Transcript Monotherapy for the polisensitized patient

Monotherapy for the
polysensitized patient
Noel Rodriguez-Perez, MD
Professor of pediatrics
State University of Tamaulipas, Mexico
Monotherapy for the polysensitized
patient
 Objectives
 To review the evidence for efficacy of
immunotherapy with the more prevalent single
allergen.
 To highlight the importance of dosing and optimal
concentration for efficacy.
Prevalence of sensitization by testing 9 allergens
45.4 %
51.9 %
28.8 %
36.4 %
39.6 %
41.2 %
33 %
41.4%
37.2 %
29.7 %
22.6 %
49.1 %
Whole population: 35.6% /11 355 subjects were sensitized
21.4 %
Bousquet PJ. Clin Exp Allergy. 2007 37: 780-7.
Prevalences of positive SPT to 10 allergens in the US
National Health and Nutrition Examination Surveys III
 No sensitized
 Monosensitized
 2 or more sensitizations
50
Percentage (%)
40
30
20
10
0
0
1
2
3
4
5
6
Number of sensitizations
7
8
9
10
NHANES III
 10,508 subjects tested to 10
allergens between 1988-1994
 54.3% + SPT to 1 or more
allergens
 15.5% + SPT to a single allergen
 38.8% + SPT to 2 or more
allergens
Mean 3.5, median 3
 HDM (28%), Perennial rye (27%),
Short ragweed (26%), Cockroach
(26%), Bermuda grass (18%)
Arbes SJ. J Allergy Clin Immunol 2005; 116: 377-383
Sensitization patterns to allergens in
Childhood
 No sensitized
 Monosensitized
 2 or more sensitizations
90
80
70
% within age group
60
50
40
30
20
10
0
0
1
2
3
4
5
6
7
8
9
Age (years)
10
11
12
13
14
15
16
17
18
 Retrospective analysis of all sIgE
tests in children 0–18 yrs
 9044 children tested. The
ImmunoCap. sIgE ≥0.35 kU/l.
 60.1% were not sensitized
 39.9% were sensitized to 1 or
more allergens:
31.1% + sIgE to a single allergen
47.4% + sIgE to 2 to 4 allergens
21.5% + sIgE to 5 or more
allergens
de Jong AB. Pediatr Allergy Immunol 2011; 22: 166-71
Clinical characteristics of
polysensitized patients
Number of cases of AR or AR + Asthma
Rhinitis
Asthma
70
60
50
40
30
20
10
0
1
2
3
4
5
6
7
8
9
Characteristics of polysensitized patients wit
AR. The POLISMAIL study (Italy)
418 subjects, age 3.5–65 years
52.6% had AR and 47.4 had AR and asthma.
90% of patients were polysensitized (3.6 allergns)
Polysensitized patients had more severe
symptoms
Ciprandi G. Eur Ann Allergy Clin Immunol 2008; 40: 77-83.
Number of sensitizations
7
Mean number of positive skin tests
6
Aeroallergen sensitization in asthmatics
 SPT to 1338 subjects 12-65 YoA. with asthma
 95% were sensitized to 1 or more allergens
14% + sIgE to a single allergen
81% + sIgE to 3 or more allergens
Average of +SPT 5 allergens
5
4
3
2
1
0
All ages
10 to 20
20 to 30
30 to 40
Age group
40 to 50
50 to 60
60 to 70
Craig TJ. J Allergy Clin Immunol 2008; 121: 671-7
The average allergic patient
is polysensitized
Canonica GW. WAO Journal 2009; 2: 233-281.
Is specific immunotherapy with
single allergen effective in
polysensitized patients?
Sublingual immunotherapy
Response to sublingual immunotherapy with grass pollen
extract: Monotherapy versus combination in a multiallergen
extract
 Methods
 Single-center, randomized, double-blind, placebo-controlled trial with
SLIT.
 After an observational grass season, SLIT was administered for 10
months to 54 patients randomized to 1 of 3 arms:
 Placebo
 Timothy extract (19 μg Phl p 5/day) as monotherapy
 Same dose of Timothy extract plus 9 additional pollen extracts.
