Original Article
Effectiveness of Subcutaneous Versus Sublingual Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and Asthma: A Systematic Review Yohalakshmi Chelladurai, MBBS, MPHa, Catalina Suarez-Cuervo, MDa, Nkiruka Erekosima, MD, MPHa, Julia M. Kim, MD, MPHb, Murugappan Ramanathan, MDc, Jodi B. Segal, MD, MPHb, and Sandra Y. Lin, MDc Baltimore, Md
What is already known about this topic? Both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) are effective in treatment of allergic rhinoconjunctivitis and asthma. What does this article add to our knowledge? SCIT is better than SLIT in reducing symptoms of asthma (low-grade evidence) and rhinoconjunctivitis (moderate-grade evidence). How does this study impact current management guidelines? Both SCIT and SLIT should remain treatment options until high-quality evidence allows for more definitive comparisons of the 2 therapies. BACKGROUND: Allergen-specific immunotherapy is widely used in the management of patients with allergic rhinoconjunctivitis and asthma, but the best route of delivery is unclear. OBJECTIVE: We performed a systematic review of studies with head-to-head comparison of effectiveness and safety of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) in the treatment of allergic rhinoconjunctivitis and asthma. METHODS: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials databases were searched through December 21, 2012. We included English language randomized
a
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md b Department of Pediatrics, Division of General Pediatrics and Adolescent Medicine, Johns Hopkins University School of Medicine, Baltimore, Md c Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Md Supported by a grant from the Agency for Healthcare Research and Quality. Conflicts of interest: Y. Chelladurai, C. Suarez-Cuervo, N. Erekosima, and J. B. Segal have received research support from the Agency for Healthcare Research and Quality (AHRQ). J. M. Kim has received research support and fellowship training funds from the AHRQ. S. Y. Lin has received research support from the AHRQ and is president of the American Academy of Otolaryngic Allergy. The rest of the authors declare that they have no relevant conflicts of interest. Received for publication November 2, 2012; revised April 9, 2013; accepted for publication April 12, 2013. Available online June 6, 2013. Cite this article as: Chelladurai Y, Suarez-Cuervo C, Erekosima N, Kim JM, Ramanathan M, Segal JB, et al. Effectiveness of subcutaneous versus sublingual immunotherapy for the treatment of allergic rhinoconjunctivitis and asthma: A systematic review. J Allergy Clin Immunol: In Practice 2013;1:361-9. http://dx .doi.org/10.1016/j.jaip.2013.04.005. Corresponding author: Sandra Y. Lin, MD, 601 N Caroline St, #6254, Baltimore, MD 21287. E-mail: [email protected]. 2213-2198/$36.00 Ó 2013 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2013.04.005
controlled trials that enrolled patients with allergic rhinoconjunctivitis and/or asthma with head-to-head comparisons of SCIT with SLIT. Paired reviewers extracted detailed information from included articles on standardized forms and assessed the risk of bias in each article. RESULTS: Eight trials compared the effectiveness and safety of SCIT and SLIT. The effectiveness of the 2 forms of immunotherapy in managing allergic asthma and rhinoconjunctivitis were reported in 4 and 6 clinical trials, respectively. Low-grade evidence supports greater effectiveness of SCIT than SLIT for asthma symptom reduction and also at reducing a combined measure of rhinitis symptoms and medication use. Moderate-grade evidence supports greater effectiveness of SCIT than SLIT for nasal and/or eye symptom reduction. All 8 trials reported on adverse events with an episode of anaphylaxis reported in a child treated with SCIT. CONCLUSION: Our review provides low-grade evidence to support that SCIT is superior to SLIT for reduction in asthma symptoms and moderate-grade evidence for reduction of allergic rhinoconjunctivitis. Additional studies are required to strengthen this evidence base for clinical decision making. Ó 2013 American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol: In Practice 2013;1:361-9) Key words: Allergen-specific immunotherapy; Subcutaneous immunotherapy; Sublingual immunotherapy; Allergic rhinitis; Allergic rhinoconjunctivitis; Allergic asthma; Atopy
