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Once-daily sublingual allergen-specific immunotherapy improves quality of life in patients with grass pollen-induced allergic rhinoconjunctivitis: A double-blind, randomised study

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The effect of sublingual immunotherapy on quality of life (QoL) was examined in patients with grass pollen-induced rhinoconjunctivitis. Patients (n = 855) were randomised to once-daily grass allergen tablets (2,500; 25,000; or 75,000 SQ-T Phleum pratense extract; GRAZAX or placebo. Treatment was initiated 8 weeks before the start of the grass pollen season and continued throughout. If symptoms were present, patients received loratadine or placebo rescue medication. There were three major findings: in patients using loratadine, grass allergen tablets provided QOL benefits over placebo; Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score was 17% (p = 0.006) and 20% (p = 0.020) greater with 75,000 SQ-T tablet than with placebo at first and second seasonal visit, respectively; in patients not using loratadine, grass allergen tablets improved QoL more than placebo; RQLQ score was 21% greater (p = 0.021) with 75,000 SQ-T tablet at second seasonal visit; grass tablets (without loratadine) had a greater effect on QoL than loratadine alone. RQLQ score was 26% (p = 0.014) greater with 75,000 SQ-T tablets than loratadine at second seasonal visit. These data show that sublingual immunotherapy with grass allergen tablets improves QOL in allergic rhinoconjunctivitis, reduces symptoms, and that this effect is greater than rescue antihistamine alone.
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Once-daily sublingual allergen-specific immunotherapy improves quality
of life in patients with grass pollen-induced allergic rhinoconjunctivitis:
A double-blind, randomised study
Sabina Rak
1
, William H. Yang
2
, Martin R. Pedersen
3
& Stephen R. Durham
4
1
Section of Allergy, Sahlgrenska University Hospital, Go
¨
teborg, Sweden (E-mail: sabina.rak@med-
fak.gu.se);
2
Allergy & Asthma Research Centre, Ottawa, Ontario, Canada;
3
ALK-Abello
´
A/S, Hørsholm,
Denmark;
4
National Heart and Lung Institute, Allergy and Respiratory Medicine, London, UK
Accepted in revised form 11 August 2006
Abstract
The effect of sublingual immunotherapy on quality of life (QoL) was exami ned in patients with grass
pollen-induced rhinoconjunctivitis. Patients (n = 855) were randomised to once-daily grass allergen tablets
(2,500; 25,000; or 75,000 SQ-T Phleum pratense extract; GRAZAXÒ) or placebo. Treatment was initiated
8 weeks before the start of the grass pollen season and continued throughout. If symptoms were present,
patients received loratadine or placebo rescue medication. There were three major findings: in patients
using loratadine, grass allergen tablets provided QOL benefits over placeb o; Rhinoconjunctivitis Quality of
Life Questionnaire (RQLQ) score was 17% (p = 0.006) and 20% (p = 0.020) greater with 75,000 SQ-T
tablet than with placebo at first and second seasonal visit, respectively; in patients not using loratadine,
grass allergen tablets improved QoL more than placebo; RQLQ score was 21% greater (p = 0.021) with
75,000 SQ-T tablet at second seasonal visit; grass tablets (without loratadine) had a greater effect on QoL
than loratadine alone. RQLQ score was 26% (p = 0.014) greater with 75,000 SQ-T tablets than loratadine
at second seasonal visit. These data show that sublingual immunotherapy with grass allergen tablets
improves QOL in allergic rhinoconjunctivitis, reduces symptoms, and that this effect is greater than rescue
antihistamine alone.
Key words: Grass pollen allergy, Quality of life, RQLQ, Seasonal allergic Rhinoconjunctivitis, Sublingual
immunotherapy
Abbreviations: SF-36 Medical Outcome Study Short Form Health Survey; IgE immunoglobulin E;
FEV1 Forced Expiratory Volume; RQLQ Rhinoconjunctivitis Quality of Life Questionnaire; ANOVA
analysis of variance; CI confidence interval; ITT intention to treat; PP per protocol
Introduction
Allergic respiratory diseas e is a major health
problem affecting a significant proportion of the
global population. In a recent study involving
individuals aged 16–60 years from 10 European
countries, the prevalence of allergic respiratory
disorders was estimated to be between 12 and 34%
[1], and in a second study of 6 countries in Western
Europe the average prevalence of allergic rhinitis
was 23% (range 17–29%) [2].
Allergic respiratory disorders include allergic
rhinitis, allergic rhinoconjunctivitis, and allergic
asthma. Allergic rhinitis encompasses nasal symp-
toms such as sneezing, an d running, congested or
itchy nose, while allergic rhinoconjunctivitis
incorporates additional ocular symptoms (e.g.
itchiness, redness or irritation). Asthma symptoms
Quality of Life Research (2006) Ó Springer 2006
DOI 10.1007/s11136-006-9110-3
include difficulty in breathing, wheezing, and
tightness in the chest. Regardless of the exact nature
of the symptoms, these allergic disorders result
from a pathological immune response to allergens,
most commonly grass and tree pollen (seasonal
allergens), and dust mites and animal dander
(perennial allergens).