 Outcomes included: Symptom and medication scores, titrated nasal
challenges, titrated skin prick tests, sIgE, IgG4 and INF-g.
Amar SM. J Allergy Clin Immunol 2009; 124: 150-156
Response to sublingual immunotherapy with grass pollen
extract: Monotherapy versus combination in a multiallergen
extract
 Log10 Dose (BAU/mL)
Titrated nasal challenge
0.9
*
0.4
-0.1
-0.6
 Log10 Dose (BAU/mL)
t Skin Prick Tests
1.4
1.2
1
0.8
0.6
0.4
0.2
0
-0.2
**
*
Monotherapy Timothy
Multiallergen IT
Placebo
Amar SM. J Allergy Clin Immunol 2009; 124: 150-156
Response to sublingual immunotherapy with grass pollen
extract: Monotherapy versus combination in a multiallergen
extract
Timothy specific IgG4
0.1
*
 Log10 IgG4 (µcg/mL)
0.08
0.06
0.04
0.02
0
-0.02
-0.04
Monotherapy Timothy
Multiallergen IT
Placebo
Amar SM. J Allergy Clin Immunol 2009; 124: 150-156
Efficacy of sublingual immunotherapy with house dust mite extract
in polyallergen sensitized patients with allergic rhinitis
 Objective
 To compare the efficacy of SLIT with standardized HDM extract in
monosensitized and polysensitized patients with allergic rhinitis.
 Methods
 This study was a prospective case series conducted at a tertiary
referral center.
 Patients
with allergic rhinitis sensitized only to HDM were
compared with patients sensitized to HDM and other unrelated
allergens after 1 year of SLIT with house dust mite extract.
 Medication scores (AMS) and total nasal symptoms score (TNSS),
including rhinorrhea, sneezing, nasal obstruction, and itchy nose,
were evaluated before and 1 year after SLIT.
Lee JE. Ann Allergy Asthma Immunol 2011; 107: 79–84.
Efficacy of sublingual immunotherapy with house dust mite
extract in polyallergen sensitized patients with allergic
rhinitis
p < 0.001
p < 0.001
Symptoms scores
Allergic symptoms in the polysensitized group
Symptoms scores
Allergic symptoms in the monosensitized group
 Pre-treatment
 Post-treatment
Lee JE. Ann Allergy Asthma Immunol 2011; 107: 79–84.
Efficacy of sublingual immunotherapy with house dust mite
extract in polyallergen sensitized patients with allergic
rhinitis
Comparison of changes symptoms score and medication score between the 2 groups.
 Pre-treatment
Total nasal symptom score (TNSS)
 Post-treatment
Antiallergic medication score (AMS)
Lee JE. Ann Allergy Asthma Immunol 2011; 107: 79–84.
Sublingual immunotherapy in polysensitized patients:
effect on quality of life
 Methods
 167 polysensitized patients
prospectively evaluated
with
allergic
rhinitis
were
 QOL was measured in all cases with the Rhinoconjunctivitis
Quality of Life Questionnaire at baseline and after 1 year of SLIT
 The mean number of sensitizations per patient was 3.65
 SLIT using one extract was given to 123 patients (73.6%), with 2
extracts to 31 patients (18.6%), and with more than 2 extracts to
13 patients (7.8%)
Ciprandi G. J Investig Allergol Clin Immunol 2010; 20: 274-9.
Sublingual immunotherapy in polysensitized patients: effect
on quality of life
Changes in health-related quality of life scores before and after sublingual
immunotherapy
Baseline
1 year after
4.5
4
*
*
*
3.5
*
Mean Scores
3
2.5
*
*
Sleep
General
problems
*
2
1.5
1
0.5
0
Activity
Practical
problems
Nose
symptoms
Eye
symptoms
Emotional
aspects
Ciprandi G. J Investig Allergol Clin Immunol 2010; 20: 274-9.
