nasal antihistamines
• Azelastine
• Levocabastine
• Olopatadine
Simplified two-state model of the
histamine H1-receptor
Copyright permission for reproduction pending
Simons, F. E. R. N Engl J Med 2004;351:2203
Efficacy of an antihistamine over 6 months in
persistent allergic rhinitis
Sneezing
*
0.8
Pruritus Nose
*
*
1.0
mean
Individual
symptom
score
improvement
Rhinorrhea
*
*
*
*
*
0.6
Congestion
*
*
*
*
Pruritus Eyes
*
0.4
0.2
0
* P<0.05
1 wk
6 mo
1 wk
4 wk
6 mo
4 wk
1 wk
6 mo
4 wk
1 wk
6 mo
4 wk
1 wk
6 mo
4 wk
Baseline total symptom score: 8.95
Levocetirizine, 5 mg, N = 276
Placebo, N = 271
Bachert C et al. J Allergy Clin Immunol 2004:114:838
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
Newer antihistamines are equally effective
in the treatment of allergic rhinitis
0
Placebo
N =201
-0.5
Change from
baseline in
total symptom
score
(AM, instantaneous,
trough)
Fexofenadine 120 mg
N =211
-1.0
-1.5
Fexofenadine 180 mg
N =202
-2.0
-2.5
-3.0
*: <0.05 compared to placebo
Howarth P et al. J Allergy Clin Immunol 1999;104:927
*
Cetirizine 10 mg
N =207
*
*
Baseline symptoms
Study duration
Effectiveness of a nasal antihistamine in
allergic rhinitis with seasonal symptoms
Copyright permission for reproduction pending
Storms WW et al. Ear Nose Throat J. 1994;73:382.
Newer generation oral antihistamines
somnolence/drowsiness
Active
Placebo
Data Source
Cetirizine
10 mg qd
13.7%
6.3%
www.PDR.net
Desloratadine
5 mg qd
2.1%
1.8%
www.PDR.net
Fexofenadine
60 mg bid
1.3%
0.9%
www.PDR.net
Levocetirizine
5 mg qd
6.8%
1.8%
Bachert et al
JACI 2004;114:838
Loratadine
10 mg qd
8%
6%
www.PDR.net
Newer generation oral antihistamines
•
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
Decongestants: alpha-2
adrenergic agonists
• Oral
Pseudoephedrine
• Nasal
Phenylephrine
Oxymetazoline
Xylometazoline
Decongestants: alpha-2
adrenergic agonists
nasal septum
nasal
turbinates
nasal airway lumen
vasoconstriction
Effect of a nasal decongestant under MRI imaging
Copyright permission for reproduction pending
Adapted from Ng BA et al. Ear, Nose and Throat J 1999;78:159
Efficacy of pseudoephedrine in
seasonal allergic rhinitis
Pseudoephedrine 120 mg twice daily, N=211
Placebo, N=212
1.0
*
0.8
*
Mean reduction
in “nasal stuffiness” score
from baseline
0.6
*
0.4
0.2
0.0
Day 4
Adapted from Bronsky E. et al. J Allergy Clin Immunol 1995;96:139
Endpoint
Overall
(15 days)
Nasal obstruction: antihistamine vs decongestant vs
vombination in allergic rhinitis with perennial symptoms
Cetirizine 5mg twice daily, N=70
Pseudoephedrine 120 mg twice daily , N=70
2.1
Combination, N=70
1.7
Nasal
obstruction
severity score
(scale: 0-3)
1.3
0.9
0.5
0
2
4
6
8
10
Day
Bertrand et al. Rhinology 1996;34:91
12
14
16
18
20
21
Decongestants
EFFICACY:
•
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
indirect effect:
cholinergic
Acetylcholine
on
muscarinic
receptors
X
brain
sensory
nerves
vidian nerve
epithelium
X
RHINORRHEA
submucosal glands
direct effect of mediators:
not cholinergic
Efficacy of ipratropium bromide against
rhinorrhea in allergic rhinitis with perennial symptoms
6.0
3.0
5.0
2.5
4.0
Mean Duration
(hours/day)
*
*
*
*
3.0
*
*
2.0
Mean Severity
1.5
Score
(scale: 0-5)
2.0
1.0
1.0
0.5
0
0
Baseline Wk 1
Wk 2
Wk 3
Wk 4
*
Baseline Wk 1
Wk 2
Wk 3
Ipratropium, 42 µg/nostril three times daily, N=42
Ipratropium, 21 µg/nostril three times daily, N=39
Placebo, N=42
* p<0.05 against Placebo
Adapted from Meltzer E at al. J Allergy Clin Immunol 1992;90:242
Wk 4
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
5-Lipoxygenase
Antagonists
Inhibitors
Montelukast *
Zileuton
Pranlukast *
Zafirlukast
* Approved for allergic rhinitis
Cysteinyl-leukotriene production and
the CysLT1 receptor
CysLT1
receptor
cytosolic
phospholipase A2
leukotriene C4
arachidonic
nucleus
acid
+
5-lipoxygenase
activating
protein
5-lipoxygenase
leukotriene A4
leukotriene C4
leukotriene D4
leukotriene E4
leukotriene C4
synthase
mast cells
basophils
eosinophils
macrophages
Efficacy of a CysLT1 receptor antagonist
in allergic rhinitis with seasonal symptoms
Daytime Nasal Symptoms Score
(0-3 point scale)
0
Change from
baseline
(mean, 95% CI)
-0.2
-0.4
-0.6
*
*
placebo, N=149
montelukast, N=155
mean baseline=2.0
*p<0.01 vs placebo
Adapted from Nayak, et al. Ann Allergy Asthma Immunol. 2002;88: 592
loratadine, N=301
Additive effects of CysLT1 receptor antagonists and
H1 receptor antagonists in allergic rhinitis ?