While the symptoms of allergic rhinitis and
allergic rhinoconjunctivitis are not life-threat-
ening, they can have a substantial impact on
patients’ quality of life (QoL) and daily func-
tioning, causing daytime sleepiness, sleep dis-
turbances, impaired social functioning, and
diminished productivity [3–6]; disturbances in
mood and cognition have also been documented
[7, 8]. In one study, patients with seasonal
allergic rhinitis (n = 33), reported significantly
poorer QoL in terms of physical functioning,
limitations in physical role, bodily pain, and
vitality during the pollen season than outside of
the pollen season [9], as assessed by the Medical
Outcome Study Short Form Health Survey (SF-
36). In a second study using the same survey,
individuals with seasonal allergic rhinitis re-
ported increased daytime s leepiness, and limi-
tations in physical role and physical functioning
during the pollen season; but no such change
was reported in individuals without allergic
rhinitis [6]. Deterioration in QoL is also re-
ported in individuals with perennial rhinitis.
For example, Bousquet et al. [3] reported that
perennial allergic rhinitis was associated with
significantly poorer QoL on eight of the nine
SF-36 domains when compared with healthy
individuals.
Treatment strategies for allergic respiratory
disorders include allergen avoidance, symptom-
atic therapies (e.g. antihistamines, nasal cortico-
steroids, and decongestants), and specific
immunotherapy. Immunotherapy should only be
used when sensitivity to a specific allergen can be
identified. Once iden tified, the basic principle of
specific immunotherapy is to provide consistent,
controlled exposure to the allergen. This over-
exposure results in hyposensitisation, reducing
symptoms in response to exposure to the natu-
rally occurring allergen. The most effective way to
prevent allergy symptoms is to treat the allergic
condition, and specific immunotherapy is the only
treatment capable of modifying the unde rlying
immunological response to allergens.
Specific immunotherapy involving a series of
subcutaneous injections has been available for
many years for the treatment of allergic disorders.
Its efficacy is well documented and has been
shown to persist after treatment has been dis-
continued [10–13]. A minor disadvantage of this
treatment is that the safety profile of injection-
based specific immunotherapy restricts its use to
specialist centres. More recently, non-injection
routes for immunotherapy administration have
been developed to increase safety and patient
accessibility; sublingual immunotherapy is the
most widely used of these non-injection routes.
Over 20 studies and a meta-analysis have dem-
onstrated the efficacy of sublingual immunother-
apy in reducing symptoms and rescue medication
use in patients with allergic rhinitis, with the
magnitude of clinical benefit ranging from 20 to
50% (e.g. [14–17]).
Few studies have examined the effect of specific
immunotherapy on QoL, however. We have only
been able to find five studies that have investi-
gated this issue, and all suggest that specific
immunotherapy can improve QoL. Three of these
studies involved injection immunotherapy
[18–20]; while the remaining two studies involved
sublingual immunotherapy in patients with aller-
gic asthma (with or without rhinitis) to house
dust mites [21, 22]. Therefore, there appear to be
no data available examining the effects of sub-
lingual immunotherapy on QoL in patients with
seasonal allergic rhinoconjunctivitis.
The grass allergen tablets (GRAZAXÒ, ALK-
Abello
´
A/S, Denmark) used in this study have
been developed to increase patient accessibility to
specific immunotherapy. Their active ingredient is
a standardised allergen extract derived from pol-
len of Phle um pratense grass. How ever, there is
substantial cross-reactivity between allergenic
elements of grass pollen species [23], so this tablet
is expected to be effective in treating grass pollen
allergies in general. In this study, we examined
the effect of specific sublingual immunotherapy
with grass allergen tablets on QoL in patie nts
with allergic rhinoconjunctivitis. The primary
efficacy and safety variables from this patient
cohort have been reported elsewhere [24].
Methods
Participants and setting
Participants were aged 18–65 years with mild to
moderate grass pollen-induced allergic rhinocon-
junctivitis (requiring treat ment and/or causing
significant restrictions in activities) for at least
2 years; both men and women were included. All
patients had a positive skin prick test and specific
immunoglobulin E (IgE) to Phleum praten se.
Exclusion criteria included: clinical history of sig-
nificant asthma outside of the grass pollen season;
Forced Expiratory Volume (FEV
1
) < 70% of that
predicted; significant medication-requiring allergic
rhinitis due to allergens other than grass; signifi-
cant recurrent acute or chronic sinusitis, conjunc-
tivitis, asthma or rhinitis at randomisation or
screening visits; history of anaphylaxis or angio-
dema; immunosuppressive treatment; serious con-
ditions including cystic fibrosis, diabetes, renal
insufficiency, cardiovascular disease; hypersensi-
tivity to excipients of trial medications; and previ-
ous immunotherapy with grass pollen allergen
within the previous 10 years, or any other allergen
within the previous 5 years.
