REVIEW URRENT C 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 symptom–medication 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 Allergic rhinoconjunctivitis and asthma are common global health problems. In North America, about 40% of the population suffer from allergic rhinitis [1–5]. 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. Subcutaneous immunotherapy (SCIT) has been used for decades now and it is also the only form of immunotherapy 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
approved and widely utilized in European countries. Around 45% of allergen desensitization therapy in Europe is with SLIT [8]. The effectiveness of individual forms of immunotherapy, SCIT and SLIT, has been evaluated in many systematic reviews [9–15]. The Agency for Healthcare Research and Quality published an evidence report on specific immunotherapy in March 2013 [16]. There is strong evidence to suggest that both SCIT and SLIT are effective in reducing symptoms 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: [email protected]. Curr Opin Otolaryngol Head Neck Surg 2014, 22:211–215 DOI:10.1097/MOO.0000000000000045
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Allergy
Symptom score
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 immunotherapy, 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 comparative 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 immunotherapy’ and ‘subcutaneous immunotherapy’ to identify systematic reviews and meta-analyses that compared SCIT to SLIT for inhalant allergic rhinoconjunctivitis and/or asthma through head-tohead 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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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 symptom–medication score Two systematic reviews evaluated the effectiveness of SCIT versus SLIT in reducing combined symptom–medication use [18 ,19 ]. Whereas the qualitative head-to-head comparative review found lowgrade evidence to support SCIT over SLIT for combined symptom–medication reduction, the metaanalysis found that SCIT and SLIT had equal probabilities for effective reduction of combined symptom–medication scores. &
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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 significant and more considerable clinical response than SLIT. A review of qualitative head-to-head comparisons of SCIT versus SLIT studies also demonstrated 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).
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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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SLIT-T versus placebo: 0.30; 95% CI 0.44 to 0.16
SLIT-T versus placebo: 0.40 (95% CI 0.54 to 0.27; P < 0.001)
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3 SCIT versus SLIT (pediatrics only)
8 SCIT versus SLIT
11 SLIT versus placebo (update to Cochrane Review)
Low-grade evidence favoring SCIT
Moderate-grade evidence favoring SCIT
SCIT versus SLIT: 0.351 (95% CrI 0.127–0.586) favoring SCIT
Low grade evidence favoring SCIT
Low grade evidence- no difference in treatment effectiveness between SCIT and SLIT
SCIT versus SLIT: 0.273 (95% CrI 0.027–0.529) favoring SCIT
SSD:
NR
NR
SCIT versus SLIT: 0.383; 95% CrI, 0.042 to 0.804, P ¼ NS) favoring SCIT
SSD:
SLIT: 0
SCIT: 1
Anaphylaxis (episodes)
SLIT: 0
SCIT: 4
Systemic reactions (patients):
SLIT: 3
SCIT: 3
Local reactions (patients):
SLIT: 0
SCIT: 1
Anaphylaxis (episodes)
SLIT: 6.7–56%
SCIT: 20%
Local reactions (frequency):
NR
SCIT/SLIT: 12/1
Anaphylaxis (episodes):
SLIT: 2.13 AEs/patient
SCIT: 0.86 AEs/patient
Treatment-emerged AE:
Safety
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.
Kim et al. [20 ]
&
Chelladurai et al. & [19 ]
&
Dretzke et al. [18 ]
SSD:
SLIT-D versus placebo: 0.37; 95% CI 0.7 to 0.00
SLIT-D versus placebo: 0.25 (95% CI 0.45 to 0.05; P < 0.01)
17 SCIT versus placebo
SCIT versus placebo: 0.58; 95% CI 0.86 to 0.30
SCIT versus placebo: 0.92 (95% CI 1.26 to 0.58; P < 0.0001)
Pooled SMD for treatment effect:
Pooled SMD for treatment effect:
14 SCIT versus placebo
&
Quality of life
Evidence summary
22 SLIT versus placebo
Medication score
Di Bona et al. [17 ]
Symptom score
No. of RCTs
Systematic review
Table 1. Summary of evidence from systematic reviews
Immunotherapy in allergic rhinitis Chelladurai and Lin
213
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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, anaphylaxis was reported to occur more in SCIT-treated participants than SLIT-treated participants (Table 1). &
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LIMITATIONS All reviews identified several important limitations 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 heterogeneity between studies. Possible sources for heterogeneity 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 outcomes 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 outcome assessment measures and antigen quantification. Studies differ widely in their assessment of symptom and medication scores. These scores are the primary outcome measures of clinical effectiveness of immunotherapy and high degree of heterogeneity 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 heterogeneity 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 immunotherapies 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 heterogeneity. These reviews of monosensitized allergen immunotherapies trials might not apply to treatment 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 effectiveness of SCIT versus SLIT. The four systematic reviews published in the past 12–14 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 comparisons of SCIT and SLIT are needed to strengthen this evidence base. Indirect comparisons of treatment options have many limitations and must be taken into consideration for clinical decisionmaking. Acknowledgements None. Conflicts of interest Y.C. and S.L. declare no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Nathan RA. The burden of allergic rhinitis. Allergy Asthma Proc 2007; 28: 3–9.
