2. Introduction
Epidemiologic data shows a high and increasing
prevalence of allergic rhinitis (AR) worldwide. AR
is particularly frequent in children, in whom the
atopic disease usually starts with atopic
dermatitis and then develops into AR and asthma
by the picture of the so-called “allergic march”.
AR is generally managed by allergen avoidance,
which in reality is rarely feasible, drug treatment,
which is mainly based on antihistamines and
topical corticosteroids, and allergen-specific
immunotherapy (AIT)
2Prof DR Dr Ariyanto Harsono SpA(K)
3. In 1987, the sublingual route was proposed for AIT ,
and in the ensuing years it emerged as the best
option for immunotherapy, by demonstrating a
comparable efficacy and better safety when
compared to the classical subcutaneous route of
administration. Today, a high number of studies
showing the efficacy of sublingual
immunotherapy (SLIT) have made the use of this
treatment more frequent than subcutaneous IT
(SCIT) in several European countries, and recent
studies are paving the way for the introduction of
SLIT also in the USA
3Prof DR Dr Ariyanto Harsono SpA(K)
4. The World Health Organization and various
allergy, asthma, and immunology societies
throughout the world met on January 27
through 29, 1997, in Geneva, Switzerland to
write guidelines for allergen immunotherapy.
Over the ensuing year, the editors and panel
members reached a consensus about the
information to include in the WHO position
paper “Allergen immunotherapy: Therapeutic
vaccines for allergic diseases.”
4Prof DR Dr Ariyanto Harsono SpA(K)
5. The goal of this review is to analyze up to date the
role of SLIT in the treatment of AR through the
evidence which demonstrates its efficacy and
safety, while highlighting the pharmacoeconomic
issue.
5Prof DR Dr Ariyanto Harsono SpA(K)
12. Allergic Rhinitis and co-morbid conditions
Allergic rhinitis
Nasal polyps
Sleep disturbance,
including sleep-
disordered breathing
Rhinosinusitis (acute and chronic)
Asthma with AR
Congestion
Inflammation
Common cold
12Prof DR Dr Ariyanto Harsono SpA(K)
20. ARIA = Allergic Rhinitis and its Impact on Asthma.
Bousquet et al. J Allergy Clin Immunol. 2001;108 (5 suppl):S147.
ARIA Guidelines: Recommendations for
Management of Allergic Rhinitis
Mild
intermittent
Moderate
severe
intermittent
Mild
persistent
Moderate
severe
persistent
Immunotherapy
Allergen and irritant avoidance
Intranasal decongestant (<10 days) or oral decongestant
Second-generation nonsedating H1 antihistamine
Leukotriene receptor antagonists
Local cromone
Intra-nasal steroid
20Prof DR Dr Ariyanto Harsono SpA(K)
21. EFFICACY OF SUBLINGUAL
IMMUNOTHERAPY
The clinical efficacy of SLIT in AR, similarly to AIT in general, is evaluated by the
decrease in symptom scores of rhinitis and in the consumption of symptomatic anti-
allergic drugs. Currently, more than 60 double-blind, placebo-controlled studies are
available, and provided the material for numerous meta-analyses on SLIT.
The first meta-analysis was published in 2005, 22 controlled trials were available,
showing a significantly higher efficacy of SLIT versus placebo, with a standardized
mean difference (SMD) corresponding to -0.42 for symptom scores (p = 0.002) and
to -0.43 for medication scores (p = 0.00003) [12]. In 2011, the same group updated
meta-analysis: 60 controlled trials were retrieved from the literature and 49 were
suitable for pooling in meta-analysis. A significant reduction was found in symptoms
(SMD -0.49, p < 0.00001) and in medication use (SMD -0.32, p< 0.00001)
compared to the placebo. Therefore, the authors concluded that the updated review
reinforced the statement of the previous meta-analysis that SLIT is effective for AR.
21Prof DR Dr Ariyanto Harsono SpA(K)
22. However, a subsequent meta-analysis on SLIT in
children, concerning only the efficacy on AR,
showed positive outcomes, with a significant
reduction of symptoms (SMD -0.56, p = 0.02)
and medication scores (SMD -0.76, p = 0.03)
22Prof DR Dr Ariyanto Harsono SpA(K)
23. Compalati et al. considered 8 controlled studies
for house dust mite-induced AR, including 194
adults and children, and found a significant
reduction in symptoms of AR (SMD -0.95; p =
0.02) and in antiallergic medication use (SMD -
1.88; p = 0.04) in SLIT treated patients when
compared to the placebo
23Prof DR Dr Ariyanto Harsono SpA(K)
24. In a study on SLIT performed by a dust mite extract, 137 patients
were divided in 2 groups, 67 receiving the treatment for 2
years and 70 receiving the treatment for 3 years; all patients
were followed-up for 3 years after stopping SLIT, and a greater
improvement of symptoms was found in patients treated for
3 years. In a prospective open controlled study, patients
monosensitized to mites were divided in 4 groups, 1 receiving
only drug treatment and the other 3 receiving SLIT for 3, 4, or
5 years. The observation period was extended to 15 years,
and the clinical scores showed that the clinical benefit
continued for 7 years in patients treated for 3 years, while it
continued for 8 years in those treated for 4-5 years.