Two cohorts with a combined total of 855
participants were enrolled from 55 centres in
Austria, Belgium, Canada, Denmark, Germany,
Norway, Sweden, and the U.K. Cohort 1 was
enrolled in 2002 and provided baseline data (not
presented here). Cohort 2 was enrolled in 2003.
Participants in cohort 2, and all completed and
protocol-compliant participants from cohort 1,
were randomised to treatment in the 2003
season.
Trial design
This was a randomised, double-blind, placebo-
controlled trial, in which participants were
randomised using a computer-generated schedule.
The study evaluated the efficacy of immunother-
apy with grass allergen tablets 2,500, 25,000, and
75,000 SQ-T (75,000 SQ-T corres ponds to 15 lgof
the major allergen Phleum pratense phl p 5)
compared with placebo tablets, as assessed by
rhinoconjunctivitis symptom and medication score
over the pollen season [24].
QoL was determined at each visit using the
disease-specific Juniper’s Rhinoconjunctivitis
Quality of Life Questionnaire (RQLQ; [25]); the
number of well days was also assessed. The RQLQ
was used instead of the SF-36 because it was
developed specifically for use in patients with
rhinoconjunctivitis as opposed to the SF-36, which
is a generic QoL measure. The RQLQ contains 28
questions to evaluate 7 QoL domains: activity
limitations, sleep problems, non-nose/non-eye
symptoms, practical problems, na sal symptoms,
eye symptoms, and emotional function. Patients
rate how troublesome each item has been based on
their experience during the preceding week using a
7-point scale (0–6; higher scores indicate more
severe symptoms). The investigator was not pres-
ent during the completion of the RQLQ. Well days
were days without the use of rescue medication
and with a total rhinoconjunctivitis symptoms
score of 2 or less; the rhinoconjunctivitis symp-
toms score is the sum of ratings of six rhinocon-
junctivitis symptoms, each measured on a scale of
0 (no symptoms) to 3 (severe symptoms); the
maximum score is therefore 18. Adverse events,
withdrawals and laboratory assessments were used
to measure safety.
The trial consisted of six visits (visit 1,
10–14 weeks before the pollen season; visit 2,
8 weeks before the season (pre-season visit); visit
3, at the start of the season; visits 4 and 5, during
the season (on-season visits); and visit 6, 1 week
after the end of the season (post-season visit), and
a telephone follow-up. The visits took place in
hospitals and private specialist clinics. Treatment
was initiated 8 weeks before the an ticipated start
of the grass pollen season and continued for a
maximum of 24 weeks.
The study had three broad aims, and a number
of different treatment regimens were used to assess
these. The first aim was to compare different doses
of grass allergen tablet with placebo tablets when
patients were also allocated loratadine rescue
medication, to be taken as necessary (Groups 1–4).
The second aim was to compare grass allergen
tablets with placebo tablets without the use of
loratadine rescue medication (Group 6 vs. Group
5). The third aim was to compare directly grass
allergen tablets (without concomitant loratadine)
with loratadine alone (Group 6 vs. Group 1)
(Table 1).
Allocation of loratadine or placebo rescue
medication was termed Step 1 rescue medication.
If this Step 1 rescue medication was ineffective or if
asthma was present, patients were assigned further
open-label rescue medication with intranasal
budesonide, oral prednisone, salbutamol, or fluti-
casone, as deemed appropriate by the investigator.
Investigators were instructed to ‘step-down’ these
additional medications when possible. At each
visit, participants were asked to bring any unused
medication. Tablet count was used to assess
treatment adherence.
During the trial, participants were instructed to
place the grass allergen or placebo tablet under the
tongue and refrain from swallowing for 1 min.
Eating and drinking were not permitted for 5 min.
Pollen counts were measured daily in the vicinity
of the trial sites (assuming that most patients en-
rolled in the trial lived or worked in these areas),
and expressed as grains per cubic metre of air. The
start of the pollen season was defined as the first
day of three consecutive days in which the pollen
count was 10 or more; the last day was the day
prior to 3 days with a pollen count less than 10.
Statistical analysis
The primary objective of this clinical trial was
clinical efficacy as assessed by average rhinocon-
junctivitis symptom and medication score (results
reported elsewhere, [24]). Data from the baseline
season (2002) indicated that 125 participants per
group would provide sufficient power to detect a
20% (a = 0.05; two-sided) decrease in symptom
score. Power was not calculated for QoL mea-
surements.