Monosensitized
Passalacqua 2006
Guez
Passalacqua 1998
Marcucci
Feliziani
Troise
Casanovas
Passalacqua 1999
D’Ambrosio
Bahceciler
Caffarelli
Voltolini
Sensitized to 2 or more allergens
Ariano
Bowen
Panzner
Drachenberg
Di Rienzo
La Rosa
Pajno
Durham
Dahl 2006 a
Bufe
Hordijk
Roder
Nelson
Pradalier
Dahl 2006 b
Vourdas
Ott
Bufe
Valovirta
Lima
Andre
Amar
Wahn
Hirsh
Didier
No data available
Cao
Dubakiene
Tari
de Blay
Pfaar
Peter
Tonnel
Rolinck-Werninghaus
Palma Carlos
Smith
Wessner
Vervloet
Radulovic S. Cochrane Database Syst Rev. 2010 Dec 8;(12):CD002893.
Optimal dose, efficacy, and safety of once-daily SLIT with a
5 –grass pollen tablet for seasonal allergic rhinitis
 Randomized, double-blind, placebo-controlled study
 628 adults with grass pollen ARC received 1 of 3 doses of
a standardized 5–grass pollen extract, or placebo,
administered sublingually using a once-daily tablet
formulation
 The treatment was initiated 4 months before the estimated
pollen season and continued throughout the season
 Outcomes: ARC Total Symptom Score,(6 most common
symptoms), rescue medication use, quality of life, and
safety
Placebo
100 IR
300 IR
500 IR
Randomized
156
157
155
160
ITT
148
142
136
143
PP
136
132
123
133
29.1 ±
7.60
29.3 ±
6.90
28.7 ±
7.34
30.4 ±
7.45
59.5
51.4
54.4
62.2
23.7 ±
3.54
23.8 ±
3.59
24.5 ±
4.13
24.0 ±
3.91
Polysensitized patients (%)
57.4
54.9
51.5
54.5
Patients with asthma (%)
8.8
9.9
11.0
10.5
Age (y)
Sex (% male)
Body mass index (kg/m2)
Didier A. J Allergy Clin Immunol 2007; 120: 1338-45.
Long-term clinical efficacy in grass pollen–induced RC after
treatment with SQ-standardized grass allergy immunotherapy
tablet
 A randomized, double-blind, placebo-controlled, phase
III trial
 257 Adults with a history of moderate-to-severe grass
pollen
induced
rhinoconjunctivitis
inadequately
controlled by symptomatic medications were included.
 Efficacy end points were rhinoconjunctivitis symptom
and medication scores, quality of life, and percentages
of symptom and medication free days.
Active group
Placebo group
Year 3
Year 4
Year 3
Year 4
Subjects
No. (%)
170 (100)
157 (100)
138 (100)
126 (100)
Sex
Male, no. (%)
109 (64)
101 (64)
86 (62)
81 (64)
Women, N (%)
61 (36)
56 (36)
52 (38)
45 (36)
Age at inclusion Mean (SD)
Median
Sensitizations
35.7 (9.87) 36.4 (9.89) 36.4 (9.86) 36.8 (9.86)
35.0
36.0
35.0
36.0
Grass
155 (100)
139 (100)
126 (100)
114 (100)
Birch
60 (39)
57 (41)
50 (40)
45 (39)
Weed
34 (22)
31 (22)
27 (21)
23 (20)
Cat
37 (24)
32 (23)
33 (26)
26 (23)
Dog
56 (36)
69 (50)
58 (46)
66 (58)
Horse
9 (6)
6 (4)
14 (11)
8 (7)
Der pt
26 (17)
24 (17)
25 (20)
24 (21)
Der fa
17 (11)
17 (12)
15 (12)
16 (14)
Alternaria
21 (14)
21 (15)
12 (10)
7 (6)
Durham SR. J Allergy Clin Immunol 2010;125:131-38.
Injective immunotherapy
Grass pollen immunotherapy as an effective
therapy for childhood seasonal allergic asthma
Details of subjects
 A randomized, double-blind, placebo-controlled
study assessing the efficacy of grass pollen SIT
over 2 pollen seasons was performed.