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Immunotherapy in allergic rhinitis Chelladurai and Lin 2. Wright AL, Holberg CJ, Martinez FD, et al. Epidemiology of physiciandiagnosed allergic rhinitis in childhood. Pediatrics 1994; 94:895– 901. 3. Min YG. The pathophysiology, diagnosis and treatment of allergic rhinitis. Allergy Asthma Immunol Res 2010; 2:65–76. 4. Brozek JL, Bousquet J, Baena-Cagnani CE, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision. J Allergy Clin Immunol 2010; 126:466–476. 5. Fanta CH. Asthma. N Engl J Med 2009; 360:1002–1014. 6. Expert Panel Report 3 (EPR-3): guidelines for the diagnosis and management of asthma – summary report 2007. J Allergy Clin Immunol 2007; 120:S94– S138. 7. Gergen PJ, Arbes SJ Jr, Calatroni A, et al. Total IgE levels and asthma prevalence in the US population: results from the National Health and Nutrition Examination Survey 2005-2006. J Allergy Clin Immunol 2009; 124:447–453. 8. Cox L, Jacobsen L. Comparison of allergen immunotherapy practice patterns in the United States and Europe. Ann Allergy Asthma Immunol 2009; 103:451–459; quiz 459-461, 495. 9. Matricardi PM, Kuna P, Panetta V, et al. Subcutaneous immunotherapy and pharmacotherapy in seasonal allergic rhinitis: a comparison based on metaanalyses. J Allergy Clin Immunol 2011; 128:791–799; e796. 10. Calderon MA, Alves B, Jacobson M, et al. Allergen injection immunotherapy for seasonal allergic rhinitis. Cochrane Database Syst Rev (Online) 2007; 1–93; CD001936. 11. Abramson MJ, Puy RM, Weiner JM. Injection allergen immunotherapy for asthma. Cochrane Database Syst Rev 2010; 1–88; CD001186. 12. Wilson DR, Torres LI, Durham SR. Sublingual immunotherapy for allergic rhinitis. Cochrane Database Syst Rev 2003; 1–48; CD002893. 13. Radulovic S, Wilson D, Calderon M, Durham S. Systematic reviews of sublingual immunotherapy (SLIT). Allergy 2011; 66:740–752. 14. Lin SY, Erekosima N, Kim JM, et al. Sublingual immunotherapy for the treatment of allergic rhinoconjunctivitis and asthma: a systematic review. JAMA 2013; 309:1278–1288. 15. Erekosima N, Suarez-Cuervo C, Ramanathan M, et al. Effectiveness of subcutaneous immunotherapy for allergic rhinoconjunctivitis and asthma: a systematic review. Laryngoscope 2014; 124:616–627. 16. Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-specific immunotherapy for the treatment of allergic rhinoconjunctivitis and/or asthma: comparative effectiveness review. Rockville, MD: Agency for Healthcare Research and Quality; 2013.
