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Original Investigation |

Efficacy of Grass Pollen Allergen Sublingual Immunotherapy Tablets for Seasonal Allergic Rhinoconjunctivitis A Systematic Review and Meta-analysis FREE

Danilo Di Bona, MD, PhD1; Antonella Plaia, PhD2; Maria Stefania Leto-Barone, MD, PhD3; Simona La Piana, MD3; Gabriele Di Lorenzo, MD3
[+] Author Affiliations
1Unità Operativa di Immunoematologia e Medicina Trasfusionale, Azienda Ospedaliera Universitaria Policlinico di Palermo, Palermo, Italy
2Dipartimento di Scienze Economiche, Aziendali e Statistiche, Università degli Studi di Palermo, Palermo, Italy
3Dipartimento BioMedico di Medicina Interna e Specialistica, Università degli Studi di Palermo, Palermo, Italy
JAMA Intern Med. 2015;175(8):1301-1309. doi:10.1001/jamainternmed.2015.2840.
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Published online

Importance  Randomized clinical trials (RCTs) and meta-analyses of sublingual immunotherapy (SLIT) for the treatment of seasonal allergic rhinoconjunctivitis (SARC) have shown a modest clinical benefit compared with placebo. Furthermore, indirect comparison by meta-analyses showed that subcutaneous immunotherapy is more effective than SLIT. Despite these data, SLIT has become the most prescribed treatment of SARC in Europe in recent years, and it was approved by the US Food and Drug Administration for the treatment of SARC to grass pollen in the United States on April 1, 2014.

Objective  To assess the efficacy and safety of the grass pollen sublingual tablets licensed as drugs in the treatment of patients with SARC to grass pollen.

Data Sources  Computerized bibliographic searches of MEDLINE, EMBASE, the Cochrane Library, and ClinicalTrials.gov (from inception to April 30, 2014) were supplemented with a manual search of reference lists.

Study Selection  Randomized clinical trials were included if they compared the grass pollen SLIT tablets approved by regulatory authorities in the European Union and the United States for SARC with placebo.

Data Extraction and Synthesis  Data on populations, interventions, and outcomes were extracted from each RCT according to the intent-to-treat method by 2 independent observers and were combined using the method by DerSimonian and Laird.

Main Outcomes and Measures  The primary end point was the difference in the symptom score and medication score between SLIT and placebo. We pooled data using random-effects meta-analysis, with standardized mean differences (SMDs) and 95% CIs reported.

Results  Data were available in 13 RCTs for the symptom score (4659 patients) and in 12 RCTs for the medication score (4558 patients). We found a small treatment benefit in the symptom score (SMD, −0.28; 95% CI, −0.37 to −0.19; P < .001) and in the medication score (SMD, −0.24; 95% CI, −0.31 to −0.17; P < .001). Adverse events were reported in 1384 of 2259 patients (61.3%) receiving SLIT and in 477 of 2279 patients (20.9%) receiving placebo. Seven patients in the SLIT group reported treatment-related adverse events requiring epinephrine.

Conclusions and Relevance  Findings show a small benefit of the grass pollen sublingual tablets in reducing symptoms and in decreasing the use of symptomatic medication (antihistamines and corticosteroids) in patients with SARC. Considering the low magnitude of the benefit, the convenience and easy administration do not seem to be sufficient reasons for the choice of SLIT.

Figures in this Article

Allergic rhinoconjunctivitis is a common condition, affecting 5% to 40% of the general population, and there is evidence that its prevalence is increasing.13 To our knowledge, allergen-specific immunotherapy is the only current treatment that modifies the disease process. Allergen-specific immunotherapy for the treatment of allergic respiratory diseases has traditionally been administered by subcutaneous injections. Subcutaneous immunotherapy (SCIT) has proven efficacy in treating allergic rhinitis, but it requires regular injections at a physician’s office and carries the risk of potentially serious adverse events.4 The favorable safety profile and convenience of sublingual immunotherapy (SLIT) are likely factors for its widespread use in Europe, where it is now the preferred route of administration of allergen-specific immunotherapy and was licensed as a drug on September 26, 2009 (Grazax; Alk-Abellò and Oralair; Stallergenes).5

On April 1, 2014, the US Food and Drug Administration (FDA) announced approval of the 5–grass pollen sublingual tablet (Oralair; Stallergenes), followed by approval of the timothy grass pollen sublingual tablet (Grazax; ALK-Abellò [marketed by Merck in the United States under the brand name Grastek]).6,7 Before that date, SLIT with liquid allergen extracts had been used for off-label indications in the United States.8

Several clinical trials and meta-analyses have reported the efficacy of SCIT and SLIT compared with placebo for seasonal allergic rhinoconjunctivitis (SARC) to grass pollen.4,912 In our group’s previously published meta-analysis12 of randomized clinical trials (RCTs) on the efficacy, we showed that SLIT was effective for SARC to grass pollen but that its clinical benefit vs placebo was modest. We also showed that SLIT tablets are more effective than drops, likely because of a higher allergen content. All the RCTs of SLIT published at that time had been performed in Europe.1323 Since then, 5 additional RCTs have been published, all conducted in North America.2428

Therefore, we performed an expanded systematic review and meta-analysis. Our objective was to provide more reliable and up-to-date evidence on the effect of the grass pollen SLIT tablets approved as drugs in the European Union and the United States.

The primary sources of the reviewed studies were MEDLINE, EMBASE, the Cochrane Library, and ClinicalTrials.gov (from inception to April 30, 2014), with a specific search strategy (eMethods in the Supplement). Two separate reviewers (M.S.L.-B. and S.L.P.) independently extracted detailed information on the study characteristics, participants, interventions, primary and secondary outcome measures and their methods of ascertainment, and safety outcomes. The accuracy of data extraction was confirmed by 2 other reviewers (D.D.B. and G.D.L.). Disagreements were resolved by consensus adjudication. Studies were included in the meta-analysis if (1) they were RCTs comparing grass pollen SLIT administered as tablets with placebo, (2) they involved patients having a clinical history of SARC to grass pollen with or without mild allergic asthma with a positive grass pollen allergen–specific skin test and elevated serum grass pollen allergen–specific IgE levels, and (3) the symptom score (SS) and medication score (MS) were assessed as outcome measures of the treatment effect, regardless of whether these were the primary end points. In most of the RCTs, the results were reported as the means (SDs). In studies15,19,22,26,28 that did not report all the values required for the analysis, data were provided by the authors of the original studies or by the pharmaceutical companies.

We used a modification of the Cochrane Collaboration Tool for Assessing Risk of Bias from the Cochrane Handbook for Systematic Reviews of Interventions (eMethods in the Supplement).29 We used the Jadad score to assess the study quality.30,31

The SS and MS were assessed as outcome measures of the treatment effect. The outcome data analyzed were continuous, but different scoring systems and scales for symptoms and medications were used by the authors of the included studies. Therefore, to compare the results, analyses were performed by the method of standardized mean differences (SMDs), expressing the differences in the means between SLIT and placebo in terms of units of the pooled SDs. The overall SMD among patients treated with SLIT and placebo was estimated using models based on fixed-effects and random-effects assumptions, and data were combined using the method by DerSimonian and Laird.32 The magnitude of the overall effect was classified according to guidelines by Cohen33: effect sizes of 0.2, 0.5, and 0.8 correspond to small, medium, and large effects, respectively.

Because 11 of 13 RCTs used as the outcome measure the same SS, ranging from 0 to 18 points (higher scores indicate worse disease severity), we compared the results of these studies using the original SS, reporting the results as the mean difference of SS points. All of our analyses were computed in R (R Foundation) using the Meta (version 2.0.1) and Metafor (version 1.6) statistical packages.3436

A descriptive subgroup analysis was performed on the SS and MS. A graphical procedure was preferred to a meta-regression because of the likelihood of false-positive results positively correlated with the number of characteristics investigated. The selection of characteristics defining subgroups was motivated by clinical and methodological hypotheses (eMethods in the Supplement). The I2 statistic, which describes the percentage of variability due to heterogeneity rather than sampling errors, was used to quantify heterogeneity.37 Publication bias was assessed with funnel plots, Egger test for asymmetry,38 and the fail-safe calculation (eMethods in the Supplement).

Our search strategy identified 550 unique publications, including more than 80 peer-reviewed studies published from inception of the databases to April 30, 2014, the titles and abstracts of which were screened for inclusion in the study. The full text of 16 studies1328 was retrieved, of which 13 met the inclusion criteria.13,1519,21,22,2428 We excluded the study by Caffarelli et al14 because they used an allergoid (Lais; Lofarma SpA), the study by Horak et al20 because it used an allergen challenge chamber, and the study by Halken et al,23 which is a secondary analysis of a previously published data set22 (eFigure 1 in the Supplement).

Table 1 summarizes descriptive data for the 13 qualifying trials.13,1519,21,22,2428 All studies except for one17 reported the results of an intent-to-treat analysis.

Table Graphic Jump LocationTable 1.  Patient Characteristics Among Trials in the Meta-analysisa

The methodological quality of the studies included in the meta-analysis was good (eTable 1 in the Supplement). The risk of bias was estimated as high in one study,15 medium in 4 RTCs,13,16,21,27 and low in the remaining 8 RCTs1719,22,2426,28 (eTable 2 in the Supplement). A rigorous method of randomization was explicitly described in 8 studies,1719,22,2426,28 and allocation concealment was not reported in any studies. In the remainder, this information was absent or unclear (eTable 2 in the Supplement).