Allergic rhinitis is a common clinical problem that affects up to 40% of the general population in North America.1-5 Asthma affects 9% of the US population, and 62% of patients with asthma have atopy.6,7 Allergen-specific immunotherapy is typically recommended for patients whose allergic rhinoconjunctivitis and asthma symptoms cannot be controlled by environmental control and pharmacotherapy, patients who cannot tolerate their medications, or patients who do not comply with chronic medication 361
362
CHELLADURAI ET AL
Abbreviations used RCT- Randomized controlled trial SCIT- Subcutaneous immunotherapy SLIT- Sublingual immunotherapy
regimens.8,9 Currently in the United States, allergen-specific immunotherapy is being administered as subcutaneous injections or sublingual drops placed under the tongue. Although the US Food and Drug Administration has approved the use of only subcutaneous allergen extracts for the treatment of seasonal and perennial allergic rhinitis and asthma, a number of US physicians are using sublingual immunotherapy (SLIT) off label. Subcutaneous immunotherapy (SCIT) is administered as increasing doses of an allergen-containing extract, composed of the relevant allergens to which the patient is sensitive, to suppress or eliminate allergic symptoms. With continued administration, it is expected that the treatment regimen will make the patient tolerant to the offending allergen and suppress future untoward responses to the allergen(s) through modulation of the patient’s immune system.10-13 SLIT involves desensitization by placement of the allergen extract under the tongue as an aqueous solution or as a dissolvable tablet for local absorption. In this review, we sought to compare the effectiveness and safety of SCIT with SLIT from studies with head-to-head comparison of the 2 forms of immunotherapy. This review is part of an evidence report commissioned by the US Agency for Healthcare Research and Quality.
METHODS We recruited a panel of technical experts, which included experts on the treatment of allergies and asthma in the adult and pediatric populations, for input on the research questions and search strategy. A protocol was drafted and finalized with input from the technical expert panel and representatives from the Agency for Healthcare Research and Quality (http:// effectivehealthcare.ahrq.gov/ehc/products/270/665/SIT_Protocol_ 20110824.pdf). Data sources and selection We searched the following databases to December 21, 2012: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, and LILACS (Literatura Latino Americana em Ciências da Saúde) with a specific search strategy. We reviewed titles and then abstracts to identify randomized controlled trials (RCTs) that reported on the effects of SCIT and SLIT. Abstracts were reviewed independently by 2 investigators and were excluded if both investigators agreed that the article met one or more of the exclusion criteria, and disagreements were resolved by consensus. We included English language RCTs that enrolled patients with allergic rhinoconjunctivitis and/or allergic asthma due to airborne allergies, and these diagnoses were confirmed with objective testing. The trials must have tested SCIT and SLIT alone or in combination with usual care, which included pharmacotherapy and environmental interventions. The trials must have reported symptoms, medication use, results of provocation tests, quality of life, harms of treatment, adherence measures, convenience measures, or the long-term effects of treatment, including prevention of sequelae of allergic disease or the development of new sensitivities. We excluded articles in
J ALLERGY CLIN IMMUNOL: IN PRACTICE JULY/AUGUST 2013
which oral immunotherapy was immediately swallowed without prolonged mucosal contact and studies that did not clearly report the dose of allergen delivered.