17. Di Bona D, Plaia A, Leto-Barone MS, et al. Efficacy of subcutaneous and sublingual immunotherapy with grass allergens for seasonal allergic rhinitis: a meta-analysis-based comparison. J Allergy Clin Immunol 2012; 130:1097– 1107; e1092. This is the first systematic review and meta-analysis that compared the effectiveness 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 headto-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 comparison. J Allergy Clin Immunol 2013; 131:1361–1366. 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; 1:361–369. This review systematically identified eight head-to-head comparison trials of SCIT versus SLIT. The comparative effectiveness of the two treatment options was synthesized qualitatively. This review also supported greater effectiveness of SCIT when compared with SLIT for reduction in symptoms of allergic rhinoconjunctivitis. Metaanalysis 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; 131:1155–1167. 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 accordance 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. &
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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 symptom–medication 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 Allergic rhinoconjunctivitis and asthma are common global health problems. In North America, about 40% of the population suffer from allergic rhinitis [1–5]. 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. Subcutaneous immunotherapy (SCIT) has been used for decades now and it is also the only form of immunotherapy 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
approved and widely utilized in European countries. Around 45% of allergen desensitization therapy in Europe is with SLIT [8]. The effectiveness of individual forms of immunotherapy, SCIT and SLIT, has been evaluated in many systematic reviews [9–15]. The Agency for Healthcare Research and Quality published an evidence report on specific immunotherapy in March 2013 [16]. There is strong evidence to suggest that both SCIT and SLIT are effective in reducing symptoms 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: [email protected]. Curr Opin Otolaryngol Head Neck Surg 2014, 22:211–215 DOI:10.1097/MOO.0000000000000045
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Allergy
Symptom score
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 immunotherapy, 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 comparative 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 immunotherapy’ and ‘subcutaneous immunotherapy’ to identify systematic reviews and meta-analyses that compared SCIT to SLIT for inhalant allergic rhinoconjunctivitis and/or asthma through head-tohead 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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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 symptom–medication score Two systematic reviews evaluated the effectiveness of SCIT versus SLIT in reducing combined symptom–medication use [18 ,19 ]. Whereas the qualitative head-to-head comparative review found lowgrade evidence to support SCIT over SLIT for combined symptom–medication reduction, the metaanalysis found that SCIT and SLIT had equal probabilities for effective reduction of combined symptom–medication scores. &
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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 significant and more considerable clinical response than SLIT. A review of qualitative head-to-head comparisons of SCIT versus SLIT studies also demonstrated 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).
&
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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SLIT-T versus placebo: 0.30; 95% CI 0.44 to 0.16
SLIT-T versus placebo: 0.40 (95% CI 0.54 to 0.27; P < 0.001)
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3 SCIT versus SLIT (pediatrics only)
8 SCIT versus SLIT
11 SLIT versus placebo (update to Cochrane Review)
Low-grade evidence favoring SCIT
Moderate-grade evidence favoring SCIT
SCIT versus SLIT: 0.351 (95% CrI 0.127–0.586) favoring SCIT
Low grade evidence favoring SCIT
Low grade evidence- no difference in treatment effectiveness between SCIT and SLIT
SCIT versus SLIT: 0.273 (95% CrI 0.027–0.529) favoring SCIT
SSD:
NR
NR
SCIT versus SLIT: 0.383; 95% CrI, 0.042 to 0.804, P ¼ NS) favoring SCIT
SSD:
SLIT: 0
SCIT: 1
Anaphylaxis (episodes)
SLIT: 0
SCIT: 4
Systemic reactions (patients):
SLIT: 3
SCIT: 3
Local reactions (patients):
SLIT: 0
SCIT: 1
Anaphylaxis (episodes)
SLIT: 6.7–56%
SCIT: 20%
Local reactions (frequency):
NR
SCIT/SLIT: 12/1
Anaphylaxis (episodes):
SLIT: 2.13 AEs/patient
SCIT: 0.86 AEs/patient
Treatment-emerged AE:
Safety
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.
Kim et al. [20 ]
&
Chelladurai et al. & [19 ]
&
Dretzke et al. [18 ]
SSD:
SLIT-D versus placebo: 0.37; 95% CI 0.7 to 0.00
SLIT-D versus placebo: 0.25 (95% CI 0.45 to 0.05; P < 0.01)
17 SCIT versus placebo
SCIT versus placebo: 0.58; 95% CI 0.86 to 0.30
SCIT versus placebo: 0.92 (95% CI 1.26 to 0.58; P < 0.0001)
Pooled SMD for treatment effect:
Pooled SMD for treatment effect:
14 SCIT versus placebo
&
Quality of life
Evidence summary
22 SLIT versus placebo
Medication score
Di Bona et al. [17 ]
Symptom score
No. of RCTs
Systematic review
Table 1. Summary of evidence from systematic reviews
Immunotherapy in allergic rhinitis Chelladurai and Lin
213
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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, anaphylaxis was reported to occur more in SCIT-treated participants than SLIT-treated participants (Table 1). &
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LIMITATIONS All reviews identified several important limitations 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 heterogeneity between studies. Possible sources for heterogeneity 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 outcomes 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 outcome assessment measures and antigen quantification. Studies differ widely in their assessment of symptom and medication scores. These scores are the primary outcome measures of clinical effectiveness of immunotherapy and high degree of heterogeneity 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 heterogeneity 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 immunotherapies 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 heterogeneity. These reviews of monosensitized allergen immunotherapies trials might not apply to treatment 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 effectiveness of SCIT versus SLIT. The four systematic reviews published in the past 12–14 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 comparisons of SCIT and SLIT are needed to strengthen this evidence base. Indirect comparisons of treatment options have many limitations and must be taken into consideration for clinical decisionmaking. Acknowledgements None. Conflicts of interest Y.C. and S.L. declare no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Nathan RA. The burden of allergic rhinitis. Allergy Asthma Proc 2007; 28: 3–9.