24Prof DR Dr Ariyanto Harsono SpA(K)
25. SAFETY AND TOLERABILITY OF
SUBLINGUAL IMMUNOTHERAPY
The first observations on safety and tolerability of
SLIT were reported in the meta-analyses on
efficacy, and showed that the most common
adverse events were local reactions in the mouth
followed by gastrointestinal reactions (including
vomiting and diarrhea), that systemic reactions
such as asthma, rhinitis, or urticaria were quite
rare, and that no anaphylactic reaction was
described in controlled trials. However, reviews
specifically addressing SLIT safety are also
available, concerning only children or patients of
any age.
25Prof DR Dr Ariyanto Harsono SpA(K)
26. Of interest, differently from SCIT, a dose-
dependence of safety was not apparent, since
the rate of systemic reactions was comparable
in studies using low doses and in studies using
high doses. The local reactions are generally
estimated to affect 20-40% of patients, but
they can be easily managed and generally do
not require to withdraw the treatment
26Prof DR Dr Ariyanto Harsono SpA(K)
27. We found significant reductions in symptoms (SMD
-0.49; 95%CI (-0.64 to -0.34, P < 0.00001)) and
medication requirements (SMD -0.32; 95%CI (-
0.43 to -0.21, P < 0.00001)) compared with
placebo. None of the trials reported severe
systemic reactions, anaphylaxis or use of
Adrenaline. This updated review reinforces the
conclusion of the original 2003 Cochrane Review
that sublingual immunotherapy is effective
for allergic rhinitis and appears a safe route of
administration
Allergy, 2011;66:740-52
27Prof DR Dr Ariyanto Harsono SpA(K)
29. SCIT
The weighted mean RCI of SCIT on TNSSs (-34.7% ± 6.8%) was
higher than those of mometasone (-31.7% ± 16.7%, P <
.00001) and montelukast (-6.3% ± 3.0%, P < .00001). The
weighted mean RCI of SCIT on TSSs (-32.9% ± 12.7%) was
higher than that of desloratadine (-12.0% ± 5.1%, P <
.00001). The overall ES of SCIT in terms of TNSSs (SMD, -
0.94; 95% CI, -1.45 to -0.43) was similar to that of
mometasone (SMD, -0.47; 95% CI, -0.63 to -0.32; P > .05)
and higher than that of montelukast (SMD, -0.24; 95% CI, -
0.33 to -0.16; P < .05). The overall ES of SCIT in terms of
TSSs (SMD, -0.86; 95% CI, -1.17 to -0.55) was comparable
with that of desloratadine (SMD, -1.00; 95% CI, -1.68 to -
0.32; P > .05).
J Allergy Clin Immunol 2011 Oct;128(4):791-799
29Prof DR Dr Ariyanto Harsono SpA(K)
30. Subcutaneous immunotherapy and pharmacotherapy in
seasonal allergic rhinitis: a comparison based on meta-analyses
The weighted mean RCI of SCIT on TNSSs (-34.7% ± 6.8%) was higher
than those of mometasone (-31.7% ± 16.7%, P < .00001) and
montelukast (-6.3% ± 3.0%, P < .00001). The weighted mean RCI of
SCIT on TSSs (-32.9% ± 12.7%) was higher than that of desloratadine
(-12.0% ± 5.1%, P < .00001). The overall ES of SCIT in terms of TNSSs
(SMD, -0.94; 95% CI, -1.45 to -0.43) was similar to that of
mometasone (SMD, -0.47; 95% CI, -0.63 to -0.32; P > .05) and
higher than that of montelukast (SMD, -0.24; 95% CI, -0.33 to -0.16;
P < .05). The overall ES of SCIT in terms of TSSs (SMD, -0.86; 95% CI,
-1.17 to -0.55) was comparable with that of desloratadine (SMD, -
1.00; 95% CI, -1.68 to -0.32; P > .05).
J Allergy Clin Immunol. 2011 Oct;128(4):791-799.
30Prof DR Dr Ariyanto Harsono SpA(K)
31. We retrieved 1111 publications of which 51 satisfied our inclusion criteria. In
total there were 2871 participants (1645 active, 1226 placebo), each receiving on
average 18 injections. Duration of immunotherapy varied from three days to three
years. Symptom score data from 15 trials were suitable for meta-analysis and
showed an overall reduction in the immunotherapy group (SMD -0.73 (95% CI -
0.97 to -0.50, P < 0.00001)). Medication score data from 13 trials showed an
overall reduction in the immunotherapy group (SMD of -0.57 (95% CI -0.82 to -
0.33, p<0.00001)). Clinical interpretation of the effect size is difficult. Adrenaline
was given in 0.13% (19 of 14085 injections) of those on active treatment and in
0.01% (1 of 8278 injections) of the placebo group for treatment of adverse
events. There were no fatalities.
This review has shown that specific allergen injection immunotherapy in suitably
selected patients with seasonalallergic rhinitis results in a significant reduction in
symptom scores and medication use. Injection immunotherapy has a known and
relatively low risk of severe adverse events. We found no long-term
consequences from adverse events.