Data extraction and quality assessment We created standardized forms for data extraction. Reviewers extracted detailed information on the study characteristics, study participants, the interventions, primary and secondary outcome measures and their methods of ascertainment, and safety outcomes. All information from the article review process was entered into the DistillerSR database by the reviewer completing the review. A second reviewer confirmed the accuracy of the first reviewer’s data abstraction. Differences in opinion were resolved through consensus adjudication. We used a modification of the Cochrane Collaboration Tool for Assessing Risk of Bias from the Cochrane Handbook for Systematic Reviews of Interventions.14 We assessed the following 6 categories of potential bias: (1) lack of randomization, (2) lack of allocation concealment, (3) inadequate blinding, (4) incomplete data reporting, (5) other sources of bias, and (6) participation of sponsor company in the study design and interpretation of data.15,16 For each bias category present, a point was assigned, and, depending on their point count across the six categories, studies were categorized as having a low (0-1 point), medium (2-3 points), or high (4-6 points) risk of bias. Data synthesis and analysis We categorized the studies by intervention, by disease, and then by allergen. Given the substantial heterogeneity between studies and the lack of reporting of measures of variability, we did not quantitatively pool the data on efficacy. We graded the quantity, quality, and consistency of the best available evidence by adapting an evidence grading scheme recommended by the GRADE Working Group’s guide for conducting comparative effectiveness reviews.17 In our grade assignments, we considered the limitations of each individual study’s quality (using the risk of bias classification), the consistency of the direction of the effect across studies, the directness of the body of evidence to the question of interest, and the magnitude of the effects reported across trials. We could not comment on the precision of the effect sizes because there were seldom measures of variance within the individual studies. We did not use the reported statistical significance of the differences between groups to grade the evidence because this was rarely reported. We calculated the percentage of change in outcomes in the intervention arm and also the percentage of change in the comparator arm to determine the magnitude of effect. Magnitude of effect was classified as weak if there was less than a 15% difference in percentage of change between the SIT group and comparator arm, a 15% to 40% difference was called moderate, and greater than 40% was considered a strong effect. We applied this scheme to all graded outcomes in this review. When evidence is graded as having a low strength of evidence it means that additional research is likely to change the conclusions. Moderate strength of evidence indicates that additional research is unlikely to change the conclusions although it might, and high strength of evidence indicates that additional research is unlikely to change the conclusions. When evidence is unavailable, we graded it as insufficient evidence. One investigator assigned the evidence grades, and the team reviewed these and came to consensus.
CHELLADURAI ET AL
J ALLERGY CLIN IMMUNOL: IN PRACTICE VOLUME 1, NUMBER 4
363
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• • • • • • • • • • •
• • • vs
vs
• • • • • • • •
FIGURE 1. Summary of the literature search. *Total may exceed number in corresponding box, because articles were excluded by 2 reviewers at this level. **Other reasons include control group is healthy population, routes of administration not included (eg, oral, nasal, lymph node), abandoned interventions, outcomes not reported, no comparator group, continued medical education reports, editorials or reviews, studies about mechanism of action, other allergies (food, aspirin), study in animals or in vitro,
Effectiveness of Subcutaneous Versus Sublingual Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and Asthma: A Systematic Review Yohalakshmi Chelladurai, MBBS, MPHa, Catalina Suarez-Cuervo, MDa, Nkiruka Erekosima, MD, MPHa, Julia M. Kim, MD, MPHb, Murugappan Ramanathan, MDc, Jodi B. Segal, MD, MPHb, and Sandra Y. Lin, MDc Baltimore, Md
What is already known about this topic? Both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) are effective in treatment of allergic rhinoconjunctivitis and asthma. What does this article add to our knowledge? SCIT is better than SLIT in reducing symptoms of asthma (low-grade evidence) and rhinoconjunctivitis (moderate-grade evidence). How does this study impact current management guidelines? Both SCIT and SLIT should remain treatment options until high-quality evidence allows for more definitive comparisons of the 2 therapies. BACKGROUND: Allergen-specific immunotherapy is widely used in the management of patients with allergic rhinoconjunctivitis and asthma, but the best route of delivery is unclear. OBJECTIVE: We performed a systematic review of studies with head-to-head comparison of effectiveness and safety of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) in the treatment of allergic rhinoconjunctivitis and asthma. METHODS: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials databases were searched through December 21, 2012. We included English language randomized
