REVIEW

CURRENT
OPINION Effectiveness of subcutaneous versus sublingual
immunotherapy for allergic rhinitis: current update
Yohalakshmi Chelladurai a and Sandra Y. Lin b

Purpose of review
The effectiveness of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) in treatment
of patients suffering from allergic rhinitis have been evaluated in a number of randomized controlled trials,
systematic reviews and meta-analyses conducted over the past few decades. Currently, there is a growing
interest in evaluating comparative effectiveness of SCIT versus SLIT to identify whether one form of
immunotherapy is better than the other. In this current update, we discuss pertinent systematic reviews that
have addressed this concern.
Recent findings
The four systematic reviews identified in this update are the only reviews of effectiveness of SCIT versus SLIT
for allergic rhinitis available in the literature. Through direct and indirect comparisons, these four reviews
demonstrate that SCIT is better than SLIT in reducing symptoms of allergic rhinitis and rescue medication
use in adults and children. However, there was no difference between the two forms of immunotherapy in
reducing combined symptommedication scores and improving quality of life. With regard to safety, SLIT
had fewer systemic reactions when compared with SCIT.
Summary
The evidence of effectiveness of SCIT versus SLIT was principally derived from indirect comparisons and
meta-regression. Additional randomized controlled trials of head-to-head comparisons of SCIT versus SLIT
are required to strengthen this evidence base. Future research should focus on development of
standardized outcome assessment, allergen dosing, content, and treatment regimes.
Keywords
review, subcutaneous immunotherapy, sublingual immunotherapy

INTRODUCTION approved and widely utilized in European countries.

Allergic rhinoconjunctivitis and asthma are com-
mon global health problems. In North America,
about 40% of the population suffer from allergic
rhinitis [15]. More than half of the patients with
asthma in the United States suffer from atopy [6,7].
Inhalant allergic health problems have primarily
been managed with environmental control and
pharmacotherapy. Patients who are resistant to
these modalities of treatment are commonly treated
with immunotherapy.
Immunotherapy has been administered widely
via subcutaneous and sublingual routes. Subcu-
taneous immunotherapy (SCIT) has been used for
decades now and it is also the only form of immu-
notherapy approved by the US Food and Drug
Administration. However, many physicians in the
United States are using sublingual preparations of
aqueous solution of SCIT off label. Sublingual
immunotherapy (SLIT), both drops and tablets, is
Around 45% of allergen desensitization therapy in
Europe is with SLIT [8].
The effectiveness of individual forms of immu-
notherapy, SCIT and SLIT, has been evaluated in
many systematic reviews [915]. The Agency for
Healthcare Research and Quality published an evi-
dence report on specific immunotherapy in March
2013 [16]. There is strong evidence to suggest that
both SCIT and SLIT are effective in reducing symp-
toms of allergic rhinoconjunctivitis and asthma,
and medication use when compared with control
a
The Johns Hopkins Evidence-Based Practice Center and bDepartment
of Otolaryngology-Head and Neck Surgery, Johns Hopkins University
School of Medicine, Baltimore, Maryland, USA
Correspondence to Sandra Y. Lin, MD, 601 North Caroline Street,
#6254, Baltimore, MD 21287, USA. E-mail: slin30@jhmi.edu.
Curr Opin Otolaryngol Head Neck Surg 2014, 22:211215
DOI:10.1097/MOO.0000000000000045

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 Allergy
KEY POINTS

Both SCIT and SLIT are effective in treatment of
allergic rhinitis.

Systematic reviews and meta-analyses of SCIT versus SLIT
demonstrate better reduction in allergic rhinitis symptoms
and rescue medication use with SCIT than SLIT.