Data on the SS were available in all 13 trials,13,1519,21,22,2428 and data on the MS were available in 12 studies.13,1619,21,22,2428 The 13 RCTs included a total of 4659 patients (Table 1). Seven studies13,1517,19,21,22 were conducted in Europe, 5 studies2428 in North America, and one study18 in Europe and Canada. Only one study15 was conducted in a single center. The sample size of the studies varied greatly (range, 114 in the study by Dahl et el17 to 1501 in the study by Maloney et al28). Three studies21,22,24 enrolled only individuals 17 years or younger, and 2 other studies13,28 included mainly adults, with few children. The study completion rate ranged from 72% to 96%.15,18 The median percentage of male participants was 56.9% (range, 46.5% in the study by Murphy et al27 to 67.5% in the study by Dahl et al17). The median of the mean age of patients in the adult studies was 35.9 years (range, 28.9 years in the study by Didier et al19 to 38.5 years in the study by Smith et al15). The percentage of patients with mild to moderate asthma was reported in 10 of 13 studies (range, 10% in the study by Didier et al19 to 100% in the study by Dahl et al17). The percentage of patients sensitized to allergens other than grass pollen was reported in 9 of 13 studies17,19,21,22,2428 (range, 59%-85%). Eight studies clearly reported the severity of SARC among the enrolled population (severe,15,26 moderate to severe,16,17,19,22 or mild to severe with few mild cases18,21), 3 other studies24,25,27 likely included individuals with moderate to severe SARC, and the remaining 2 studies13,28 did not define the severity of SARC. Eight studies (4 in Europe1618,21 and 4 in North America24,25,27,28) used the grass pollen allergen extract tablets at the same dosage (75 000 standard quality units–tablet, 2800 bioequivalent allergy units, approximately 15 μg of Phleum p5) with a comparable treatment duration (mean length of preseasonal treatment, 14.3 weeks and mean length of coseasonal treatment, 8.5 weeks). Four studies (3 in Europe13,19,22 and one in the United States26) used tablets containing 5–grass pollen allergen extracts at the same dosage standardized in index of reactivity units (IR) (concentration, 300 IR/mL, corresponding to approximately 25 μg of the group of 5 major allergens) for similar duration of treatment (mean length of preseasonal treatment, 16.7 weeks and mean length of coseasonal treatment, 5.7 weeks). The remaining RCT used tablets containing 5–grass pollen allergen extracts administered at a lower concentration (100 IR/mL, approximately 8.5 μg of the group of 5 major allergens).13

Figure 1 shows the results of the meta-analysis. All studies showed a beneficial effect of SLIT on the SS compared with placebo, but 6 of them did not achieve statistical significance.13,15,18,21,25,27 The pooled SMD for the treatment effect was −0.28 (95% CI, −0.37 to −0.19; P < .001), indicating a statistically significant reduction in symptoms in patients receiving SLIT compared with placebo (Figure 1A). Significant heterogeneity between the results of individual studies was reported (Q12 = 26.18, P = .01, I2 = 54.2%, τ2 = 0.0142), but it decreased to 28% (Q11 = 15.21, P = .17, τ2 = 0.0049), with a similar effect size (pooled SMD, −0.24, 95% CI, −0.32 to −0.16; P < .001), with exclusion of an influential study16 (eMethods in the Supplement). This low between-study heterogeneity reported for the SS after exclusion of the influential study (I2 = 28.0%, τ2 = 0.0049) explains the observation that the results between the random-effects (pooled SMD, −0.24; 95% CI, −0.32 to −0.16; P < .001) and fixed-effects (pooled SMD, −0.22; 95% CI, −0.28 to −0.16; P < .001) models are almost overlapping.

Place holder to copy figure label and caption
Figure 1.
Meta-analysis of the Efficacy of Sublingual Immunotherapy vs Placebo for Seasonal Allergic Rhinoconjunctivitis

MD indicates mean difference; NA, not applicable; SMD, standardized mean difference.

Graphic Jump Location

All studies used as the outcome measure an SS ranging from 0 to 18 points except for the studies by Pradalier et al13 and Smith et al,15 which used a score range of 0 to 21. Excluding these 2 studies, we could compare the studies using the original SS, which is easier to interpret. With this method, the mean difference between SLIT and placebo was −0.83 (95% CI, −1.03 to −0.63; P = .001), without significant heterogeneity (I2 = 16.4%) (Figure 1B). The SMD that excluded 2 studies did not change (SMD, −0.28; 95% CI, −0.39 to −0.18; P < .001), indicating that an SMD of −0.28 corresponds to a mean difference of −0.83 SS point.

Data on the MS were obtained for 12 RCTs13,1619,21,22,2428 (4558 patients). A statistically significant difference between SLIT and placebo was observed in only 7 RCTs1619,22,26,28 (Figure 1C). The pooled estimate of treatment on the MS was statistically significant (SMD, −0.24; 95% CI, −0.31 to −0.17; P < .001). An analysis using the original MS was not performed owing to the different scoring systems used.

Funnel plots and Egger test for the SS and MS did not show substantial evidence of bias toward positive results, suggesting no selective reporting (eFigure 2 in the Supplement). The fail-safe numbers were 237 for the SS and 172 for the MS, high enough to confirm the robustness of the results against publication bias.

Subgroup analyses suggested a greater benefit in European vs American studies, in studies using the 5-allergen grass pollen extract tablets vs studies using the 1-allergen grass pollen extract tablets, and in smaller studies. No age effect was found. These results are summarized in Figure 2 and in the eResults in the Supplement.

Place holder to copy figure label and caption
Figure 2.
Descriptive Subgroup Analysis

Analyses of symptom score (A) and medication score (B) for the efficacy of sublingual immunotherapy in seasonal allergic rhinoconjunctivitis. The boxplots include the middle 50% of the data. The horizontal bars inside the boxes represent the median standardized mean difference (SMD). The dotted lines to the whiskers extend to the most extreme data points, which are no more than 1.5 times the interquartile range from the box. Outliers in panel A include the study by Murphy et al27 and a study by Dahl et al.16 The outlier in panel B is a study by Cox et al.26

Graphic Jump Location

A sensitivity analysis that excluded the 5 studies at high15 or moderate13,16,21,27 risk of bias and the study17 using a per-protocol analysis produced similar results (SMD, −0.25; 95% CI, −0.34 to −0.15; P < .001). These results suggested that trial quality affects outcomes only marginally.

In total, 1817 of 2597 patients (70.0%) receiving SLIT vs 1137 of 2555 patients (44.5%) receiving placebo reported adverse events (Table 2 and eTable 3 in the Supplement). Probable treatment-related adverse events were reported in 9 of 13 studies, and there were 3 times as many adverse events in patients receiving SLIT (1384 of 2259 [61.3%]) compared with those receiving placebo (477 of 2279 [20.9%]). Most adverse events were moderate in severity for both groups. The withdrawal rate for adverse events was higher in the SLIT group (159 patients [6.0%]) than in the placebo group (58 patients [2.2%]). No episode of anaphylaxis was reported in the RCTs; however, 9 adverse events requiring epinephrine were reported in the SLIT group, of which 7 were treatment related. Three serious adverse events requiring epinephrine were reported in the placebo group, but none of them were treatment related.

Table Graphic Jump LocationTable 2.  Adverse Events During Treatment

This meta-analysis provides evidence of a small benefit of grass pollen allergy immunotherapy tablets in the treatment of SARC. The low level of heterogeneity after exclusion of the influential study16 suggests that the results are not influenced by uncertainties about study quality or publication bias.

Most of the studies included in this meta-analysis enrolled patients with reported moderate or severe SARC, which are the inclusion criteria as recommended by the World Allergy Organization,39 corresponding to a mean SS without any treatment of 12.5 on an 18-point SS scale. On average, the SS during the treatment period reported in the RCTs is 3 to 4 points, with a SLIT vs placebo difference of −0.83 SS point. This means that, of a mean SS reduction of approximately 8 to 9 points, SLIT is responsible for only about 10% (<1 SS point). Therefore, the symptomatic treatment (antihistamines or corticosteroids) administered on demand is likely responsible for most of the relief of the symptoms in both groups. Some critics might assert that the higher use of rescue medication to alleviate symptoms in the placebo group decreases the mean difference between SLIT and placebo. However, with this set of data, we observed no substantial role of rescue medication in modifying the SS because the MS difference between SLIT and placebo was small (SMD, −0.23).33

Besides a statistically significant difference between SLIT and placebo, the FDA requires for drug approval that SLIT studies must demonstrate at least a 15% improvement in the total combined score (TCS [the SS plus the MS]) compared with placebo (the World Allergy Organization recommends a 20% improvement).39,40 Most of the studies analyzed herein seem to fulfill these requirements. However, the group difference is less than 1 SS point, which is not significant in clinical practice according to the criteria by Cohen.33 Despite the limits of Cohen’s threshold for clinical effectiveness, comparisons with other treatments such as SCIT for grass pollen allergen (SMD, −0.92)4 or oral antihistamines or nasal corticosteroids41,42 showing higher benefits confirm that the clinical benefit of the SLIT tablets reported in our meta-analysis is small. This is likely due to several methodological defects in the analysis of the data.

First, the calculation of the percentage of improvement in the TCS of 15% or 20% between active and placebo as a measure of SLIT efficacy reported in the RCTs is questionable because the TCS is the sum of different clinical outcomes. Therefore, a distinct evaluation for each of them would be more appropriate from a clinical point of view.

Second, the SS and MS are calculated using different scales (0-18 points for the SS and up to 36 points for the MS), and the results of these 2 different scales are summed to obtain the TCS. This is incorrect from a statistical point of view because scales have different weights depending on their range. However, there is a more serious statistical problem: the MS is a qualitative variable, and it can be considered on an ordinal scale but cannot be treated as interval data because intervals between each value (ie, 1 point for antihistamines, 2 points for nasal corticosteroids, and 3 points for oral corticosteroids, as arbitrarily assigned by investigators,) are not equal. Therefore, a TCS cannot be computed. The comparison would be valid only if limited to the SS.