a
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md b Department of Pediatrics, Division of General Pediatrics and Adolescent Medicine, Johns Hopkins University School of Medicine, Baltimore, Md c Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Md Supported by a grant from the Agency for Healthcare Research and Quality. Conflicts of interest: Y. Chelladurai, C. Suarez-Cuervo, N. Erekosima, and J. B. Segal have received research support from the Agency for Healthcare Research and Quality (AHRQ). J. M. Kim has received research support and fellowship training funds from the AHRQ. S. Y. Lin has received research support from the AHRQ and is president of the American Academy of Otolaryngic Allergy. The rest of the authors declare that they have no relevant conflicts of interest. Received for publication November 2, 2012; revised April 9, 2013; accepted for publication April 12, 2013. Available online June 6, 2013. Cite this article as: Chelladurai Y, Suarez-Cuervo C, Erekosima N, Kim JM, Ramanathan M, Segal JB, et al. Effectiveness of subcutaneous versus sublingual immunotherapy for the treatment of allergic rhinoconjunctivitis and asthma: A systematic review. J Allergy Clin Immunol: In Practice 2013;1:361-9. http://dx .doi.org/10.1016/j.jaip.2013.04.005. Corresponding author: Sandra Y. Lin, MD, 601 N Caroline St, #6254, Baltimore, MD 21287. E-mail: [email protected]. 2213-2198/$36.00 Ó 2013 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2013.04.005
controlled trials that enrolled patients with allergic rhinoconjunctivitis and/or asthma with head-to-head comparisons of SCIT with SLIT. Paired reviewers extracted detailed information from included articles on standardized forms and assessed the risk of bias in each article. RESULTS: Eight trials compared the effectiveness and safety of SCIT and SLIT. The effectiveness of the 2 forms of immunotherapy in managing allergic asthma and rhinoconjunctivitis were reported in 4 and 6 clinical trials, respectively. Low-grade evidence supports greater effectiveness of SCIT than SLIT for asthma symptom reduction and also at reducing a combined measure of rhinitis symptoms and medication use. Moderate-grade evidence supports greater effectiveness of SCIT than SLIT for nasal and/or eye symptom reduction. All 8 trials reported on adverse events with an episode of anaphylaxis reported in a child treated with SCIT. CONCLUSION: Our review provides low-grade evidence to support that SCIT is superior to SLIT for reduction in asthma symptoms and moderate-grade evidence for reduction of allergic rhinoconjunctivitis. Additional studies are required to strengthen this evidence base for clinical decision making. Ó 2013 American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol: In Practice 2013;1:361-9) Key words: Allergen-specific immunotherapy; Subcutaneous immunotherapy; Sublingual immunotherapy; Allergic rhinitis; Allergic rhinoconjunctivitis; Allergic asthma; Atopy
Allergic rhinitis is a common clinical problem that affects up to 40% of the general population in North America.1-5 Asthma affects 9% of the US population, and 62% of patients with asthma have atopy.6,7 Allergen-specific immunotherapy is typically recommended for patients whose allergic rhinoconjunctivitis and asthma symptoms cannot be controlled by environmental control and pharmacotherapy, patients who cannot tolerate their medications, or patients who do not comply with chronic medication 361
362
CHELLADURAI ET AL
Abbreviations used RCT- Randomized controlled trial SCIT- Subcutaneous immunotherapy SLIT- Sublingual immunotherapy
regimens.8,9 Currently in the United States, allergen-specific immunotherapy is being administered as subcutaneous injections or sublingual drops placed under the tongue. Although the US Food and Drug Administration has approved the use of only subcutaneous allergen extracts for the treatment of seasonal and perennial allergic rhinitis and asthma, a number of US physicians are using sublingual immunotherapy (SLIT) off label. Subcutaneous immunotherapy (SCIT) is administered as increasing doses of an allergen-containing extract, composed of the relevant allergens to which the patient is sensitive, to suppress or eliminate allergic symptoms. With continued administration, it is expected that the treatment regimen will make the patient tolerant to the offending allergen and suppress future untoward responses to the allergen(s) through modulation of the patient’s immune system.10-13 SLIT involves desensitization by placement of the allergen extract under the tongue as an aqueous solution or as a dissolvable tablet for local absorption. In this review, we sought to compare the effectiveness and safety of SCIT with SLIT from studies with head-to-head comparison of the 2 forms of immunotherapy. This review is part of an evidence report commissioned by the US Agency for Healthcare Research and Quality.