The overall, mean RQLQ score (range 0–6)
was calculated for each participant from the
mean scores of each domain. This calculation was
made for the screening visit, pre-season visit, both
on-season visits and the post-season visit. The
data were analysed using a repeated-measurement
model assuming the RQLQ response to be nor-
mally distributed with treatment, pollen region,
visit, and treatment visit (interaction) as fixed
effects. Participants were included as a random
effect and screening visit values as a covariate. All
available data from the treatment groups were
included in each pairwise comparison. It seems
reasonable to assume that a 20% change in
RQLQ score would be clinically relevant.
The percentage of well days was defined for each
participant by summing the well days, dividing this
by the duration of the grass pollen season and
multiplying by 100. The data were analys ed using
an analysis of variance (ANOVA) with treatment
group and pollen region as fixed effects. In the
analysis of RQLQ and well days, the following
pairwise comparisons were made: Group 1 vs.
Group 2; Group 1 vs. Group 3; Group 1 vs. Group
4; Group 2 vs. Group 3; Group 2 vs. Group 4;
Group 3 vs. Group 4; Group 6 vs. Group 5; Group
6 vs. Group 1.
Results
Of the 855 randomised patients, 790 (92%) com-
pleted the study (Figure 1). Baseline characteristics
of the patients included in each treatment group
were similar (Table 2).
The mean total duration of treatment was
124.5 ± 28 days (range 1–174 days). Mean dura-
tion of treatment pre-season was 62.2 ±
14.3 days, and during the season was 48.7 ±
21.8 days. Overall adherence to treatment
appeared to be high in all groups throughout the
trial, with 94–98% of tablets taken.
Average rhinoconjunctivitis scores showed that
symptoms were reduced by 16% (p = 0.071) and
Table 1. Treatment regimens
Group Initial randomisation Step 1 rescue medication
1 Placebo tablet Loratadine (active)
2 Grass allergen tablet 2,500 SQ-T Loratadine (active)
3 Grass allergen tablet 25,000 SQ-T Loratadine (active)
4 Grass allergen tablet 75,000 SQ-T Loratadine (active)
5 Placebo tablet Placebo
6 Grass allergen tablet 75,000 SQ-T Placebo
medication use by 28% (p = 0.047) in patients
allocated 75,000 SQ-T grass allergen tablet with
loratadine, compared with those allocated pla-
cebo tablets with loratadine. There were no sig-
nificant differences in symptoms or medication
use in patients receiving 2,500 SQ-T or 25,000
SQ-T tablets compared with placebo (groups
were also allocated loratadine, taken when nec-
essary). In patients not allocated loratadine,
symptoms and medication use were reduced by
13% (p = 0.088), and by 30% (p = 0.017) in
patients receiving 75,000 SQ-T compared with
those receiving placebo tablets (for more detailed
efficacy results see Durham et al. [24]).
Figure 1. Participant allocation and completion.
Table 2. Baseline demographics
Group 1
Placebo tablet
with loratadine
rescue
medication
(n = 136)
Group 2
2,500 SQ-T tablet
with loratadine
rescue medication
(n = 136)
Group 3
25,000 SQ-T
tablet with
loratadine rescue
medication
(n = 139)
Group 4
75,000 SQ-T
tablet with
loratadine rescue
medication
(n = 141)
Group 5
Placebo tablet
with loratadine
rescue
medication
(n = 150)
Group 6
75,000 SQ-T tablet
without loratadine
rescue medication
(n = 153)
Cohort I 87 85 91 92
Cohort II 49 51 48 49 150 153
Canada 24 23 24 23 71 70
Male/female 89/47 84/52 92/47 84/57 89/61 95/58
Age 33 34 34 37 36 36
IgE class 3.46 3.53 3.47 3.46 3.11 3.45
Other allergens (%) 17 15 18 18 42 43
Any rescue med. (%) 96 96 96 98 93 90
AH eye drops (%) 49 44 60 53 22 17
RQLQ
The results are reported according to the three
study aims outlined in the methods.
Grass allergen tablets vs. placebo tablets
in patients also allocated loratadine rescue
medication (Groups 1–4)
There was a clear dose–response relationship in
the effect of grass allergen tablets on QoL as
measured by RQLQ score in the groups also tak-
ing loratadine when necessary. Treatment with
75,000 SQ-T grass allergen tablet and 25,000 SQ-T
grass allergen tablet significantly improved QoL
relative to placebo tablet (Figure 2); mean RQLQ
score (95% confidence interval; CI) was 17% (5–
29%) and 14% (2–26%) greater in patients
receiving 75,000 SQ-T grass allergen tablets and
25,000 SQ-T grass allergen tablets, respectively,
compared with placebo tablet, at the first seasonal
visit, (p = 0.006 and p = 0.023, respectively,
intention-to-treat (ITT ) population). At the sec-
ond seasonal visit, the difference in mean RQLQ
score between patients receiving 75 ,000 SQ-T grass
allergen table ts and those receiving placebo tablets
was even more marked (20% (95% CI: 3–37%);
p = 0.020), although the difference between
25,000 SQ-T grass allergen tablet and placebo
tablet did not reach statistical significance (12%
(95% CI: ) 5–29%); p = 0.158).