The third and most important concern is that the calculation of the percentage of improvement in the SS between SLIT and placebo shown in the individual studies does not take into account the SS scale range and consequently does not reflect the real clinical difference between the groups. The difference in the mean daily SS between SLIT and placebo recorded during the pollen season is the primary outcome of each study. This difference is also expressed as the percentage of improvement and is calculated as the placebo score minus the SLIT score, divided by the placebo score. For example, in the study by Cox et al,26 reporting the highest efficacy among North American studies, the difference between SLIT and placebo is −0.95 (3.21 minus 4.16) SS point, corresponding to a 22.8% (3.21 minus 4.16, divided by 4.16) improvement in the SLIT group compared with the placebo group (eTable 4 in the Supplement). This seems to fulfill the FDA requirement for SLIT efficacy (difference of ≥15%), but an improvement of only 0.95 SS point is observed in the SLIT group compared with the placebo group. This difference is not clinically significant according to the criteria by Cohen33 because it corresponds to −0.26 SMD (Figure 1A), a value close to the assumed subjective threshold of inefficacy (−0.20 SMD). A different calculation must be made to reflect the real clinical difference between the groups. The correct evaluation of an improvement between SLIT and placebo cannot take into account only the SS values during the treatment period but should compare these SS values with the SS values that are retrospectively reported in the absence of any treatment for each group. This approach allows us to incorporate the scale range in the evaluation of the clinical improvement. We considered again the study by Cox et al,26 which is the only included study that precisely reports all the data useful for an accurate comparison between SLIT and placebo (eTable 4 in the Supplement). In their study, the severity of SARC is defined by the retrospective rhinoconjunctivitis SS, which is comparable between SLIT and placebo owing to the randomization (14.90 SS points for each group). Therefore, patients receiving SLIT have an improvement of 11.69 (14.9 minus 3.21) SS points, which corresponds to a 78% improvement compared with the retrospective SS while patients receiving placebo have an improvement of 10.74 (14.9 minus 4.16) SS points, corresponding to a 72% improvement. Although the difference between SLIT and placebo in SS points remains unchanged at −0.95 (10.74 minus 11.69) SS point, the percentage of improvement decreases to 6% (78% minus 72%), which is much less than the 22.9% reported in the study (an analysis that includes all the studies is shown in eFigure 3 in the Supplement). Computing the improvement according to the method described above, we take into account the actual scale of the SS, thus mirroring the true clinical difference (<1 SS point on a scale of 0-18). In contrast, using the method of the authors of each study, a 1-point difference between 2 groups is the same percentage whether a 10-point scale or a 100-point scale is used.

Subgroup analysis showed that the treatment efficacy was lower in North American studies2428 than in European studies.13,1519,21,22 The reason for this difference is unclear. North American RCTs are the most recent, feature larger sample sizes on average, and are unaffected by bias owing to study quality, suggesting that these studies likely provide a more reliable estimation of the treatment effect. On the other hand, the proportion of polysensitized participants was higher in North American studies than in European studies. This may mask the treatment effect, although researchers tried to control for the geographic- and weather-related variability of pollen seasons, as well as the negative influence of confounding allergens.

Four of five North American SLIT studies24,25,27,28 used a tablet containing an extract of a single grass pollen (Phleum p5). However, in North America a 5–grass pollen allergen extract can be expected to better represent natural exposure and sensitization conditions encountered by patients with grass pollen allergy than an extract of a single grass pollen. This may explain the greater benefit, particularly in the MS, reported in the study by Cox et al,26 which used a 5–grass pollen allergen extract. However, this evidence was not found in European studies, which showed the same efficacy between the 1–grass pollen and 5–grass pollen allergen extracts.

There are limitations of this meta-analysis owing to imperfections in all single studies, including the participation of sponsor companies in the study design and interpretation of data.43,44 Other limitations include potential conflicts of interest by 1 or more authors in studies, the fact that some studies did not describe the randomization or the allocation concealment method, the use of a low dosage of allergens in one study, the small sample sizes in some studies, and the use of a per-protocol analysis by one study. However, our study also has strengths, including the following: the total number of participants is large for assessment of the treatment effect, many individual studies are well powered, most studies used similar treatment regimens and similar allergen dosages, the risk of publication bias is low and unlikely to influence the final result, and the level of heterogeneity is minimal after exclusion of the influential study.16 Therefore, we believe that the results showing a small clinical benefit of SLIT administered as tablets likely represent a valid finding. Furthermore, in contrast to previous meta-analyses,4,12,45,46 RCTs using the same 18-point SS scale were included in this meta-analysis (except for 2 studies13,15). This allowed us to report the results as SS units (mean differences), which are much easier to interpret than SMDs.

The overall results of our analysis are consistent with previous investigations. Lin et al47 reported a moderate level of evidence to support the effectiveness of SLIT for the treatment of allergic rhinitis. Dretzke et al46 reported a mild reduction in the SS with SLIT compared with placebo. Our review, which is the most comprehensive to date because it analyzes studies up to 2014, indicates that the benefit is even lower than previously assessed owing to inclusion of the most recent and powerful SLIT studies. Moreover, in contrast to previous reviews that analyzed studies with extreme variability in the type of allergens, dosing, and treatment schedules, this review included studies with standardized high dosages of grass pollen only, which have been established as the most effective by previous studies.

The clinical implication of our findings is that the continued widespread use of SLIT in Europe, as well as future use of the treatment in the United States, is questionable. As shown by previous meta-analyses4,46 indirectly comparing SCIT and SLIT, SCIT seems to be the most effective treatment. The main reasons for the choice of SLIT have been the convenience and safety profile. However, in the studies included in this meta-analysis, there were 7 patients in the SLIT group with treatment-related adverse events requiring epinephrine. For this reason, the FDA requires that patients who commence SLIT treatment must be provided with epinephrine for self-injection.6,7 Furthermore, the number of episodes of anaphylaxis reported in SCIT RCTs is negligible4; in contrast, the total number of adverse events is higher in SLIT than in SCIT.4 In addition, serious complications such as eosinophilic esophagitis with the use of SLIT for grass pollen allergens have been reported.48

On the other hand, it is important to emphasize that no fatality has been reported with the use of SLIT. However, there are reports of systemic reactions, including those resulting in death, associated with SCIT.49

Regarding the convenience, factors such as the availability of therapy (in some areas it would be impossible for patients to receive injections weekly) and the ability to tolerate therapy (particularly in children, who tolerate SLIT at a much younger age than SCIT) may be important reasons for the choice of SLIT. This cannot be discounted because it represents a substantial benefit of SLIT compared with placebo.

The results of this meta-analysis are sufficient to conclude that the grass pollen allergy immunotherapy tablets show an allergen-specific effect, but its magnitude is small and is complicated by adverse events. Therefore, the convenience and ease of administration do not seem to be sufficient reasons for the choice of SLIT. However, SLIT can be appropriate for certain patients. Our data suggest that further studies are needed to identify variables to predict the response to SLIT,50,51 permitting the targeting of this treatment to individuals who are likely to respond.

Accepted for Publication: May 4, 2015.

Corresponding Author: Gabriele Di Lorenzo, MD, Dipartimento BioMedico di Medicina Interna e Specialistica, Università degli Studi di Palermo, 141 Via del Vespro, 90127 Palermo, Italy (gabriele.dilorenzo@unipa.it).

Published Online: June 29, 2015. doi:10.1001/jamainternmed.2015.2840.

Author Contributions: Dr Di Lorenzo had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: All authors.

Acquisition, analysis, or interpretation of data: Stefania Leto-Barone, La Piana.

Drafting of the manuscript: Di Bona.

Critical revision of the manuscript for important intellectual content: Di Lorenzo.

Statistical analysis: Plaia.

Administrative, technical, or material support: Di Bona, Di Lorenzo.

Conflict of Interest Disclosures: None reported.

Additional Contributions: Crude data were provided by Michel Melac, MD (Stallergenes), Jeremy Jacobsen, JD (Merck), and Robert K. Zeldin, MD (Stallergenes). No financial compensation was provided.