Active group
Placebo group
18 (100.0%)
17 (100.0%)
5 (27.8%)
5 (29.4%)
White/English/Scottish/Welsh
12 (66.7%)
13 (76.5%)
Black African/Caribbean/Other
2 (11.1%)
1 (5.9%)
Indian subcontinent
4 (22.2%)
1 (11.8%)
White other
0 (0.0%)
1 (5.9%)
Mean age (SD)
9.2 (4.4)
10.6 (2.9)
Mean weight (SD)
37.3 (22.0)
39.3 (12.1)
Mean height (SD)
134 (27.2)
139 (17.8)
0 (0.0%)
0 (0.0%)
Moderate symptoms
15 (83.3%)
15 (88.2%)
Severe symptoms
3 (16.7%)
2 (11.8%)
Mild symptoms
3 (16.7%)
0 (.0.0%)
Moderate symptoms
15 (83.3%)
14 (82.4%)
Severe symptoms
0 (0.0%)
3 (17.6%)
Atopic dermatitis
9 (50.0%)
5 (29.4%)
Symptoms on exposure to tree pollen
2 (11.1%)
0 (0.0%)
Symptoms on exposure to house dust mite
5 (27.8%)
2 (11.8%)
Symptoms on exposure to animal hair and dander
8 (44.4%)
6 (35.3%)
400 (400-400)
400 (200-400)
All subjects
Female subjects
Ethnic origin
 Children (3-16 years) with a history of seasonal
allergic asthma sensitized to grass pollen (P
pratense) and requiring at least 200 μg of
inhaled beclomethasone equivalent per day
were enrolled.
 The primary outcome measure was a
combined asthma symptom-medication score
during the second pollen season.
Summer asthma
Mild symptoms
Summer rhinoconjunctivitis
 Secondary outcome measures included endpoint titration skin prick testing and conjunctival
and bronchial provocation testing to allergen,
sputum eosinophilia, exhaled nitric oxide, and
adverse events.
Median (IQR) daily inhaled beclomethasone
Mild symptoms had only a minimal effect on daily life, moderate symptoms were defined as having a
significant effect on at least 50% of days, and severe symptoms have a major effect on life with daily
symptoms. Subjects only had mild symptoms on exposure to tree pollen or house dust mite.
Roberts G. J Allergy Clin Immunol 2006;117:263-8.
Grass pollen immunotherapy as an effective
therapy for childhood seasonal allergic asthma
Change in cutaneous allergen reactivity
Grass pollen counts and symptom-medication scores for the second summer
Change in conjunctival allergen reactivity
Asthma symptom-medication scores
First season
Second season
Active group
Placebo group
p
Active group
Placebo group
p
18
17
–
18
17
–
Median symptom scores
(IQR)
0.9 (0.4-1.8)
1.5 (0.5-2.3)
.52
0.5 (0.1-0.8)
0.8 (0.4-2.1)
.07
Median medication scores
(IQR)
0.6 (0.0-1.5)
1.4 (0.5-1.9)
.21
0.5 (0.0-1.7)
1.2 (0.0-3.2)
.56
Median symptommedication scores (IQR)
1.0 (0.7-1.8)
1.5 (0.4-2.2)
.35
0.5 (0.1-0.9)
1.0 (0.4-2.0)
.04
No. of subjects
Change in bronchial allergen reactivity
Roberts G. J Allergy Clin Immunol 2006;117:263-8.
Efficacy and safety of specific immunotherapy with SQ
allergen extract in treatment-resistant seasonal allergic
rhinoconjunctivitis
 410 subjects with seasonal ARC were
randomized:
Pollen
Grains/m3
 Double-blind, randomized, placebo-controlled
trial
Peak season
150
100
50
203 to 100,000 SQ-U (20mcg Phl p5)
104 to 10,000 SQ-U (2mcg Phl p5)
103 to placebo
0
23
 347(85%) completed treatment.