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Immunotherapy in allergic rhinitis Chelladurai and Lin 2. Wright AL, Holberg CJ, Martinez FD, et al. Epidemiology of physiciandiagnosed allergic rhinitis in childhood. Pediatrics 1994; 94:895– 901. 3. Min YG. The pathophysiology, diagnosis and treatment of allergic rhinitis. Allergy Asthma Immunol Res 2010; 2:65–76. 4. Brozek JL, Bousquet J, Baena-Cagnani CE, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision. J Allergy Clin Immunol 2010; 126:466–476. 5. Fanta CH. Asthma. N Engl J Med 2009; 360:1002–1014. 6. Expert Panel Report 3 (EPR-3): guidelines for the diagnosis and management of asthma – summary report 2007. J Allergy Clin Immunol 2007; 120:S94– S138. 7. Gergen PJ, Arbes SJ Jr, Calatroni A, et al. Total IgE levels and asthma prevalence in the US population: results from the National Health and Nutrition Examination Survey 2005-2006. J Allergy Clin Immunol 2009; 124:447–453. 8. Cox L, Jacobsen L. Comparison of allergen immunotherapy practice patterns in the United States and Europe. Ann Allergy Asthma Immunol 2009; 103:451–459; quiz 459-461, 495. 9. Matricardi PM, Kuna P, Panetta V, et al. Subcutaneous immunotherapy and pharmacotherapy in seasonal allergic rhinitis: a comparison based on metaanalyses. J Allergy Clin Immunol 2011; 128:791–799; e796. 10. Calderon MA, Alves B, Jacobson M, et al. Allergen injection immunotherapy for seasonal allergic rhinitis. Cochrane Database Syst Rev (Online) 2007; 1–93; CD001936. 11. Abramson MJ, Puy RM, Weiner JM. Injection allergen immunotherapy for asthma. Cochrane Database Syst Rev 2010; 1–88; CD001186. 12. Wilson DR, Torres LI, Durham SR. Sublingual immunotherapy for allergic rhinitis. Cochrane Database Syst Rev 2003; 1–48; CD002893. 13. Radulovic S, Wilson D, Calderon M, Durham S. Systematic reviews of sublingual immunotherapy (SLIT). Allergy 2011; 66:740–752. 14. Lin SY, Erekosima N, Kim JM, et al. Sublingual immunotherapy for the treatment of allergic rhinoconjunctivitis and asthma: a systematic review. JAMA 2013; 309:1278–1288. 15. Erekosima N, Suarez-Cuervo C, Ramanathan M, et al. Effectiveness of subcutaneous immunotherapy for allergic rhinoconjunctivitis and asthma: a systematic review. Laryngoscope 2014; 124:616–627. 16. Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-specific immunotherapy for the treatment of allergic rhinoconjunctivitis and/or asthma: comparative effectiveness review. Rockville, MD: Agency for Healthcare Research and Quality; 2013.
17. Di Bona D, Plaia A, Leto-Barone MS, et al. Efficacy of subcutaneous and sublingual immunotherapy with grass allergens for seasonal allergic rhinitis: a meta-analysis-based comparison. J Allergy Clin Immunol 2012; 130:1097– 1107; e1092. This is the first systematic review and meta-analysis that compared the effectiveness 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 headto-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 comparison. J Allergy Clin Immunol 2013; 131:1361–1366. 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; 1:361–369. This review systematically identified eight head-to-head comparison trials of SCIT versus SLIT. The comparative effectiveness of the two treatment options was synthesized qualitatively. This review also supported greater effectiveness of SCIT when compared with SLIT for reduction in symptoms of allergic rhinoconjunctivitis. Metaanalysis 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; 131:1155–1167. 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 accordance 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. &
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