These reviews have several limitations and further
research is required to corroborate the results.
or placebo. These reviews have also evaluated the
safety profile of the individual forms of immuno-
therapy, SLIT having a more favorable safety profile
for systemic adverse reactions.
The growing popularity of SLIT among patients
and physicians as an alternative to SCIT has
prompted, in the last year, many reviews of com-
parative effectiveness of SCIT versus SLIT to be
undertaken. In this update, we sought to highlight
the important systematic reviews and meta-analyses
conducted over the last year that compared SCIT to
SLIT directly or indirectly.
CURRENT SYSTEMATIC REVIEWS
A search in MEDLINE and Cochrane database was
carried out with keywords sublingual immuno-
therapy and subcutaneous immunotherapy to
identify systematic reviews and meta-analyses that
compared SCIT to SLIT for inhalant allergic rhino-
conjunctivitis and/or asthma through head-to-
head or indirect comparisons over the last
year. Four systematic reviews, published between
November 2012 and December 2013 that evaluated
the comparative effectiveness of SCIT versus SLIT
were identified.
All four were reviews of randomized controlled
trials (RCTs) only; double blinding was an essential
& &
inclusion criterion for one of the reviews [17 20 ].
Two reviews carried out indirect comparisons of the
& &
two therapies [17 ,18 ], whereas the remaining were
reviews of articles with head-to-head comparisons
& &
[19 ,20 ]. A single review was conducted exclusively
&
in the pediatric population [20 ]. Three reviews
included patients with both allergic rhinitis and
& &
asthma to any allergen [18 20 ], but one was
focused on allergic rhinitis patients to grass pollen
&
alone [17 ]. SLIT studies of both drops and tablets
& &
were evaluated in two reviews [17 ,18 ], but the
remaining reviews included studies of SLIT drops
& &
exclusively [19 ,20 ]. There were no restrictions
for study inclusion by geographic location in any
review.
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Symptom score
All four reviews evaluated the effectiveness of SCIT
versus SLIT for allergic symptom reduction. Two
meta-analyses calculated the standardized mean
differences (SMDs) in treatment effects for SCIT
& &
and SLIT compared with placebo [17 ,18 ] and in
the remaining two systematic reviews, the evidence
was synthesized qualitatively. All reviews favored
SCIT over SLIT for reduction in symptoms of allergic
rhinitis. The pooled estimates of SMDs from two
reviews comparing SCIT and SLIT with placebo
demonstrated that SCIT produced statistically sig-
nificant and more considerable clinical response
than SLIT. A review of qualitative head-to-head
comparisons of SCIT versus SLIT studies also dem-
onstrated that evidence to support SCIT over SLIT
for rhinitis symptom reduction was moderate [19 ].
&
Similarly in the pediatric population, SCIT was
favored over SLIT, but the evidence was low grade
&
[20 ] (Table 1).
Medication score
Effectiveness of SCIT versus SLIT for reduction in
medication score was evaluated in four reviews.
Even though pooled SMDs of both therapies showed
statistically significant reduction in medication
scores, when compared with placebo, the reduction
with SCIT was greater when compared with SLIT.
Similarly, the qualitative review in children also
favored SCIT over SLIT, but evidence was low-grade.
However, the remaining review that qualitatively
synthesized the evidence found that there was little
difference in treatment effectiveness for reduction
in medication use when SCIT was compared with
SLIT (Table 1).
Combined symptommedication score
Two systematic reviews evaluated the effectiveness
of SCIT versus SLIT in reducing combined symp-
& &
tommedication use [18 ,19 ]. Whereas the qualita-
tive head-to-head comparative review found low-
grade evidence to support SCIT over SLIT for com-
bined symptommedication reduction, the meta-
analysis found that SCIT and SLIT had equal prob-
abilities for effective reduction of combined symp-
tommedication scores.
Quality of life
A systematic review and meta-analysis that assessed
the effectiveness of SCIT versus SLIT in improving
quality of life favored SCIT over SLIT; however, the
standardized score difference was not statistically
&
significant [18 ] (Table 1).
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Number 3
June 2014
 Table 1. Summary of evidence from systematic reviews