Between-group differences in different doses of
grass allergen tablets were also evident. At the first
seasonal visit, patients receiving 75,000 SQ-T g rass
allergen tablets and those receiving 25,000 SQ-T
grass allergen tablets had significantly greater
mean RQLQ scores than patients receiving 2,500
SQ-T (by 22% (95% CI: 11–33%) and 19% (95%
CI: 8–30%), respectively, p < 0.001); this differ-
ence was maintained at the second seasonal visit
for the 75,000 SQ-T group only (18% (95% CI:
1–35%); p = 0.039). None of the other pairwise
comparisons was signi ficant. Similar results were
obtained for the per protocol data set. Further-
more, the dose-dependent effect of grass allergen
tablets on mean RQLQ score was clearly evident
across all domains of the scale, with the exception
of sleep (no statistical analysis was performed)
(Figure 3).
Grass allergen tablets vs. placebo tablets
in patients not allo cated loratadine rescue
medication (Group 6 vs. Group 5)
When loratadine rescue medication was not used,
differences between grass allergen tablet and pla-
cebo tablet were also evident. While there was no
significant difference at the first seasonal visit, by
the second seasonal visit mean RQLQ score (95%
CI) was 21% (3–40%) greater in patients receiving
75,000 SQ-T grass allergen tablets, than in those
receiving placebo tablets (p = 0.021, Figure 4).
Grass allergen tablet without loratadine vs.
placebo tablets with loratadine (Group 6 vs. Group 1)
The direct comparison of the QoL benefits of grass
allergen tablets vs. loratadine also favoured the use
of specific immunotherapy. Mean RQLQ score
(95% CI) was 26% (5–46%) greater at the second
seasonal visit in patients receiving 75,000 SQ-T
grass allergen tablets without loratadine than in
patients receiving placebo tablets with loratadine
(p = 0.014, Figure 5).
At the post-seasonal visit, 1 week after the end
of the pollen season, there were no differences in
mean RQLQ score between any of the treatment
groups in the ITT or per protocol (PP) popula-
tions.
Patients receiving at least 8 weeks’ pre-season
treatment
Because the onset of the grass pollen season can
only be estimated, some patients did not receive
the planned 8 weeks of pre-sea son treatment. An
exploratory analysis was theref ore performed on
RQLQ scores from the subset of ITT patients
Figure 2. Difference in mean RQLQ score at the first and sec-
ond seasonal visit following treatment with grass allergen tab-
lets compared with placebo tablets in patients receiving
loratadine rescue medication.
(n = 640, 75%) who received at least 8 weeks of
pre-season treatment. Generally, these results were
consistent with those of the complete cohort.
Mean RQLQ score was significantly great er with
75,000 SQ-T grass allergen tablet with loratadine
than with placebo table t with loratadine, by 21%
(95% CI: 7–34%; p = 0.002) and 20% (2–38%,
p = 0.028) for seasonal visit 1 and 2, respectively.
Additionally, the dose–response of tablet immuno-
therapy was evident. Compared with patients
receiving 2,500 SQ-T grass allergen tablets with
loratadine, mean RQLQ was 23% (95% CI:
10–36%) greater in patients recei ving 75,000 SQ-T
grass allergen tablets with loratadine (p < 0.001)
and 15% (95% CI: 3–27%) greater in patie nts
receiving 25,000 SQ-T grass allergen tablets with
loratadine (p = 0.017) at the first seasonal visit.
In patients not allocated loratadine, mean
RQLQ score was 21% (95% CI: 1–42%) greater at
the second seasonal visi t with 75,000 SQ-T grass
allergen tablets than with placebo tablets
(p = 0.044) . There were no other differences
between groups in this exploratory analysis.
Well days
Grass allergen tablets vs. placebo tablets
in patients allocated loratadine rescue medication
(Groups 1–4)
For patients randomised to loratadine, those
receiving 75,000 SQ-T grass allergen tablets had
an 18% increase in the percentage of well days
during the pollen season compared with those
receiving placebo tablets (95% CI: 1–35%;
p = 0.041, ITT population). Again, there was
evidence of a dos e-dependent effect of tablet
immunotherapy; a higher percentage of well days
was reported in the 75,000 SQ-T grass allergen
tablet with loratadine group compared with the
25,000 SQ-T grass allergen tablets with loratadine
Figure 3. Effect of grass allergen tablets on each domain of the RQLQ at the second seasonal visit in patients receiving loratadine
rescue medication.
Figure 4. Difference (%) in mean RQLQ score in patients
receiving 75,000 SQ-T grass allergen tablets and those receiv-
ing placebo tablets (both groups without loratadine) at the
first and the second seasonal visit. Significant p-value indi-
cates a significant between-group difference.
group (16% increase, 95% CI: 0–33%) and the
2,500 SQ-T grass allergen tablets with loratadine
group (13% increase, 95% CI: ) 3–30%) but
these differences did not reach significance
(p = 0.055 and 0.105, respectively). Similar
results were reported in the PP analyses.