improvement
no change
worsening
70
60
*
*
*
*
50
% of
subjects
40
30
20
10
0
placebo
montelukast
10 mg
montelukast
20 mg
Adapted from Meltzer EO, et al. J Allergy Clin Immunol. 2000;105:917
loratadine
10 mg
montelukast
10 mg
+
loratadine
10 mg
Equipotency of CysLT1 receptor antagonist/antihistamine and
decongestant/antihistamine
on nasal peak inspiratory flow
230
220
210
200
Liters/min
190
180
170
Fexofenadine/Pseudoephedrine, N = 34
160
Loratadine/Montelukast, N = 34
150
B
1
2
3
4
5
6
7
Treatment Days
Adapted from Moinuddin R et al. Ann Allergy Asthma Immunol 2004;92:73
8
9
10
11
12
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
Copyright permission for reproduction pending
Adapted from Barnes PJ. Eur J Pharmacol. 2006;533:2
Nasal corticosteroids
1
2
reduction of
mucosal mast cells
reduction of
mucosal inflammation
reduction of
late phase reactions
priming
nasal hyperresponsiveness
reduction of
acute allergic reactions
reduction of
symptoms and exacerbations
3
• suppression of
glandular activity
and vascular leakage
• induction of
vasoconstriction
Efficacy of nasal corticosteroid sprays in children with
allergic rhinitis and seasonal symptoms
Meltzer E. et al. J Allergy Clin Immunol. 1999;104:107.
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.
Comparative efficacy of
nasal corticosteroids
Mandl M. et al. Ann Allergy Asthma Immunol 1997;79:370
Various treatment combinations in
seasonal allergic rhinitis
Nasal 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 rhinitis
total symptom score
Scale: 0-12
Copyright permission for reproduction pending
Adapted from Di Lorenzo et al. Clin Exp Allergy 2004;934:259
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)
Nasal corticosteroid vs placebo: effects on 12-hour
urinary free Cortisol in 2-3 year-old children
6-week treatment
Value of 1 indicates
no change from baseline
1.0
0.8
Adjusted Geometric Mean 0.6
of the Change from Baseline 0.4
0.98
0.94
SE=1.14
SE=1.15
N=31
N=29
Fluticasone
Proprionate
Nasal Spray
200 µg daily
Placebo
0.2
0
Adapted from Galant, S. P. et al. Pediatrics 2003;112:96
Allergen immunotherapy
(vaccines)
• Subcutaneous
• Sublingual
• Nasal
Possible mechanisms of immune response
regulation by allergen immunotherapy
Th1
Treg-lymphocyte
DC
Th0-lymphocyte
Th2
Possible mechanism: allergen immunotherapy
induces regulatory T-lymphocytes
B
lymphocyte
interleukin 10
TGF
IgG4
Treg
lymphocyte
interleukin 10
TGF
TH2
lymphocyte
Subcutaneous immunotherapy:
effect on serum specific IgE
Initiation of
immunotherapy
70
60
August
November
50
Anti - ragweed
40
IgE
(ng/ml)
30
20
10
baseline
year 1
Adapted from: Peng et al. J Allergy Clin Immunol 1992;89:519
year 2
year 6
year 7
year 8
Long-term efficacy of subcutaneous immunotherapy
Copyright permission for reproduction pending
Durham et al. N Eng J Med 1999;341:468
Sublingual immunotherapy in
grass pollen-induced allergic rhinitis
SLIT, N=316
Placebo, N=318
Need:
Overall p value
Dahl R et al., J Allergy Clin Immunol. 2006;118:434.
Treatment: grass allergen
tablets
Dose?
Frequency?
Started how long before season?
Humanized monoclonal
anti-IgE antibody: omalizumab
IgE
Omalizumab
C3
region
Efficacy of omalizumab in seasonal allergic rhinitis
(ragweed pollen season)
1.4
• SQ
treatments every 3-4 weeks x 3-4
• First dose prior to the pollen season
1.2
1.0
Average
weekly
symptom
score
0.8
Placebo, N=136
0.6
Omalizumab
50mg, N=137
150mg, N=134
300mg. N=129
0.4
0.2
0.0
4
13 20 27
Aug
3
10
Casale T, et al. JAMA 2001;286:2956
Copyright © 2001 American Medical Association. All Rights reserved
17 24
Sep
1
8
15 22 29
Oct
Omalizumab and subcutaneous
immunotherapy in children: study design
SIT (birch) + placebo
SIT (birch) + omalizumab
n = 54
n = 55
Prescreening
Randomization
SIT (grass) + omalizumab
n = 59
SIT (grass) + placebo
n = 53
SIT titration
Week 0
Kuehr J et al. J Allergy Clin Immunol 2002;109:274
Week 12
SIT maintenance + study drug
Week 36
Omalizumab and subcutaneous
immunotherapy in children: symptom load
(rescue medications + symptom severity scores)
grass pollen season
Copyright permission for reproduction pending
Kuehr J et al. J Allergy Clin Immunol 2002;109:274
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 Secretariat
555 East Wells Street, Suite 1100
Milwaukee, WI 53202
United States
Tel: +1 414 276 1791
Fax: +1 414 276 3349
Email: [email protected]