Systematic review No. of RCTs
&
Di Bona et al. [17 ] 14 SCIT versus placebo
22 SLIT versus placebo
&
Dretzke et al. [18 ] 17 SCIT versus placebo
11 SLIT versus placebo
(update to Cochrane
Review)
Symptom score
Pooled SMD for treatment effect:
SCIT versus placebo:
0.92 (95% CI 1.26 to
0.58; P < 0.0001)
SLIT-D versus placebo:
0.25 (95% CI 0.45 to
0.05; P < 0.01)
SLIT-T versus placebo:
0.40 (95% CI 0.54 to
0.27; P < 0.001)
SSD:
SCIT versus SLIT: 0.351
(95% CrI 0.1270.586)
favoring SCIT
Evidence summary
Medication score Quality of life Safety
Pooled SMD for treatment effect: Treatment-emerged AE:
SCIT versus placebo: SCIT: 0.86 AEs/patient
0.58; 95% CI 0.86
to 0.30
SLIT-D versus placebo: SLIT: 2.13 AEs/patient
0.37; 95% CI 0.7 to
0.00
SLIT-T versus placebo: 0.30; Anaphylaxis (episodes):
95% CI 0.44 to 0.16
SCIT/SLIT: 12/1
SSD: SSD: NR
SCIT versus SLIT: 0.273 SCIT versus SLIT: 0.383;
(95% CrI 0.0270.529) 95% CrI, 0.042 to
favoring SCIT 0.804, P NS) favoring
SCIT

Chelladurai et al. 8 SCIT versus SLIT Moderate-grade evidence Low grade evidence- no difference NR Local reactions (frequency):
&

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[19 ] favoring SCIT in treatment effectiveness
between SCIT and SLIT
SCIT: 20%
SLIT: 6.756%
Anaphylaxis (episodes)
SCIT: 1
SLIT: 0
&
Kim et al. [20 ] 3 SCIT versus SLIT Low-grade evidence favoring Low grade evidence favoring NR Local reactions (patients):
(pediatrics only) SCIT SCIT
SCIT: 3
SLIT: 3
Systemic reactions (patients):
SCIT: 4
SLIT: 0
Anaphylaxis (episodes)
SCIT: 1

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SLIT: 0

AE, adverse event; CI, confidence interval; CrI, credible interval; NR, not reported; RCTs, randomized controlled trials; SCIT, subcutaneous immunotherapy; SLIT, sublingual immunotherapy; SLIT-D, sublingual
immunotherapy drops; SLIT-T, sublingual immunotherapy tablet; SMD, standardized mean difference; SSD, standardized score difference.

