2016 Section 5 Green Book

SUBLINGUAL IMMUNOTHERAPY FOR RHINOCONJUNCTIVITIS AND ASTHMA

dence. 7 The following system was used to assign gradewhen looking at the over- all evidence for each outcome: high- grade evidence required a minimum of 2 or more trials with low risk of bias, and

at least 1 strong magnitude of effect in the context of largely consistent overall evidence. Moderate-grade evidence re- quired 1 or more trials with low risk of bias or strong magnitude of effect, or 1

trial with low risk of bias or moderate magnitude plus 1 trial withmedium risk of bias or strong magnitude. Evidence was low grade if it did not meet any of these categories. Insufficient evidence was assigned if there were no relevant trials. The team reviewed and came to consensus on the grades. The evidence regarding indirect outcome measures (pulmonary function test results and provocation tests) was not graded. A meta-analysis was not performed due to the extreme heterogeneity of the included studies. Therewas awide range of clinical diversity in the types of par- ticipants, their allergies, allergens treated, and geographic treatment locations. The extreme variability of the publishedRCTs in dosing and treatment schedules con- foundsmeta-analysis.Methodological di- versity was evident in the study de- signs, quality, and systems for measured outcomes. The statistical reporting was incomplete in most studies and infor- mation such as confidence intervals was rarely reported. To reduce the risk of publication bias in our results, we searched public reg- istries of clinical trials and requested sci- entific information packets from rel- evant pharmaceutical companies to search for unpublished trials. Because measures of variance were not reported inmost of the included studies, we could not produce a meaningful funnel plot to look for evidence of publication bias. RESULTS We identified 8156 potentially relevant citations. After applying exclusions and triage toother topics, 63RCTs remained for this systematic review ( F IGURE ). We identified63RCTs testingsublingual im- munotherapywith5131participants in- cluded. Participants’ ages ranged from 4 to 74 years. Twenty-six studies (41%) enrolled adults only, 17 (27%) included both adults and children, 8-24 and 20 (32%) exclusivelystudiedchildren( 18 years of age; n=1814 patients). 25-44 Thestudycomparatorgroupswerepla- cebo (46 studies; 73%), another sublin- gualinterventionwithoutaplacebogroup (9 studies; 14%), andconventional treat- ment(pharmacotherapy)withoutplacebo

Figure. Flow Diagram of Sublingual Immunotherapy Studies

17222 Citations identified from electronic database searches

9650 EMBASE 6633 MEDLINE 840 Cochrane Central Register of Controlled Trials 99 LILACS

9066 Excluded (duplicates)

8156 Potentially relevant articles identified for title and abstract review

6329 Excluded a

3677 Did not apply to any of the key questions 1871 No specific immunotherapy 1337 No original data 589 Therapy or related therapy not approved in the United States 141 No patients with allergic rhinoconjunctivitis 81 Study evaluated outcomes in animals only 42 No comparison group and no report of harms 23 Number of patients in the study receiving treatment was 6 or fewer

1827 Potentially relevant articles identified for article review

1643 Excluded a

595 Did not meet all of the inclusion criteria 370 Did not apply to any of the key questions 260 Wrong study design 228 No original data 177 Therapy or related therapy not approved in the United States 66 Published in foreign language (non-English) 51 Abstract only

46 No specific immunotherapy 43 Library unable to locate article 21 Part of another study

185 Other reasons b

184 Potentially relevant articles identified for data abstraction

121 Excluded a

85 No sublingual immunotherapy

9 No diagnosis 7 No dose specified 7 Data not abstractable 6 Not a randomized controlled trial 5 No comparison group 5 No outcomes 1 Therapy or related therapy not approved in the United States 77 Subcutaneous immunotherapy 8 Sublingual immunotherapy vs subcutaneous immunotherapy

63 Randomized controlled trails included in systematic review (N=5131 participants)

a Articles were excluded by 2 reviewers at this level so this number is exceeded by the total for all of the ex- clusions listed. b The possible other reasons included control group is a healthy population, routes of administration not in- cluded (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 (eg, food, aspirin), study in animals or in vitro, or fewer than 6 patients per treatment group.

©2013 American Medical Association. All rights reserved.

JAMA, March 27, 2013—Vol 309, No. 12

Corrected on July 29, 2013

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