Grass allergen tablets vs. placebo tablets
in patients not allocated loratadine rescue
medication (Group 6 vs. Group 5)
There was a non-significant increase of 12% in the
percentage of well days in patients receiving 75,000
SQ-T grass tablets compared with placebo tablets
in the groups not allocated loratadine.
Grass allergen tablets without loratadine vs.
placebo tablets with loratadine (Group 6 vs. Group 1)
There was a non-significant increase of 5% in the
percentage of well days in patients receiving 75,000
SQ-T grass tablets compared with those allocated
loratadine alone.
Patients receiving at least 8 weeks’ pre-season
treatment
The percentage of well days was also compared in
the subset of ITT patients who received at least
8 weeks of pre-season treatment (n = 640, 75%).
Patients receiving 75,000 SQ-T grass allergen
tablets with loratadine reported a greater mean
percentage of well days (95% CI) by 19%
(1–38%), 13% () 5–31%) and 23% (4–43%)
compared with placebo tablets (p = 0.043), 2,500
SQ-T grass allergen tablets (p = 0.146) and
25,000 SQ-T grass allergen tablets (p = 0.017),
respectively. Additionally, in patients not allo-
cated loratadine, those receiving 75,000 SQ-T
grass allergen tablets had a 19% (95% CI: ) 3–
41%) increase in mean well days relative to those
receiving placebo tablets, although this did not
achieve significance (p = 0.089). No other dif-
ferences approached significance.
Safety and tolerability
The grass allergen tablets were generally well tol-
erated. The most commonly reported treatment-
related adverse events were oral itching and throat
irritation. Of patients treated with 75,000 SQ-T
grass allergen tablets, 52% reported oral itching,
but the daily duration was limited to minutes/
hours and, in 50, 75 and 90% of the affected
patients, itching did not recur after 8, 53, and
108 days, respectively. This means that 74% of
patients treated with the grass allergen tablet did
not experience oral itching after 8 days of treat-
ment. Few patients withdrew because of adverse
events. No life-threatening systemic reaction was
reported.
Discussion
This study showed that treatment with grass
allergen table ts improves QoL in patients with
seasonal allergic rhinoconjunctivitis induced by
grass pollen. A clear dose–response relationship
for grass allergen tablets was evident in terms of
overall RQLQ score, with the most marked
improvements in QoL occurring following treat-
ment with 75,000 SQ-T grass allergen tablets. In
particular, when patients could use loratadine as
needed, this 75,000 SQ-T dose led to significantly
greater mean RQLQ score relative to placebo
grass allergen tablets at both the first and second
seasonal visit, and the percentage of well days
throughout the trial was also significantly
increased. In the 25,000 SQ-T grass allergen tablet
group, mean RQLQ score was significantly greater
than placebo at the first seasonal visit only, and
Figure 5. Difference (%) in mean RQLQ score in patients
receiving 75,000 SQ-T grass allergen tablets (without lorata-
dine) and those receiving loratadine (with placebo grass aller-
gen tablets) at the first and the second seasonal visit.
Significant p-value indicates a significant between-group dif-
ference.
this dose had no effect on the pe rcentage of well
days; no significant benefit of the 2,500 SQ-T dose
on mean RQLQ score, or on well days was re-
ported. Thus, when used in combination with
loratadine rescue medication, 75,000 SQ-T grass
allergen table ts, and to a lesser extent 25,000 SQ-T
grass allergen tablets, offered significant QoL
benefits over placebo tablets. Furthermore, the
benefit of 75,000 SQ-T on QoL is clearly evident
across all RQLQ domains, with the exception of
sleep.
The 75,000 SQ-T grass allergen tablet also led to
significantly better QoL than placebo tablets when
patients were not using loratadine rescue medica-
tion. Furthermore, in a direct comparison of grass
allergen tablet (75,000 SQ-T; without loratadine)
vs. loratadine (without grass allergen tablet),
immunotherapy-treated patients reported signifi-
cantly better RQLQ scores than loratadine-treated
patients. Thus, specific immunotherapy alone also
has advantages over rescue medication alone.
Importantly, 1 week after the end of the pollen
season, there were no between-group differences in
QoL measures. A similar pattern of QoL results
was reported in the subset of patients who received
at least 8 weeks of pre-season exposure, although
there was some indication of greater QoL benefits
(at least at the first seasonal visit) in patients
receiving the 75,000 SQ-T dose.
Juniper et al. [25] previously suggested an
improvement in RQLQ score of 0.5 to be
indicative of clinically meaningful improvement.