213
Immunotherapy in allergic rhinitis Chelladurai and Lin

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 Allergy
Safety
Three reviews evaluated the evidence on safety of
& & &
SCIT versus SLIT qualitatively [17 ,19 ,20 ]. In two
reviews, SLIT was associated with an increased
number of local and treatment-emergent adverse
reactions when compared with SCIT. However, ana-
phylaxis was reported to occur more in SCIT-treated
participants than SLIT-treated participants (Table 1).
LIMITATIONS
All reviews identified several important limita-
tions and discussed future recommendations. Even
though SLIT has gained popularity over the past
2 decades, well conducted RCTs with head-to-head
comparisons of SCIT and SLIT are sparse. Even in the
two qualitative reviews that included studies with
both SCIT and SLIT arms, direct comparisons of the
two therapies were not carried out in the individual
studies. Given the current state of literature, indirect
comparison of effectiveness of SCIT and SLIT when
compared with placebo is justified.
The two reviews that carried out meta-analyses
have adequately addressed the issue of hetero-
geneity between studies. Possible sources for hetero-
geneity were explored in a meta-regression by
adjusting for various covariates such as age of
participants, allergen type and dose, duration of
treatment, and so on. In spite of this, several out-
comes suffered from a high degree of residual
heterogeneity, which must be taken into account
while interpreting the results of the reviews.
A major contributing factor to the heterogeneity
in data available is the use of nonstandardized out-
come assessment measures and antigen quantifi-
cation. Studies differ widely in their assessment of
symptom and medication scores. These scores are
the primary outcome measures of clinical effective-
ness of immunotherapy and high degree of hetero-
geneity in score reporting precludes high-quality
quantitative synthesis of evidence. Reporting of
allergen dose varies widely between allergens
and across countries, thus inhibiting an unbiased
comparative evaluation of evidence available.
Differences in duration of treatment and target
maintenance dose have also contributed to hetero-
geneity of evidence base.
The evidence on effectiveness of SCIT versus
SLIT in pediatric population is even more limited.
&
The review by Kim et al. [20 ] identified only three
RCTs of dust mite immunotherapy conducted
exclusively in children. The small sample size and
medium risk of bias of included studies resulted in
the synthesis of low-quality evidence. The safety
data of reviews are primarily from RCTs included
in the reviews. A more comprehensive review of
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literature including observational studies and case
reports is warranted to better evaluate safety profile
of SCIT and SLIT.
CLINICAL IMPLICATIONS AND FUTURE
RESEARCH
The four systematic reviews that support SCIT over
SLIT for reduction in symptoms of allergic rhinitis
and medication use must be carefully evaluated
against their limitations. There is emerging evidence
to favor SCIT over SLIT; however, additional trials of
head-to-head comparisons of the two immuno-
therapies in adults and children are crucial to
strengthen the evidence base. Standardized scoring
systems of clinical outcomes, standardized allergen
dose, content, and duration of treatment will aid in
unbiased pooling of data by minimizing heterogen-
eity. These reviews of monosensitized allergen
immunotherapies trials might not apply to treat-
ment of a patient with polysensitivities that require
multiple cross-reacting allergens to be mixed in the
same solution.
CONCLUSION
There is a growing interest in evaluating the effec-
tiveness of SCIT versus SLIT. The four systematic
reviews published in the past 1214 months are
the only reviews in the literature that address the
comparative clinical effectiveness of SCIT versus
SLIT for treatment of allergic rhinitis. All reviews
equivocally supported SCIT over SLIT for better
reduction in symptoms of allergic rhinitis and
rescue medication use, in both adult and pediatric
population. RCTs with head-to-head direct com-
parisons of SCIT and SLIT are needed to strengthen
this evidence base. Indirect comparisons of treat-
ment options have many limitations and must
be taken into consideration for clinical decision-
making.
Acknowledgements
None.
Conflicts of interest
Y.C. and S.L. declare no conflicts of interest.
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Immunotherapy in allergic rhinitis Chelladurai and Lin
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This is the first systematic review and meta-analysis that compared the effective-
ness of SCIT versus SLIT indirectly by assessing the relative effectiveness of the
two therapies against placebo. In addition to highlighting the effectiveness of SCIT
in reducing symptoms and medication use for allergic rhinitis better than SLIT, this
article also demonstrated the paucity of trials that compared SCIT and SLIT head-
to-head, hence the necessity to carry out indirect comparisons of the same.
18. Dretzke J, Meadows A, Novielli N, et al. Subcutaneous and sublingual
& immunotherapy for seasonal allergic rhinitis: a systematic review and indirect
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This is the second and a more comprehensive systematic review that sought to
study whether either SCIT or SLIT had better effectiveness in treatment of allergic
rhinitis through indirect comparison, meta-analysis, and meta-regression. The
results of this study
&
were consistent with the results of the earlier review by Di
Bona et al. [17 ]. Probabilistic analysis demonstrated a trend favoring SCIT over
SLIT for reductions in symptoms and medication use in allergic rhinitis patients, but
there was no difference between the two treatment options for reduction in
combined symptom medication scores and improvement in quality in life. This
is the only review that carried out meta-regression of several important covariates
to identify heterogeneity between studies.
19. Chelladurai Y, Suarez-Cuervo C, Erekosima N, et al. Effectiveness of sub-
& cutaneous versus sublingual immunotherapy for the treatment of allergic
rhinoconjunctivitis and asthma: a systematic review. J Allergy Clin Immunol
2013; 1:361369.
This review systematically identified eight head-to-head comparison trials of SCIT
versus SLIT. The comparative effectiveness of the two treatment options was syn-
thesized qualitatively. This review also supported greater effectiveness of SCIT when
compared with SLIT for reduction in symptoms of allergic rhinoconjunctivitis. Meta-
analysis was not carried out in this review because of heterogeneity between studies.
20. Kim JM, Lin SY, Suarez-Cuervo C, et al. Allergen-specific immunotherapy for
& pediatric asthma and rhinoconjunctivitis: a systematic review. Pediatrics
2013; 131:11551167.
This is the only systematic review that compared the effectiveness of SCIT versus
SLIT in children exclusively. This small review included three dust mite trials to
assess the comparative effectiveness of SCIT and SLIT qualitatively. In accor-
dance with the earlier reviews, this also supported SCIT over SLIT for reduction in
symptom and medication scores in children with allergic rhinitis. However, the
evidence was low grade and meta-analysis was not carried out.
www.co-otolaryngology.com 215