Bernstein  JA.  Characterizing rhinitis subtypes. Am J Rhinol Allergy. 2013;27(6):457-460.
PubMed   |  Link to Article
Greiner  AN, Hellings  PW, Rotiroti  G, Scadding  GK.  Allergic rhinitis. Lancet. 2011;378(9809):2112-2122.
PubMed   |  Link to Article
Portnoy  JM, Sampson  H.  Management of allergic rhinitis. Lancet. 2008;372(9643):1037.
PubMed   |  Link to Article
Di Bona  D, Plaia  A, Leto-Barone  MS, La Piana  S, Di Lorenzo  G.  Efficacy of subcutaneous and sublingual immunotherapy with grass allergens for seasonal allergic rhinitis: a meta-analysis-based comparison. J Allergy Clin Immunol. 2012;130(5):1097-1107.e2. doi:10.1016/j.jaci.2012.08.012.
PubMed   |  Link to Article
Canonica  GW, Cox  L, Pawankar  R,  et al.  Sublingual immunotherapy: World Allergy Organization position paper 2013 update. World Allergy Organ J. 2014;7(1):6.
PubMed   |  Link to Article
US Food and Drug Administration. Approval notification of Oralair. Approved in 2014. http://www.fda.gov/downloads/BiologicsBloodVaccines/Allergenics/UCM391580.pdf. Accessed April 4, 2014.
US Food and Drug Administration. April 11, 2014 approval letter: Grastek. http://www.fda.gov/biologicsbloodvaccines/allergenics/ucm393185.htm. Accessed April 15, 2014.
Cox  LS, Larenas Linnemann  D, Nolte  H, Weldon  D, Finegold  I, Nelson  HS.  Sublingual immunotherapy: a comprehensive review. J Allergy Clin Immunol. 2006;117(5):1021-1035.
PubMed   |  Link to Article
Durham  SR, Walker  SM, Varga  EM,  et al.  Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med. 1999;341(7):468-475.
PubMed   |  Link to Article
Cox  L, Wallace  D.  Specific allergy immunotherapy for allergic rhinitis: subcutaneous and sublingual. Immunol Allergy Clin North Am. 2011;31(3):561-599.
PubMed   |  Link to Article
Calderón  MA, Casale  TB, Togias  A, Bousquet  J, Durham  SR, Demoly  P.  Allergen-specific immunotherapy for respiratory allergies: from meta-analysis to registration and beyond. J Allergy Clin Immunol. 2011;127(1):30-38.
PubMed   |  Link to Article
Di Bona  D, Plaia  A, Scafidi  V, Leto-Barone  MS, Di Lorenzo  G.  Efficacy of sublingual immunotherapy with grass allergens for seasonal allergic rhinitis: a systematic review and meta-analysis. J Allergy Clin Immunol. 2010;126(3):558-566.
PubMed   |  Link to Article
Pradalier  A, Basset  D, Claudel  A,  et al.  Sublingual-swallow immunotherapy (SLIT) with a standardized five-grass-pollen extract (drops and sublingual tablets) versus placebo in seasonal rhinitis. Allergy. 1999;54(8):819-828.
PubMed   |  Link to Article
Caffarelli  C, Sensi  LG, Marcucci  F, Cavagni  G.  Preseasonal local allergoid immunotherapy to grass pollen in children: a double-blind, placebo-controlled, randomized trial. Allergy. 2000;55(12):1142-1147.
PubMed   |  Link to Article
Smith  H, White  P, Annila  I, Poole  J, Andre  C, Frew  A.  Randomized controlled trial of high-dose sublingual immunotherapy to treat seasonal allergic rhinitis. J Allergy Clin Immunol. 2004;114(4):831-837.
PubMed   |  Link to Article
Dahl  R, Kapp  A, Colombo  G,  et al.  Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2006;118(2):434-440.
PubMed   |  Link to Article
Dahl  R, Stender  A, Rak  S.  Specific immunotherapy with SQ standardized grass allergen tablets in asthmatics with rhinoconjunctivitis. Allergy. 2006;61(2):185-190.
PubMed   |  Link to Article
Durham  SR, Yang  WH, Pedersen  MR, Johansen  N, Rak  S.  Sublingual immunotherapy with once-daily grass allergen tablets: a randomized controlled trial in seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2006;117(4):802-809.
PubMed   |  Link to Article
Didier  A, Malling  HJ, Worm  M,  et al.  Optimal dose, efficacy, and safety of once-daily sublingual immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitis. J Allergy Clin Immunol. 2007;120(6):1338-1345.
PubMed   |  Link to Article
Horak  F, Zieglmayer  P, Zieglmayer  R,  et al.  Early onset of action of a 5-grass-pollen 300-IR sublingual immunotherapy tablet evaluated in an allergen challenge chamber. J Allergy Clin Immunol. 2009;124(3):471-477, 477.e1. doi:10.1016/j.jaci.2009.06.006.
PubMed   |  Link to Article
Bufe  A, Eberle  P, Franke-Beckmann  E,  et al.  Safety and efficacy in children of an SQ-standardized grass allergen tablet for sublingual immunotherapy. J Allergy Clin Immunol. 2009;123(1):167-173.e7. doi:10.1016/j.jaci.2008.10.044.
PubMed   |  Link to Article
Wahn  U, Tabar  A, Kuna  P,  et al; SLIT Study Group.  Efficacy and safety of 5-grass-pollen sublingual immunotherapy tablets in pediatric allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2009;123(1):160-166.e3. doi:10.1016/j.jaci.2008.10.009.
PubMed   |  Link to Article
Halken  S, Agertoft  L, Seidenberg  J,  et al.  Five-grass pollen 300IR SLIT tablets: efficacy and safety in children and adolescents. Pediatr Allergy Immunol. 2010;21(6):970-976.
PubMed   |  Link to Article
Blaiss  M, Maloney  J, Nolte  H, Gawchik  S, Yao  R, Skoner  DP.  Efficacy and safety of timothy grass allergy immunotherapy tablets in North American children and adolescents [published correction appears in J Allergy Clin Immunol. 2011;128(2):436]. J Allergy Clin Immunol. 2011;127(1):64-71, 71.e1-71.e4. doi:10.1016/j.jaci.2010.11.034.
PubMed   |  Link to Article
Nelson  HS, Nolte  H, Creticos  P, Maloney  J, Wu  J, Bernstein  DI.  Efficacy and safety of timothy grass allergy immunotherapy tablet treatment in North American adults. J Allergy Clin Immunol. 2011;127(1):72-80, 80.e1-80.e2. doi:10.1016/j.jaci.2010.11.034.
PubMed   |  Link to Article
Cox  LS, Casale  TB, Nayak  AS,  et al.  Clinical efficacy of 300IR 5-grass pollen sublingual tablet in a US study: the importance of allergen-specific serum IgE. J Allergy Clin Immunol. 2012;130(6):1327-1334.e1. doi:10.1016/j.jaci.2012.08.032.
PubMed   |  Link to Article
Murphy  K, Gawchik  S, Bernstein  D, Andersen  J, Pedersen  MR.  A phase 3 trial assessing the efficacy and safety of grass allergy immunotherapy tablet in subjects with grass pollen–induced allergic rhinitis with or without conjunctivitis, with or without asthma. J Negat Results Biomed. 2013;12:10-19.
PubMed   |  Link to Article
Maloney  J, Bernstein  DI, Nelson  H,  et al.  Efficacy and safety of grass sublingual immunotherapy tablet, MK-7243: a large randomized controlled trial. Ann Allergy Asthma Immunol. 2014;112(2):146-153.e2. doi:10.1016/j.anai.2013.11.018.
PubMed   |  Link to Article
Chapter 8: Assessing risk of bias in included studies. In: Higgins  JPT, Green  S, eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. Updated March 2011. http://handbook.cochrane.org/. Accessed May 20, 2015.
Jüni  P, Witschi  A, Bloch  R, Egger  M.  The hazards of scoring the quality of clinical trials for meta-analysis. JAMA. 1999;282(11):1054-1060.
PubMed   |  Link to Article
Jadad  AR, Moore  RA, Carroll  D,  et al.  Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17(1):1-12.
PubMed   |  Link to Article
DerSimonian  R, Laird  N.  Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177-188.
PubMed   |  Link to Article
Cohen  J. Statistical Power Analysis for the Behavioral Sciences.2nd ed. Hillsdale, NJ: Lawrence Erlbaum Associates; 1988.
R Foundation. The R Project for statistical computing.http://www.R-project.org. Accessed May 17, 2015.
Schwarzer  G. meta: Meta-Analysis With R. R package version 1.1-8. 2010. http://cran.r-project.org/web/packages/meta/index.html. Accessed May 28, 2015.
Viechtbauer  W. Metafor: Meta-Analysis Package for R. R package version 2010. http://cran.r-project.org/web/packages/metafor/index.html. Accessed May 28, 2015.
Higgins  JP, Thompson  SG.  Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539-1558.
PubMed   |  Link to Article
Egger  M, Davey Smith  G, Schneider  M, Minder  C.  Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629-634.
PubMed   |  Link to Article
Canonica  GW, Bousquet  J, Casale  T,  et al.  Sub-lingual immunotherapy: World Allergy Organization position paper 2009. World Allergy Organ J. 2009;2(11):233-281.
PubMed   |  Link to Article
Canonica  GW, Baena-Cagnani  CE, Bousquet  J,  et al.  Recommendations for standardization of clinical trials with allergen specific immunotherapy for respiratory allergy: a statement of a World Allergy Organization (WAO) taskforce. Allergy. 2007;62(3):317-324.
PubMed   |  Link to Article
Benninger  M, Farrar  JR, Blaiss  M,  et al.  Evaluating approved medications to treat allergic rhinitis in the United States: an evidence-based review of efficacy for nasal symptoms by class. Ann Allergy Asthma Immunol. 2010;104(1):13-29.
PubMed   |  Link to Article
Wilson  AM, O’Byrne  PM, Parameswaran  K.  Leukotriene receptor antagonists for allergic rhinitis: a systematic review and meta-analysis. Am J Med. 2004;116(5):338-344.
PubMed   |  Link to Article
Lundh  A, Sismondo  S, Lexchin  J, Busuioc  OA, Bero  L.  Industry sponsorship and research outcome. Cochrane Database Syst Rev. 2012;12:MR000033.
PubMed
 Drugs and devices look more effective in studies sponsored by industry. BMJ. 2012;345:e8386. doi:10.1136/bmj.e8386.
PubMed   |  Link to Article
Radulovic  S, Calderon  MA, Wilson  D, Durham  S.  Sublingual immunotherapy for allergic rhinitis. Cochrane Database Syst Rev. 2010;(12):CD002893.
PubMed
Dretzke  J, Meadows  A, Novielli  N, Huissoon  A, Fry-Smith  A, Meads  C.  Subcutaneous and sublingual immunotherapy for seasonal allergic rhinitis: a systematic review and indirect comparison. J Allergy Clin Immunol. 2013;131(5):1361-1366.
PubMed   |  Link to Article
Lin  SY, Erekosima  N, Kim  JM,  et al.  Sublingual immunotherapy for the treatment of allergic rhinoconjunctivitis and asthma: a systematic review. JAMA. 2013;309(12):1278-1288.
PubMed   |  Link to Article
Antico  A, Fante  R.  Esophageal hypereosinophilia induced by grass sublingual immunotherapy. J Allergy Clin Immunol. 2014;133(5):1482-1484.
PubMed   |  Link to Article
Bernstein  DI, Wanner  M, Borish  L, Liss  GM; Immunotherapy Committee, American Academy of Allergy, Asthma and Immunology.  Twelve-year survey of fatal reactions to allergen injections and skin testing: 1990-2001. J Allergy Clin Immunol. 2004;113(6):1129-1136.
PubMed   |  Link to Article
Di Lorenzo  G, Mansueto  P, Pacor  ML,  et al.  Evaluation of serum s-IgE/total IgE ratio in predicting clinical response to allergen-specific immunotherapy. J Allergy Clin Immunol. 2009;123(5):1103-1110, 1110.e1-1110.e4. doi:10.1016/j.jaci.2009.02.012.
PubMed   |  Link to Article
Cromwell  O, Häfner  D, Nandy  A.  Recombinant allergens for specific immunotherapy. J Allergy Clin Immunol. 2011;127(4):865-872.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.
Meta-analysis of the Efficacy of Sublingual Immunotherapy vs Placebo for Seasonal Allergic Rhinoconjunctivitis