Cochrane Database Syst Rev. 2007 Jan 24;(1):CD001936
31Prof DR Dr Ariyanto Harsono SpA(K)
35. SCIT versus SLIT
Specific immunotherapy (SIT) is the only diseases-modifying treatment
option for allergies. Meta-analysis reveals standardized mean differences
in allergic rhinitis symptom scores of -0.73 for
subcutaneous immunotherapy (SCIT) and -0.49 for
sublingual immunotherapy (SLIT); the corresponding mean differences
in medication scores are -0.57 and -0.32, respectively. The treatment
should be carried out for at least three years. It is indicated when the
symptoms are severe and allergen avoidance is not a realistic option. The
efficacy of treatment depends on the allergen dose; thus, every allergen
preparation should be evaluated individually, independent of route of
administration. SCIT can cause systemic adverse effects, including
anaphylaxis. SLIT is safer but often causes allergic symptoms of the oral
mucosa at the beginning of treatment.
35Prof DR Dr Ariyanto Harsono SpA(K)
36. • Subcutaneous and sublingual immunotherapy with grass
allergens for seasonal allergic rhinitis: The overall effect size
of SCIT for symptom score (SMD, -0.92; 95%CI, -1.26 to -
0.58) was significantly higher than SLIT, both administered
via drops (SMD, -0.25; 95% CI, -0.45 to -0.05) and tablets
(SMD, -0.40; 95%CI, -0.54 to -0.27). Similar results were
reported for medication score (SCIT: SMD, -0.58; 95% CI, -
0.86 to -0.30. SLIT drops: SMD, -0.37; 95% CI, -0.74 to -0.00.
SLIT tablets SMD, -0.30; 95% CI, -0.44 to -0.16).
• Our results provide indirect but solid evidence that SCIT is
more effective than SLIT in controlling symptoms and in
reducing the use of anti-allergic medications in seasonal
allergic rhino-conjuntivitis to grass pollen.
J Allergy Clin Immunol 130, 1097-1107.e2, 2012
36Prof DR Dr Ariyanto Harsono SpA(K)
38. PHARMACOECONOMIC ASPECTS
The significant reduction in the use of symptomatic
drugs showed by all meta-analyses on SLIT
highlights the cost-effectiveness of this
treatment. In fact, a number of studies addressed
the pharmaco-economics of AIT. The review of
such studies in 2008 led to the conclusion that
there was clear data that substantiated the
capacity of both SCIT and SLIT to be very
beneficial to the healthcare system. The major
advantage of AIT takes place when the treatment,
usually after 3 years, is stopped, because the
effectiveness of AIT persists over time
38Prof DR Dr Ariyanto Harsono SpA(K)
39. Such persistence is related to the immunologic
changes induced by AIT, especially regarding
the T lymphocytes and their cytokine profile
and the production of IgG blocking antibodies
[38] and the consequent modification of the
natural history of respiratory allergy
39Prof DR Dr Ariyanto Harsono SpA(K)
40. Recent studies expanded the concept of
economic advantage of AIT even before its
termination. In a study performed in US,
children with AR treated with AIT had
significantly lower 18-month median total
health care costs ($ 3247 vs $ 4872),
outpatients costs of AIT-related care ($1107 vs
$ 2626), and pharmacy costs ($1108 vs $
1316) compared with matched controls (p <
0.001 for all comparisons)
40Prof DR Dr Ariyanto Harsono SpA(K)
41. This data has led the authors to conclude that
“This study demonstrates the potential
Sublingual immunotherapy in allergic rhinitis
175 for early and significant cost savings in
children with AR treated with immunotherapy.
Greater use of this treatment in children could
significantly reduce AR related morbidity and
its economic burden”
41Prof DR Dr Ariyanto Harsono SpA(K)
42. Of interest, the direct comparison of costs between
SCIT and SLIT was in favour of the latter, as
expected because of the lack of the necessity for
hospital visits for the injections. In France, the
reported savings compared with drug treatment
over a 6-year period were € 393 for dust mite and
€ 1327 for pollen allergy with SCIT, but they were
€ 3158 for dust mite and € 1708 for pollen allergy
with SLIT. In the Czech Republic, the sum of direct
and indirect costs recorded, over a 3-year
treatment, € 684 for SLIT and € 1004 for SCIT.
42Prof DR Dr Ariyanto Harsono SpA(K)
43. CONCLUSION
SLIT has achieved sound evidence of efficacy and safety and
currently in some European countries is more frequently
used than the classical SCIT, due to better safety. Other
advantages over SCIT concern the cost as well as the
compliance , because SLIT does not need to be
administered in a medical setting. Still, it is important to
note that such outcomes take place only if SLIT meets its
needs, that is, the administration of high doses is
continued on a regular basis for at least 3 consecutive
years. In fact, SLIT efficacy is dose-dependent and a
sufficient duration is crucial to elicit the immunologic
changes underlying its clinical effectiveness.
43Prof DR Dr Ariyanto Harsono SpA(K)