This was calculated from a within-subject design,
however, rather than a between-subject design as
used in the present study. We suggest that an
improvement in RQLQ score of 20% could be
indicative of clinically relevant improvement in
QoL. Using this criterion, the impr ovement in
RQLQ with 75,000 SQ-T tablets (with or with-
out loratadine) compared to placebo tablets
(with loratadine) could be deemed clinicall y rel-
evant at the second seasonal visit. Similarly, the
improvement in RQLQ score with 75,000 SQ-T
vs. placebo tablets, when neither group received
rescue loratadine, at the second seasonal visit
could also be considered clinically relevant. The
confidence intervals for the results presented in
this study suggest that the difference in RQLQ
score between 75,000 SQ-T tablets and placebo
tablets could be as great as 46%.
The differences in QoL documented here are
consistent with the other efficacy findings from
this cohort. As reported by Durham et al. [24],
the greatest improvements in symptoms and
largest reduction in medication use were in indi-
viduals receiving 75,000 SQ-T grass allergen tab-
lets.
To our knowledge, this study is the first to re-
port that, in patients with seasonal allergic rhino-
conjunctivitis, specific sublingual immunotherapy
can:
1. improve disease-specific QoL compared with
placebo in patients taking rescue medication
such a s loratad ine;
2. improve disease-specific QoL compared
with placebo in patients not taking lorat-
adine;
3. when used without loratadine, improve disease-
specific QoL to a greater extent than loratadine
alone.
Improved QoL in patients with allergic rhinitis
has also been found following injectable immuno-
therapy. For example, Fell et al. [18] reported that
63% of patients with seasonal or perennial allergic
rhinitis had improvements in social functioning
following initiation of specific subcutaneous
immunotherapy, and 55% report ed an increased
energy level. In a second study, QoL during the
pollen season improved to a significantly greater
extent with immunotherapy than with placebo
overall, and in five of the seven RQLQ domains
(non-hay fever symptoms, nasal symptoms, eye
symptoms, activities, and emotions) in patients
with seasonal rhinitis and asthma [20]. Finally,
Moncayo Coello et al. [19] reported improved
QoL in 54 children (aged 7–17 years) with allergic
rhinitis receiving sp ecific immunotherapy com-
pared with those receiving placebo as assessed by
the paediatric rhinoconjunctivitis QoL question-
naire; measures of distress caused by nasal pruri-
tus, nasal obstruction, and eye rubbing were
particularly improved.
The results of this study are also consistent
with the available data on the effects of sublin-
gual immunotherapy on QoL in patients with
allergic asthma (with or without rhinitis) induced by
house dust mites. For example, Bousquet et al. [22]
showed that 25 months of sublingual immuno-
therapy improved QoL (as assessed by the short
Form Health Status Survey 20) relative to placebo
in patients with allergic asthma, with scores on
‘general perception of health’ and ‘physical pain’
showing the greatest differences (35 and 26%
greater than placebo, respectively). In a second
study of 32 children with allergic rhinitis and
asthma, 6 months of sublingual immunotherapy
resulted in a 16% improvement in QoL relative to
baseline as assessed by the paediatric asthma QoL
questionnaire (p < 0.01, [21]).
QoL improvements have also been reported
following non-immunotherapy treatment for
seasonal allergic rhinitis. For example, Meltzer
et al. [26] found that once-daily fexofenadine
hydrochloride (an antihistamine) in patients
with seasonal allergic rhinitis led to signifi cantly
greater reductions in overall work impairment
and in daily activity impairment compared with
placebo (as measured by the Work Productivity
and A ctivity Impairment instrument); overall
RQLQ score was also significantly reduced
(p < 0.01). In a separate study the use of two
intranasal corticosteroid sprays (triamcinolone
acetonide and fluticasone propionate) was
compared [27]. The preparations were equally
effective in improving health-related QoL;
scores on the RQLQ were 2.3–4.4 at baseline
compared with 1.1–2.2 at endpoint (p <0.001
vs. baseline). It is interesting to note, however,
that in this present study treatment with 75,000
SQ-T grass allergen tablets without loratadine
led to significantly better QoL (in terms of
RQLQ score, but not well days) relative to
placebo tablets with loratadine. Thus, grass
allergen tablets may have a greater impact on
QoL than standard treatments for grass pollen-
induced rhinoconjunctivitis. While seasonal
allergic rhinoconjunctivitis is r arely a life-
threatening condition, it can have a significant
negative impact on QoL. It is t herefore impor-
tant that QoL is considered alongside standard
efficacy analyses when assessing the effect of
treatment. Improvements in QoL can enhance a
patient’s life in a number of ways, allowing
them to engage in outdoor activities, improving
productivity, and increasing general feelings of
well-being. T his study has shown that 75,000
SQ-T grass allergen tablets represent an easy
to use immunotherapy, which significantly
improves QoL in patients with seasonal allergic
rhinoconjunctivitis induced by grass pollen.