MD indicates mean difference; NA, not applicable; SMD, standardized mean difference.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Descriptive Subgroup Analysis

Analyses of symptom score (A) and medication score (B) for the efficacy of sublingual immunotherapy in seasonal allergic rhinoconjunctivitis. The boxplots include the middle 50% of the data. The horizontal bars inside the boxes represent the median standardized mean difference (SMD). The dotted lines to the whiskers extend to the most extreme data points, which are no more than 1.5 times the interquartile range from the box. Outliers in panel A include the study by Murphy et al27 and a study by Dahl et al.16 The outlier in panel B is a study by Cox et al.26

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1.  Patient Characteristics Among Trials in the Meta-analysisa
Table Graphic Jump LocationTable 2.  Adverse Events During Treatment

References

Bernstein  JA.  Characterizing rhinitis subtypes. Am J Rhinol Allergy. 2013;27(6):457-460.
PubMed   |  Link to Article
Greiner  AN, Hellings  PW, Rotiroti  G, Scadding  GK.  Allergic rhinitis. Lancet. 2011;378(9809):2112-2122.
PubMed   |  Link to Article
Portnoy  JM, Sampson  H.  Management of allergic rhinitis. Lancet. 2008;372(9643):1037.
PubMed   |  Link to Article
Di Bona  D, Plaia  A, Leto-Barone  MS, La Piana  S, Di Lorenzo  G.  Efficacy of subcutaneous and sublingual immunotherapy with grass allergens for seasonal allergic rhinitis: a meta-analysis-based comparison. J Allergy Clin Immunol. 2012;130(5):1097-1107.e2. doi:10.1016/j.jaci.2012.08.012.
PubMed   |  Link to Article
Canonica  GW, Cox  L, Pawankar  R,  et al.  Sublingual immunotherapy: World Allergy Organization position paper 2013 update. World Allergy Organ J. 2014;7(1):6.
PubMed   |  Link to Article
US Food and Drug Administration. Approval notification of Oralair. Approved in 2014. http://www.fda.gov/downloads/BiologicsBloodVaccines/Allergenics/UCM391580.pdf. Accessed April 4, 2014.
US Food and Drug Administration. April 11, 2014 approval letter: Grastek. http://www.fda.gov/biologicsbloodvaccines/allergenics/ucm393185.htm. Accessed April 15, 2014.
Cox  LS, Larenas Linnemann  D, Nolte  H, Weldon  D, Finegold  I, Nelson  HS.  Sublingual immunotherapy: a comprehensive review. J Allergy Clin Immunol. 2006;117(5):1021-1035.
PubMed   |  Link to Article
Durham  SR, Walker  SM, Varga  EM,  et al.  Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med. 1999;341(7):468-475.
PubMed   |  Link to Article
Cox  L, Wallace  D.  Specific allergy immunotherapy for allergic rhinitis: subcutaneous and sublingual. Immunol Allergy Clin North Am. 2011;31(3):561-599.
PubMed   |  Link to Article
Calderón  MA, Casale  TB, Togias  A, Bousquet  J, Durham  SR, Demoly  P.  Allergen-specific immunotherapy for respiratory allergies: from meta-analysis to registration and beyond. J Allergy Clin Immunol. 2011;127(1):30-38.
PubMed   |  Link to Article
Di Bona  D, Plaia  A, Scafidi  V, Leto-Barone  MS, Di Lorenzo  G.  Efficacy of sublingual immunotherapy with grass allergens for seasonal allergic rhinitis: a systematic review and meta-analysis. J Allergy Clin Immunol. 2010;126(3):558-566.
PubMed   |  Link to Article
Pradalier  A, Basset  D, Claudel  A,  et al.  Sublingual-swallow immunotherapy (SLIT) with a standardized five-grass-pollen extract (drops and sublingual tablets) versus placebo in seasonal rhinitis. Allergy. 1999;54(8):819-828.
PubMed   |  Link to Article
Caffarelli  C, Sensi  LG, Marcucci  F, Cavagni  G.  Preseasonal local allergoid immunotherapy to grass pollen in children: a double-blind, placebo-controlled, randomized trial. Allergy. 2000;55(12):1142-1147.
PubMed   |  Link to Article
Smith  H, White  P, Annila  I, Poole  J, Andre  C, Frew  A.  Randomized controlled trial of high-dose sublingual immunotherapy to treat seasonal allergic rhinitis. J Allergy Clin Immunol. 2004;114(4):831-837.
PubMed   |  Link to Article
Dahl  R, Kapp  A, Colombo  G,  et al.  Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2006;118(2):434-440.
PubMed   |  Link to Article
Dahl  R, Stender  A, Rak  S.  Specific immunotherapy with SQ standardized grass allergen tablets in asthmatics with rhinoconjunctivitis. Allergy. 2006;61(2):185-190.
PubMed   |  Link to Article
Durham  SR, Yang  WH, Pedersen  MR, Johansen  N, Rak  S.  Sublingual immunotherapy with once-daily grass allergen tablets: a randomized controlled trial in seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2006;117(4):802-809.
PubMed   |  Link to Article
Didier  A, Malling  HJ, Worm  M,  et al.  Optimal dose, efficacy, and safety of once-daily sublingual immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitis. J Allergy Clin Immunol. 2007;120(6):1338-1345.
PubMed   |  Link to Article
Horak  F, Zieglmayer  P, Zieglmayer  R,  et al.  Early onset of action of a 5-grass-pollen 300-IR sublingual immunotherapy tablet evaluated in an allergen challenge chamber. J Allergy Clin Immunol. 2009;124(3):471-477, 477.e1. doi:10.1016/j.jaci.2009.06.006.
PubMed   |  Link to Article
Bufe  A, Eberle  P, Franke-Beckmann  E,  et al.  Safety and efficacy in children of an SQ-standardized grass allergen tablet for sublingual immunotherapy. J Allergy Clin Immunol. 2009;123(1):167-173.e7. doi:10.1016/j.jaci.2008.10.044.
PubMed   |  Link to Article
Wahn  U, Tabar  A, Kuna  P,  et al; SLIT Study Group.  Efficacy and safety of 5-grass-pollen sublingual immunotherapy tablets in pediatric allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2009;123(1):160-166.e3. doi:10.1016/j.jaci.2008.10.009.
PubMed   |  Link to Article
Halken  S, Agertoft  L, Seidenberg  J,  et al.  Five-grass pollen 300IR SLIT tablets: efficacy and safety in children and adolescents. Pediatr Allergy Immunol. 2010;21(6):970-976.
PubMed   |  Link to Article
Blaiss  M, Maloney  J, Nolte  H, Gawchik  S, Yao  R, Skoner  DP.  Efficacy and safety of timothy grass allergy immunotherapy tablets in North American children and adolescents [published correction appears in J Allergy Clin Immunol. 2011;128(2):436]. J Allergy Clin Immunol. 2011;127(1):64-71, 71.e1-71.e4. doi:10.1016/j.jaci.2010.11.034.
PubMed   |  Link to Article
Nelson  HS, Nolte  H, Creticos  P, Maloney  J, Wu  J, Bernstein  DI.  Efficacy and safety of timothy grass allergy immunotherapy tablet treatment in North American adults. J Allergy Clin Immunol. 2011;127(1):72-80, 80.e1-80.e2. doi:10.1016/j.jaci.2010.11.034.
PubMed   |  Link to Article
Cox  LS, Casale  TB, Nayak  AS,  et al.  Clinical efficacy of 300IR 5-grass pollen sublingual tablet in a US study: the importance of allergen-specific serum IgE. J Allergy Clin Immunol. 2012;130(6):1327-1334.e1. doi:10.1016/j.jaci.2012.08.032.
PubMed   |  Link to Article
Murphy  K, Gawchik  S, Bernstein  D, Andersen  J, Pedersen  MR.  A phase 3 trial assessing the efficacy and safety of grass allergy immunotherapy tablet in subjects with grass pollen–induced allergic rhinitis with or without conjunctivitis, with or without asthma. J Negat Results Biomed. 2013;12:10-19.
PubMed   |  Link to Article
Maloney  J, Bernstein  DI, Nelson  H,  et al.  Efficacy and safety of grass sublingual immunotherapy tablet, MK-7243: a large randomized controlled trial. Ann Allergy Asthma Immunol. 2014;112(2):146-153.e2. doi:10.1016/j.anai.2013.11.018.
PubMed   |  Link to Article
Chapter 8: Assessing risk of bias in included studies. In: Higgins  JPT, Green  S, eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. Updated March 2011. http://handbook.cochrane.org/. Accessed May 20, 2015.
Jüni  P, Witschi  A, Bloch  R, Egger  M.  The hazards of scoring the quality of clinical trials for meta-analysis. JAMA. 1999;282(11):1054-1060.
PubMed   |  Link to Article
Jadad  AR, Moore  RA, Carroll  D,  et al.  Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17(1):1-12.
PubMed   |  Link to Article
DerSimonian  R, Laird  N.  Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177-188.
PubMed   |  Link to Article
Cohen  J. Statistical Power Analysis for the Behavioral Sciences.2nd ed. Hillsdale, NJ: Lawrence Erlbaum Associates; 1988.
R Foundation. The R Project for statistical computing.http://www.R-project.org. Accessed May 17, 2015.
Schwarzer  G. meta: Meta-Analysis With R. R package version 1.1-8. 2010. http://cran.r-project.org/web/packages/meta/index.html. Accessed May 28, 2015.
Viechtbauer  W. Metafor: Meta-Analysis Package for R. R package version 2010. http://cran.r-project.org/web/packages/metafor/index.html. Accessed May 28, 2015.
Higgins  JP, Thompson  SG.  Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539-1558.
PubMed   |  Link to Article
Egger  M, Davey Smith  G, Schneider  M, Minder  C.  Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629-634.
PubMed   |  Link to Article
Canonica  GW, Bousquet  J, Casale  T,  et al.  Sub-lingual immunotherapy: World Allergy Organization position paper 2009. World Allergy Organ J. 2009;2(11):233-281.
PubMed   |  Link to Article
Canonica  GW, Baena-Cagnani  CE, Bousquet  J,  et al.  Recommendations for standardization of clinical trials with allergen specific immunotherapy for respiratory allergy: a statement of a World Allergy Organization (WAO) taskforce. Allergy. 2007;62(3):317-324.
PubMed   |  Link to Article
Benninger  M, Farrar  JR, Blaiss  M,  et al.  Evaluating approved medications to treat allergic rhinitis in the United States: an evidence-based review of efficacy for nasal symptoms by class. Ann Allergy Asthma Immunol. 2010;104(1):13-29.
PubMed   |  Link to Article
Wilson  AM, O’Byrne  PM, Parameswaran  K.  Leukotriene receptor antagonists for allergic rhinitis: a systematic review and meta-analysis. Am J Med. 2004;116(5):338-344.
PubMed   |  Link to Article
Lundh  A, Sismondo  S, Lexchin  J, Busuioc  OA, Bero  L.  Industry sponsorship and research outcome. Cochrane Database Syst Rev. 2012;12:MR000033.
PubMed
 Drugs and devices look more effective in studies sponsored by industry. BMJ. 2012;345:e8386. doi:10.1136/bmj.e8386.
PubMed   |  Link to Article
Radulovic  S, Calderon  MA, Wilson  D, Durham  S.  Sublingual immunotherapy for allergic rhinitis. Cochrane Database Syst Rev. 2010;(12):CD002893.
PubMed
Dretzke  J, Meadows  A, Novielli  N, Huissoon  A, Fry-Smith  A, Meads  C.  Subcutaneous and sublingual immunotherapy for seasonal allergic rhinitis: a systematic review and indirect comparison. J Allergy Clin Immunol. 2013;131(5):1361-1366.
PubMed   |  Link to Article
Lin  SY, Erekosima  N, Kim  JM,  et al.  Sublingual immunotherapy for the treatment of allergic rhinoconjunctivitis and asthma: a systematic review. JAMA. 2013;309(12):1278-1288.
PubMed   |  Link to Article
Antico  A, Fante  R.  Esophageal hypereosinophilia induced by grass sublingual immunotherapy. J Allergy Clin Immunol. 2014;133(5):1482-1484.
PubMed   |  Link to Article
Bernstein  DI, Wanner  M, Borish  L, Liss  GM; Immunotherapy Committee, American Academy of Allergy, Asthma and Immunology.  Twelve-year survey of fatal reactions to allergen injections and skin testing: 1990-2001. J Allergy Clin Immunol. 2004;113(6):1129-1136.
PubMed   |  Link to Article
Di Lorenzo  G, Mansueto  P, Pacor  ML,  et al.  Evaluation of serum s-IgE/total IgE ratio in predicting clinical response to allergen-specific immunotherapy. J Allergy Clin Immunol. 2009;123(5):1103-1110, 1110.e1-1110.e4. doi:10.1016/j.jaci.2009.02.012.
PubMed   |  Link to Article
Cromwell  O, Häfner  D, Nandy  A.  Recombinant allergens for specific immunotherapy. J Allergy Clin Immunol. 2011;127(4):865-872.
PubMed   |  Link to Article