24
25
26
27
28
29
30
31
32
33
32
33
week
8
 Both active doses were effective, but 100,000
SQ-U was more effective than 10,000 SQ-U
Symptoms
7
6
Score
 276 / 347 (78%) subjects were polysensitized
 The polysensitized group showed a similar
degree of improvement in symptoms,
medication use, RQLQ, and VAS scores
compared with the whole study group.
5
4
3
2
1
0
23
24
25
26
Alutard 100,000 SQ-U
27
28
29
30
Alutard 10,000 SQ-U
31
Placebo
Frew A. J Allergy Clin Immunol 2006; 117: 319-25.
Functional rather than immunoreactive levels of IgG(4) correlate
closely with clinical response to grass pollen immunotherapy
Combined symptom and medication scores during the pollen season
Adjusted mean (SE)
 This is an 8-month dose-response
randomized double-blind placebocontrolled study
 221 polysensitized subjects with
severe seasonal rhinitis received
Alutard SQ, Phleum pratense
100,000 SQ-U, 10,000 SQ-U or
placebo injections.
 Serum specimens were collected
before treatment, after up-dosing,
during the peak season and at the
end of the study.
Difference vs Placebo
(95% CI)
100 000 SQ-U vs 10 000
SQ-U (95% CI)
Combined symptom and medication scores whole season
Alutard 100 000 SQ-U
(n = 112)
5.84 (0.57)
−2.80 (−4.44, −1.15)
P = 0.001
Alutard 10 000 SQ-U
(n = 54)
7.05 (0.76)
−1.58 (−3.50, 0.34)
P = 0.11
Placebo
(n = 55)
8.63 (0.77)
−1.21 (−2.86, 0.44)
P = 0.15
Combined symptom and medication scores peak season
Alutard 100 000 SQ-U
(n = 112)
7.94 (0.76)
−4.57 (−6.79, −2.35)
P < 0.0001
Alutard 10 000 SQ-U
(n = 54)
10.6 (1.02)
−1.95 (−4.53, 0.63)
P = 0.14
Placebo
(n = 55)
12.5 (1.03)
−2.62 (−4.84, −0.40)
P = 0.021
 Allergen-specific IgG(4) titres and
IgG-associated inhibitory activity
were evaluated.
Shamji MH. Allergy 2011; DOI: 10.1111/j.1398-9995.2011.02745.x.
Functional rather than immunoreactive levels of IgG(4) correlate
closely with clinical response to grass pollen immunotherapy
Time course and dose dependency of SC grass pollen immunotherapy–induced
changes in allergen-specific IgG4 antibodies and serum inhibitory activities.
Phleum pratense-specific IgG4 antibody
levels were measured by enzyme-linked
immunosorbent assay.
Serum inhibitory activity was measured by
(B) IgE-FAB assay
Subcutaneous allergen immunotherapy is
associated with increases in Phleum pratensespecific IgE antibodies and blunting of seasonal
increases in IgE antibodies.
ADVIA Centaur automated analyser
measurement of IgE levels that included a
‘no-wash’ step to measure IgE-blocking
factor.
Shamji MH. Allergy 2011; DOI: 10.1111/j.1398-9995.2011.02745.x.
Immunotherapy: The Meta-Analyses. What
have we Learned?
Calderon MA, Boyle RJ, Penagos M, Sheik A. Immunol Allergy Clin North Am. 2011;31(2):159-73,
vii.
Th2
Th9
iTreg
Th17
Th1
Monotherapy for the polysensitized patient
 CONCLUSIONS
 The majority of AR and asthma patients are polysensitized
 SIT (SCIT and SLIT) with single allergen is effective in polysensitized patients
 Further head-to-head comparisons of the efficacy of SIT in polysensitized vs.
monosensitized patients are required in the context of RCTs.
 “Decision must be based on the allergen which causes:”*

The longest duration of symptoms per year

The most severe symptoms

A major impact on quality of life

Which is more difficult to avoid
* Allergy 2010; 65: 1525–1530.