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Address for correspondence: Sabina Rak, Section of Allergy
Sahlgrenska University Hospital, S-413 45, Go
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Phone: +46-31-342-1886; Fax: +46-70-729-9063;
E-mail: sabina.rak@medfak.gu.se
... A 2008 study of 351 participants found grass tablet SLIT treatment for an average of 22 months to significantly improve rhinoconjunctivitis symptom scores, medication scores, and quality of life [38]. Another RCT of 855 participants also showed improvements in quality of life and symptom scores over placebo [39]. Two additional large RCTs showed benefit of grass tablets up to 2 years after cessation of therapy [40,41]. ...
... Of note, both of these patients had prior discontinuation of SCIT due to systemic reactions. More recently, no serious treatment-related adverse events were reported in any of the large RCTs of grass tablet SLIT [38][39][40][41]. Local adverse events were more frequent and most commonly consisted of oral cavity pruritus (44-52%) [38,39,41], oral cavity swelling (19%), or throat pruritus (13%) [41]. ...
... More recently, no serious treatment-related adverse events were reported in any of the large RCTs of grass tablet SLIT [38][39][40][41]. Local adverse events were more frequent and most commonly consisted of oral cavity pruritus (44-52%) [38,39,41], oral cavity swelling (19%), or throat pruritus (13%) [41]. ...
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... Vieira-Hernández et al. 12 demonstrated the effectiveness of intradermal immunotherapy with low doses of Dp/Df and Bt. 13 Although several questionnaires reported in the literature prioritize evaluation of symptoms and reduction in the use of medications, they do not specifically aim at the general welfare. 14 The goal of the present study was to evaluate the satisfaction of the patients with SLIT treatment in a real-world setting from the patients' own perception. ...
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... Different studies explored HRQoL in allergic diseases. [10][11][12][13][14][19][20][21][22] In 2001, Sicherer et al. 20 measured parental perceptions on physical and psychosocial functioning with the Children's Health Questionnaire (CHQ-PF50) and with an additional allergy-related questionnaire in a group of food-allergic children, demonstrating that childhood food allergies deeply influenced general health perception, limited family activities and had emotional impact on parents. ...
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... A pivotal Phase II trial in adults, with three administered doses, allowed the identification of the optimum therapeutic dose of 75,000 SQ-T. [15][16][17] An additional safety and efficacy study on patients (n = 114) with mild-to-moderate asthma and rhinoconjunctivitis was performed. Safety in a severe patient subgroup was closely monitored. ...
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... Among doctors, less than 50% of general practitioners were aware of the exact placement of AIT, and almost all of them wanted detail information about AIT in Italy. 14,15 Several aspects of AIT in controlled studies have been extensively investigated, including clinical efficacy, [16][17][18] tolerability, 19 and effects on health-related quality of life (QoL); [20][21][22] however, a few studies addressing patient and physician perspectives on AIT have been published, especially in Korea. ...
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Chapter
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Chapter
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In a previous study, 39 adults with grass pollen allergy were hyposensitized for approximately 2 1/2 years. Treatment was performed in a double-blind fashion with extract made from timothy grass--either Alutard SQ 20-component extract or a purified 2-component extract, including only the two major allergens Phl p V and VI. Standardized symptom + medicine scores and challenge tests demonstrated a clinical effect, most markedly in the group receiving 20-component extract. Six years after termination of treatment, 38 patients could be approached and 16 in each group were examined and repeated symptoms scoring during the subsequent season. When adjustment for variations in pollen counts were made, medicine + symptom scores stayed low during the follow-up period. Specific IgE-antibodies against timothy showed an increase to initial values during the same period, whereas total IgE antibodies remained low. Skin prick test reactions with timothy allergen tended to increase but were still smaller than before treatment. Retrospectively, the patients reported symptoms to have stabilized or even further decreased after termination of treatment, with no significant difference between groups. In conclusion, the clinical effect was still present more than 6 years after termination of treatment. Some in vitro parameters tended to return to pretreatment level. The spontaneous course of the disease in non-hyposensitized patients was not investigated.
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Grass pollens, such as pollen from timothy grass (Phleum pratense), represent a major cause of type I allergy. In this report we attempted to determine how cross-reactive allergenic components of grass pollens from different species can be represented by a minimum number of recombinant allergens. We isolated and sequenced a timothy grass pollen cDNA coding for the major allergen Phl p I. A recombinant Phl p I-beta-galactosidase fusion protein, which bound to IgE in 87% of patients with grass pollen allergy, was produced in Escherichia coli. Using recombinant Phl p V and Phl p I, we defined representative patients' sera that bound to group I but not to group V allergens, as well as sera with reactivity against group I and group V allergens. IgE immunoblot inhibition studies were done with nitrocellulose-blotted pollen extracts from eight grass species with different geographic distribution. Preadsorption of patients' sera with recombinant nonfusion Phl p I strongly reduced IgE binding to group I allergens from the eight grasses, showing extensive cross-reactivity between species. A single recombinant group I allergen contains many of the IgE epitopes of group I isoallergens from a number of different grass species.
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