METHODS We recruited a panel of technical experts, which included experts on the treatment of allergies and asthma in the adult and pediatric populations, for input on the research questions and search strategy. A protocol was drafted and finalized with input from the technical expert panel and representatives from the Agency for Healthcare Research and Quality (http:// effectivehealthcare.ahrq.gov/ehc/products/270/665/SIT_Protocol_ 20110824.pdf). Data sources and selection We searched the following databases to December 21, 2012: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, and LILACS (Literatura Latino Americana em Ciências da Saúde) with a specific search strategy. We reviewed titles and then abstracts to identify randomized controlled trials (RCTs) that reported on the effects of SCIT and SLIT. Abstracts were reviewed independently by 2 investigators and were excluded if both investigators agreed that the article met one or more of the exclusion criteria, and disagreements were resolved by consensus. We included English language RCTs that enrolled patients with allergic rhinoconjunctivitis and/or allergic asthma due to airborne allergies, and these diagnoses were confirmed with objective testing. The trials must have tested SCIT and SLIT alone or in combination with usual care, which included pharmacotherapy and environmental interventions. The trials must have reported symptoms, medication use, results of provocation tests, quality of life, harms of treatment, adherence measures, convenience measures, or the long-term effects of treatment, including prevention of sequelae of allergic disease or the development of new sensitivities. We excluded articles in
J ALLERGY CLIN IMMUNOL: IN PRACTICE JULY/AUGUST 2013
which oral immunotherapy was immediately swallowed without prolonged mucosal contact and studies that did not clearly report the dose of allergen delivered.
Data extraction and quality assessment We created standardized forms for data extraction. Reviewers extracted detailed information on the study characteristics, study participants, the interventions, primary and secondary outcome measures and their methods of ascertainment, and safety outcomes. All information from the article review process was entered into the DistillerSR database by the reviewer completing the review. A second reviewer confirmed the accuracy of the first reviewer’s data abstraction. Differences in opinion were resolved through consensus adjudication. We used a modification of the Cochrane Collaboration Tool for Assessing Risk of Bias from the Cochrane Handbook for Systematic Reviews of Interventions.14 We assessed the following 6 categories of potential bias: (1) lack of randomization, (2) lack of allocation concealment, (3) inadequate blinding, (4) incomplete data reporting, (5) other sources of bias, and (6) participation of sponsor company in the study design and interpretation of data.15,16 For each bias category present, a point was assigned, and, depending on their point count across the six categories, studies were categorized as having a low (0-1 point), medium (2-3 points), or high (4-6 points) risk of bias. Data synthesis and analysis We categorized the studies by intervention, by disease, and then by allergen. Given the substantial heterogeneity between studies and the lack of reporting of measures of variability, we did not quantitatively pool the data on efficacy. We graded the quantity, quality, and consistency of the best available evidence by adapting an evidence grading scheme recommended by the GRADE Working Group’s guide for conducting comparative effectiveness reviews.17 In our grade assignments, we considered the limitations of each individual study’s quality (using the risk of bias classification), the consistency of the direction of the effect across studies, the directness of the body of evidence to the question of interest, and the magnitude of the effects reported across trials. We could not comment on the precision of the effect sizes because there were seldom measures of variance within the individual studies. We did not use the reported statistical significance of the differences between groups to grade the evidence because this was rarely reported. We calculated the percentage of change in outcomes in the intervention arm and also the percentage of change in the comparator arm to determine the magnitude of effect. Magnitude of effect was classified as weak if there was less than a 15% difference in percentage of change between the SIT group and comparator arm, a 15% to 40% difference was called moderate, and greater than 40% was considered a strong effect. We applied this scheme to all graded outcomes in this review. When evidence is graded as having a low strength of evidence it means that additional research is likely to change the conclusions. Moderate strength of evidence indicates that additional research is unlikely to change the conclusions although it might, and high strength of evidence indicates that additional research is unlikely to change the conclusions. When evidence is unavailable, we graded it as insufficient evidence. One investigator assigned the evidence grades, and the team reviewed these and came to consensus.
CHELLADURAI ET AL
J ALLERGY CLIN IMMUNOL: IN PRACTICE VOLUME 1, NUMBER 4
363
• • • • • • • •
• • • • • • • • • • •
• • • vs
vs
• • • • • • • •
FIGURE 1. Summary of the literature search. *Total may exceed number in corresponding box, because articles were excluded by 2 reviewers at this level. **Other reasons include control group is healthy population, routes of administration not included (eg, oral, nasal, lymph node), abandoned interventions, outcomes not reported, no comparator group, continued medical education reports, editorials or reviews, studies about mechanism of action, other allergies (food, aspirin), study in animals or in vitro,