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Grass pollen tablets benefits extend beyond clinical trials
Posted on August 8, 2015
Linda Cox, MD
Nova Southeastern University Ft. Lauderdale
Conflict of Interest: Greer advisory board 2014 not ongoing
Title: Grass pollen sublingual tablets –benefits extend beyond clinical trial
Corresponding author: Linda Cox, MD
lindaswolfcox@msn.com
5333 North Dixie Highway
Ft. Lauderdale , Florida 33334


In addition to being an author and principle investigator of the one the studies included Di Bona et al systematic review and meta-analysis of grass pollen allergen sublingual immunotherapy (SLIT) tablets, I am a community-based practicing allergist-immunologist, who has treated allergic patients for over 20 years. The authors question the value of the SLIT tablets in the treatment of seasonal allergic rhinoconjunctivitis (SAR) because they deemed the clinical improvement ‘insufficient’ to justify their use; “Considering the low magnitude of the benefit, the convenience and easy administration do not seem to be sufficient reasons for the choice of SLIT”.1 I am concerned this review does not adequately address important aspects of SAR treatment that clinicians and patients should consider in their treatment making discussions/discussions.
The review fails to discuss key differences between symptomatic medications and SLIT clinical trials that can significantly impact the magnitude of clinical improvement.2 Studies evaluating the efficacy of SAR medications are generally 7- or 14-day trials performed during the peak of pollen season in highly symptomatic patients. In these trials, the comparison group is a ‘true’ placebo group, who are not allowed access to symptomatic allergy medications.3 In contrast, in a SLIT trial, treatment is initiated before the start of the expected pollen season, when patients are asymptomatic. Patients are selected based on reported history from prior years or after a baseline observation season. Both patient selection methods have limitations. Comparisons with a baseline season can be significantly impacted by seasonal pollen variations. Likewise patient retrospective rating of prior year’s symptoms is subject to recall bias. Although our study inclusion criteria included a Retrospective Rhinoconjunctivitis Total Symptom of Score of 12 or greater (scale, 0-18), 11% of our study patients did not have significant allergy symptoms during the grass season.4
Thus, with current selection methods for SLIT trials, one cannot be assured the randomized patients will actually be symptomatic during the coming study. In contrast to SAR medication trials, clinical outcomes are assessed throughout the pollen season- not just during the 7 to 14 peak of pollen season days. Additionally, virtually all SLIT trials allow for rescue medication use. Despite being compared against a group allowed access to symptomatic treatment, the grass tablet studies have consistently demonstrated a ≥ 20% improvement in combined symptom medications scores,5 which is superior to antihistamines and comparable to nasal steroids.3, 6
Lastly, the Di Bona review presents only ‘during treatment’ outcome comparisons. It fails to consider the disease-modifying benefits of SLIT, which can translate into long-term symptomatic improvement extending years beyond the ‘during treatment’ period.3 In contrast, symptomatic medications only “work” when taken and provide no sustained clinical benefits after discontinuation.
Patient preference is an important consideration in determining the best treatment approach for SAR. A treatment offering a disease-modifying effect may be a very desirable for some patients. Thus, it is important to include SLIT as one of the options in the patient-health care professional SAR treatment dialog.


Sincerely,
Linda Cox, MD

JAMA Internal Medicine comment

1. Di Bona D, Plaia A, Leto-Barone MS, La Piana S, Di Lorenzo G. Efficacy of Grass Pollen Allergen Sublingual Immunotherapy Tablets for Seasonal Allergic Rhinoconjunctivitis: A Systematic Review and Meta-analysis. JAMA internal medicine 2015.

2. Calderon MA, Bernstein DI, Blaiss M, Andersen JS, Nolte H. A Comparative Analysis of Symptom and Medication Scoring Methods Used in Clinical Trials of Sublingual Immunotherapy for Seasonal Allergic Rhinitis. Clin Exp Allergy 2014.

3. Matricardi PM, Kuna P, Panetta V, Wahn U, Narkus A. Subcutaneous immunotherapy and pharmacotherapy in seasonal allergic rhinitis: a comparison based on meta-analyses. J Allergy Clin Immunol 2011, 128(4): 791-799 e796.

4. Cox LS, Casale TB, Nayak AS, Bernstein DI, Creticos PS, Ambroisine L, et al. Clinical efficacy of 300IR 5-grass pollen sublingual tablet in a US study: The importance of allergen-specific serum IgE. J Allergy Clin Immunol 2012, 130(6): 1327-1334 e1321.

5. Canonica GW, Cox L, Pawankar R, Baena-Cagnani CE, Blaiss M, Bonini S, et al. Sublingual immunotherapy: World Allergy Organization position paper 2013 update. The World Allergy Organization journal 2014, 7(1): 6.

6. Wilson AM, O'Byrne PM, Parameswaran K. Leukotriene receptor antagonists for allergic rhinitis: a systematic review and meta-analysis. Am J Med 2004, 116(5): 338-344.

Assessing clinical efficacy of sublingual Immunotherapy tablets
Posted on August 4, 2015
Nelson, H*, Cox L,** Claderon M^
National Jewish Health and University of Colorado Denver School of Medicine, National Jewish Health and University of Colorado Denver School of Medicine, Nova Southeratern University Ft. Lauderdale ,
Conflict of Interest: Corresponding Author
Harold S. Nelson, MD


Disclosure: Consultant Merck
Linda Cox, MD

Disclosure: served a consultant for Greer in 2014 (not ongoing)
Moises Calderon, MD, PhD
Disclosures: Lectures Honorarium and consultancy from ALK, STG, Hal, Merck and Allergopharma
We feel there are several problems in the review by Dr. Di Bona and colleagues of the efficacy of grass pollen allergen sublingual immunotherapy tablets for seasonal allergic rhinoconjunctivitis.1 First is the appropriateness of the selection of articles. Seven of the thirteen studies and over 70% of the subjects received the 2800 BAU daily dose of Timothy grass-SLIT tablet and recorded the response to treatment using similar symptom and medication scoring systems and the same method of arriving at a total combined score. Of the remaining 6 studies, 2 did not meeting the authors’ selection criteria, one administered a top dose of 100 IR and the other administered the maintenance dose only 3 times weekly both of which have been shown to be suboptimal and are not the approved treatment. The other 4 studies were conducted with the appropriate regimen for the 5-grass SLIT-tablet. We feel if a meta-analysis is to be conduct it should be for the Timothy SLIT-tablet alone and one for the 5-grass tablet alone, since the number of subjects using each is quite large and both offer homogeneity of dosing and scoring of outcomes.
We question the appropriateness of analyzing symptoms scores and medication scores separately as primary outcomes. A score combining symptoms and rescue medication use is generally favored as the primary outcome by both regulatory agencies and professional societies. Thus, the European Medicine Agency Guidelines on the Clinical development of Products for Specific Immunotherapy for the Treatment of Allergic Diseases (November 2008) states: “The use of rescue medication has an impact on symptom severity. Therefore, the primary endpoint has to reflect both symptom severity as well as the intake of rescue medication.” 2 AEuropean Academy of Allergy and Clinical Immunology Position Statement recommended, for standardization of clinical outcomes used in allergen immunotherapy trials for allergic rhinoconjunctivitis, “as the primary outcome, a homogenous combined symptom and medication score as a simple and standardized method that balances both symptoms and the need for anti-allergic medication in an equally weighted manner.”3 While the U.S. Food and Drug Agency (FDA) used the total combined score to list the outcomes of studies of both Timothy grass pollen SLIT-tablets (Table 5) and 5-grass SLIT tablets (Table 3) in their briefing documents for their December 2013 Allergenic Products Advisory Committee meetings.4
For these and other reasons we cannot accept the conclusions drawn by Dr. Di Bona and colleagues.


References:
1) Di Bona D, Plaia A, Leto-Barone MS, La Piana S, Di Lorenzo G. Efficacy of Grass pollen allergen sublingual immunotherapy tablets for seasonal allergic rhinoconjunctivitis: A systematic review and met-analysis. JAMA Intern Med doi:10.1001/jamainternmed.2015.2840. Published online June 29, 2015.
2) European Medicines Agency. Committee for Medicinal Products for Human Use. Guidelines on the Clinical Development of Products for Specific Immunotherapy for the Treatment of Allergic Diseases. London, 20 November 2008. Doc.Ref.CHMP/EWP/18504/2006.
3) Pfaar O, Demoly P, van Wijk RG, Bonini S, Bousquet J, Canonica GW, et al. Recommendations for the standardization of clinical outcomes used in allergen immunotherapy trials for allergic rhinoconjunctivitis; an EAACI Position Paper. Allergy 2014;69:854-867.
4) FDA Briefing Document: Biologic License Application for Timothy Grass Pollen Allergen extract Tablet for Sublingual Use. Accessed at: www.fda.gov/AdvisoryCommittee. Allergenic Products Advisory Committee 2013. Meeting Materials Allergenic Products Advisory Committee (APAC) Meeting December, 2013.
5) FDA Briefing Document. Biologic License Application for sweet vernal, orchard, perennial rye, timothy and Kentucky blue grass mixed pollens allergen extract tablet for sublingual use. Accessed at: www.fda.gov/AdvisoryCommittee. Allergenic Products Advisory Committee
Reply to Nelson, H, Cox L, Calderon M comment “Assessing clinical efficacy of sublingual Immunotherapy tablets”
Posted on September 3, 2015
Danilo Di Bona,1 MD, PhD, Antonella Plaia,2 PhD, and Gabriele Di Lorenzo,3 MD
1 Unità Operativa di Medicina Trasfusionale, Azienda Ospedaliera Universitaria Policlinico di Palermo, Italy2Dipartimento di Scienze Economiche, Aziendali e Statistiche, Università di Palerm
Conflict of Interest: None Declared
We read with interest the comments by Nelson, Cox and Calderon on our study.1 Regarding the criticism of the appropriateness of including the Pradalier2 (100 IR tablets) and Smith3 (tablets administered 3 times/week) studies, it must be noted that an analysis not including these two studies is already present in the result section, using both SMD and MD, as measure of efficacy: “The SMD excluding these two studies did not change (SMD -0.28, 95%CI, -0.39, -0.18; p<0.0001), indicating that SMD of -0.28 corresponds to a MD of -0.83 SS points”. Therefore, the exclusion of these two studies did not make any difference, as already clearly pointed out in the text, and would have only led to a loss of data, along with the information they provided. In contrast, it showed that the benefit does not change even if patients are treated with a low dose of grass allergens.
Regarding the separate analysis for studies using the timothy SLIT tablet and those using the 5-grass pollen tablet, this information is also already present in the study as subgroup analyses both for symptom score (SS) and medication score (MD) (Fig. 2A, 2B).1
Regarding the appropriateness of analyzing SS and MS separately, and not as a combined score, we want to emphasize that this is precisely the most critical problem in the SLIT RCTs. The total combined score, as clearly discussed in the text, is mathematically incorrect since the SS and MS scales have different weights depending on their range. The only study out of 13 that takes into account this aspect is the Cox study,4 in which a MS with a comparable scale (0-3) was used and the TCS was normalized to obtain a correct result. Moreover, a standardization for MS, similarly to SS has never been done with different points assigned to the same drugs in a totally arbitrary fashion. For example oral or ocular antihistamine drops are equal to 1 point in the Cox study, and up to 6 points in the score used by Nelson5; the same for corticosteroids: 2 or 3 points in the Cox study,4 8 to 16 points in the Nelson study5). But the problem is more serious from a statistical point of view: as already pointed out in our article, MS is a qualitative variable; it can be considered on an ordinal scale, but cannot be treated as interval data, because intervals between each value (i.e., antihistamines = 1 point, nasal steroids =2 points, oral steroids = 3 points arbitrarily assigned) are not equal. Thus, a TCS, even considering the adjustment proposed in the Cox study,4 or even a standardization between the different MS scales, cannot be computed, and Scientific Societies and Regulatory Agencies should confront this problem. If an adjustment must be made in SS, it must be mathematically correct, rather than using a measure, such as the total combined score (SS+MS), that only leads to a misleading magnification of a small SLIT benefit, as shown by the small SMD for SS and MS, and the small percent difference between SLIT and placebo SS (6% on average, far below the FDA 15% threshold of minimum clinical efficacy) obtained using our correct metric, specified by WAO6.

References
1. Di Bona D, Plaia A, Leto-Barone MS, La Piana S, Di Lorenzo G. Efficacy of Grass Pollen Allergen Sublingual Immunotherapy Tablets for Seasonal Allergic Rhinoconjunctivitis: A Systematic Review and Meta-analysis. JAMA internal medicine. 2015;175(8):1301-9.
2. Pradalier A, Basset D, Claudel A, et al. Sublingual-swallow immunotherapy (SLIT) with a standardized five-grass-pollen extract (drops and sublingual tablets) versus placebo in seasonal rhinitis. Allergy. 1999;54(8):819-928.
3. Smith H, White P, Annila I, Poole J, Andre C, Frew A. Randomized controlled trial of high-dose sublingual immunotherapy to treat seasonal allergic rhinitis. J Allergy Clin Immunol. 2004;114(4):831-837.
4. Cox LS, Casale TB, Nayak AS, et al. Clinical efficacy of 300IR 5-grass pollen sublingual tablet in a US study: the importance of allergen-specific serum IgE. J Allergy Clin Immunol. 2012; 130(6):1327-1334.e1.
5. Nelson HS, Nolte H, Creticos P, Maloney J, Wu J, Bernstein DI. Efficacy and safety of timothy grass allergy immunotherapy tablet treatment in North American adults. J Allergy Clin Immunol. 2011;127(1):72-80.
6. Canonica GW, Baena-Cagnani CE, Bousquet J, et Al. Recommendations for standardization of clinical trials with Allergen Specific Immunotherapy for respiratory allergy. A statement of a World Allergy Organization (WAO) taskforce. Allergy. 2007; 62(3):317-24
Reply to Linda Cox comment “Grass pollen sublingual tablets –benefits extend beyond clinical trial”
Posted on September 3, 2015
Danilo Di Bona,1 MD, PhD, Antonella Plaia,2 PhD, and Gabriele Di Lorenzo,3 MD
1 Unità Operativa di Medicina Trasfusionale, Azienda Ospedaliera Universitaria Policlinico di Palermo, Italy2Dipartimento di Scienze Economiche, Aziendali e Statistiche, Università di Palerm
Conflict of Interest: None Declared
We read with interest the comments on our article1 posted by Dr. Linda Cox, who is concerned about our conclusions mainly because of the metric we used to analyze the data.
We sustain that the treatment benefit should be calculated as the difference between the symptom score (SS) improvement from baseline to treatment period in each group. The baseline is the prior year’s SS (retrospective SS), that is also one of the inclusion criteria (SS equal or greater to 12 in a 0-18 point SS-scale in the Cox study,2 or moderate to severe allergic rhino-conjunctivitis in other studies). Therefore, we assumed that each patient included in the RCTs was affected by a moderate to severe allergic rhino-conjunctivitis, according to the inclusion criteria. This metric is the same used for symptomatic drugs (e.g. anti-histamines or corticosteroids), and was indicated to be used for SLIT in the 2007 WAO position paper.3
Cox asserts that this metric based on the difference between baseline and during treatment SS cannot be used because: 1) the baseline SS may vary from one season to the next, and therefore the prior year’s SS may be different from the SS of the treatment season; hence, the prior year’s SS cannot be used as the baseline SS; 2) a recall bias may influence the reliability of the retrospective SS.
The 2007 WAO position paper on Sublingual Immunotherapy,3 indicating that \"the minimum relevant magnitude of efficacy\" of SLIT should be \"at least 20% higher than placebo\", refers to a meta-analysis4 of comparisons between different rhinoconjunctivitis interventions that calculates the benefit as difference from baseline between the groups. In the method section of this meta-analysis the example is \"if one treatment reduces symptoms by 10% and the second treatment (or placebo) reduces symptoms by 8%, the weighted mean difference is 2% in favor of the first treatment\". However, the SLIT RCTs did not use this metric. When the benefit in the SLIT studies was calculated according to the calculation that we propose (the same indicated by WAO), it does not reach the 20% threshold (or even the 15% threshold established by the FDA), as already indicated in our manuscript for the Cox2 study. The most important point is that the 20% (WAO) threshold of efficacy for SLIT was established on the basis on the metric reported in the above mentioned meta-analysis,4 the same we used. Therefore, SLIT studies should use this metric to calculate the benefit. They can’t use the threshold calculated with one metric and estimate the benefit using a different metric, that is the difference in the mean SS between SLIT and placebo during the pollen season. Worse, this metric is mathematically incorrect because it does not take into account the symptom score or medication score scale range. So, a one point difference between two treatments would be the same in a 10-point scale and in a 100-point scale, as demonstrated in the article.
Therefore, the only way to estimate the improvement is to assume that the baseline SS is the prior year’s SS. Although, it can be impacted by recall bias and the variability of pollen season, this measure reflects the baseline value with an acceptable approximation, especially if a measurement of the pollen count in the treatment season is provided. Even considering the worst case in the Cox study,2 that is a retrospective SS of 12 in the season of the study (the inclusion criteria is SS equal or greater than 12) instead of the 14.9 SS points of the prior year’s season reported in the study, the percent difference between SLIT and placebo would have been about 8% (3.21-4.16= -0.95/12= -7.9%), still far from the 15% difference FDA threshold of minimum clinical efficacy. So, even admitting an imprecision of the baseline SS depending on the variability of pollen season or recall bias, it does not significantly impact our calculation. Obviously the baseline SS cannot be assumed less than 12 points in this study (more than 3 SS point difference with the retrospective SS reported in Table 1 of the Cox study,2 14.9), since in this case the inclusion criteria would not have been fulfilled, not including patients with severe disease, raising concern about the reliability of the study itself. But, we are confident that this is not the case, since Linda Cox is an expert physician with over 20 years’ experience in this field.
In any case, regarding the recall bias that we acknowledge may be present in the Cox2 as in all other studies, we have to assume that this could have biased retrospective SS in both directions, that is that the reported retrospective SS could have been not only overestimated, but also underestimated and therefore being even higher than that reported in the study (14.9).2 The presence of 11% of Cox study patients without significant symptoms during the grass season seems to be unrelated to the recall bias, but rather to the inclusion of 11% of patients with undetectable timothy grass-specific-IgE at screening, as clearly reported in the text of this study. This may explain why they were asymptomatic during the grass pollen season and did not benefit from therapy. So, a confirmatory diagnosis by specific-timothy grass IgE should have been considered as an additional inclusion criteria, since specific immunotherapy for that allergen had to be performed, as it is commonly done in the immunotherapy RCTs.
In any case, it is worth underlining that we also estimated the treatment benefit with the metric used in the individual studies, that is the difference between the during treatment mean symptom score, although we consider it mathematically incorrect, by means of the Standardized Mean Difference (SMD). The pooling estimate was -0.28 SS points, -0.24 SS with the exclusion of the influential study.5 Cohen’s criteria represent the reference for estimating the magnitude of a difference expressed in SMD6. Cohen defines a small effect as a standard deviation of k population means one-tenth as large as the standard deviation of the observation within the population (corresponding to 0.2 standard deviation considering a comparison between two groups). From this calculation derives the “minimum clinically important difference”(MCID) that is: “the smallest difference in score in the domain of interest which patients would perceive as beneficial and which would mandate, in the absence of troublesome side-effects and excessive cost, a change in the patient’s management” according to the original Jaeschke definition.7 Therefore, the benefit of SLIT compared to placebo (-0.28 SMD, or -0.24 SMD with the exclusion of the influential study5) is very close to the assumed threshold of inefficacy (-0.20 SMD), even with the incorrect method used in the individual studies.
Regarding the criticism that our review does not take into account the long term benefit of the treatment, it should be emphasized that the long term benefit was not the focus of this review, nor of the Cox study, nor all the other RCTs.
Regarding the patient preference, we know that Evidence Based Medicine was intended to help physicians in the decision-making process providing all the information needed for the best therapeutic choice respecting the patient’s preference.8,9 The point is that the patient has to be correctly informed about the benefit (or absence of benefit) and the risks of the treatment, and this does not seem to be the case.
So, our conclusion is that, in the interest of patients, caution must be exercised when such small treatment benefit is reported, especially if one considers that sponsored studies always show greater benefits compared to independent studies using the same drugs or devices.10,11

References
1. Di Bona D, Plaia A, Leto-Barone MS, La Piana S, Di Lorenzo G. Efficacy of Grass Pollen Allergen Sublingual Immunotherapy Tablets for Seasonal Allergic Rhinoconjunctivitis: A Systematic Review and Meta-analysis. JAMA internal medicine. 2015;175(8):1301-9.
2. Cox LS, Casale TB, Nayak AS, et al. Clinical efficacy of 300IR 5-grass pollen sublingual tablet in a US study: the importance of allergen-specific serum IgE. J Allergy Clin Immunol. 2012; 130(6):1327-1334.e1.
3. Canonica GW, Baena-Cagnani CE, Bousquet J, et Al. Recommendations for standardization of clinical trials with Allergen Specific Immunotherapy for respiratory allergy. A statement of a World Allergy Organization (WAO) taskforce. Allergy. 2007; 62(3):317-24
4. Wilson AM, O'Byrne PM, Parameswaran K. Leukotriene receptor antagonists for allergic rhinitis: a systematic review and meta-analysis. Am J Med. 2004;116(5):338-44.
5. Dahl R, Kapp A, Colombo G, et al. Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2006;118(2):434-440.
6. Cohen J. Statistical power analysis for the behavioral sciences. 2nd edition. Hillsdale (NJ): Lawrence Erlbaum Associates; 1988.
7. Jaeschke R, Singer J, Guyatt GH. Measurement of health status. Ascertaining the minimal clinically important difference. Control Clin Trials 1989; 10:407–15.
8. Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS. Evidence based medicine: what it is and what it isn't. BMJ. 1996; 312:71-2.
9. Haynes RB, Devereaux PJ, Guyatt GH. Physicians' and patients' choices in evidence based practice. BMJ. 2002; 324: 1350.
10. Lundh A, Sismondo S, Lexchin J, Busuioc OA, Bero L. Industry sponsorship and research outcome. Cochrane Database Syst Rev. 2012; 12:MR000033. doi: 10.1002/14651858.MR000033.pub2.
11. Drugs and devices look more effective in studies sponsored by industry. BMJ 2012; 345:e8386. doi: 10.1136/bmj.e8386.
A landmark Systemic Review!!
Posted on November 24, 2015
Massimo Milani
ISDIN Sa
Conflict of Interest: No
I want to congratulate Di Bona and coll. for this exaustive and illuminating meta-analysis!!

Finally an objective evaluation of the real clinical impact of new \"anti- allergic\" tablets for which their limited clinical effect is not able to justify the price.

The funny thing is that several European Regulatory Agencies have already given their OK for the reimbursed price : another demonstration that very often the public \"decision makers\" have not a clear view of the real effectiveness of new \"expensive\" drugs.
Massimo Milani
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Multimedia

Supplement.

eMethods. Supplemental Methods

eFigure 1. Flow Diagram of Sublingual Immunotherapy Studies

eFigure 2. Funnel Plots of (A) Symptom Score and (B) Medication Score Data, Testing for Publication Bias

eFigure 3. Meta-analysis of the Efficacy of SLIT vs. Placebo for ARC (SS, Mean Difference)

eTable 1. Study Quality Assessment by the Jadad Score

eTable 2. Potential Bias

eTable 3. Most Common Treatment-Related Adverse Events (TRAE), Occurring in at Least 5% of Patients in the Treatment Group

eTable 4. Proposed Calculation for Quantification of Symptom Score Differences Between Groups

eResults. Supplemental Results

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