Sublingual Immunotherapy Tablets Relieve Symptoms in Adults with Allergic Rhinitis: A Meta-analysis of Randomized Clinical Trials.

BACKGROUND: Sublingual immunotherapy (SLIT) has been proven to be effective against house dust mite-induced allergic rhinitis. However, the efficacy in adults with allergic rhinitis has never been reported on SLIT tablets. The current meta-analysis aimed to illustrate the differentiated efficacy of SLIT tablets on allergic rhinitis.
METHODS: Our systematic review and meta-analysis were performed on allergic rhinitis patients and aimed to summarize those randomized controlled studies (RCTs). PubMed, EMBASE, Cochrane library, and MEDLINE were screened for associated articles. We included RCTs on allergic rhinitis patients undergoing SLIT therapy and reporting outcomes on symptom relief and serum-specific IgE levels. The effect of SLIT tablets on the Rhinitis Quality Life Questionnaire Score (RQLQ), Rhinitis Total Symptom Score (RTSS), and serum-specific IgE levels was evaluated using RevMan 5.3.
RESULTS: Seven studies were included, with 2723 patients identified. All of the studies were RCT. The included seven studies were all conducted on adults. Among the included seven articles, five researches administered patients with SLIT tablets and were eligible for meta-analysis of RTSS, consisting of 1490 patients. Overall, RTSS was significantly reduced in the SLIT tablet group compared with that in the placebo group (standard mean difference = -0.33, 95% confidence interval [-0.54, -0.13], P < 0.01). There was no significant difference in specific IgE levels between SLIT and placebo patients.
CONCLUSIONS: SLIT tablets effectively relieve rhinitis symptoms in adults with allergic rhinitis. Nevertheless, the current evidence may be limited due to sample size and the heterogeneity between studies. Large sample size and multiple center RCTs on the efficacy of different formulations of SLIT drugs are still needed to provide further evidence and a more precise recommendation.

INTRODUCTION

Allergic rhinitis (AR) is a mild-to-moderate allergic disease affecting approximately 10% to 30% of the population worldwide.[1] House dust mite (HDM) is one of the most common AR allergens in the world, and the most common species are Dermatophagoides pteronyssinus and Dermatophagoides farinae. The two types differ from each other to some extent, but patients are suffering from HDM-induced AR are usually cosensitized to both species.[2] AR symptoms include runny nose, sneezing, nasal itching, and nasal obstruction, among other symptoms. The symptoms vary by individual, and patients can be in great pain during exacerbations.[3] The current therapeutic treatment includes allergen avoidance, antihistamine treatment, intranasal glucocorticoid treatment, and immunotherapy.[4]

Immunotherapy modulates immune system function and is currently considered to be the only option with a potential long-term posttreatment effect on allergic diseases.[5] The molecular and cellular mechanisms of AIT include early mast cell and basophil desensitization effects, regulation of T- and B-cell responses, regulation of IgE and IgG4 production, and inhibition of responses from eosinophils, mast cells, and basophils in the affected tissues.[6] However, the mechanism has not yet been completely illustrated. Sublingual immunotherapy (SLIT) has been demonstrated as a potential effective treatment for HDM-induced allergic rhinitis.[7] SLIT drugs contain a low dose of an extract from HDM, aiming to modulate the immune reaction and achieving long-term efficacy.[8] SLIT is more convenient and safer than subcutaneous immunotherapy (SCIT), which is another commonly used immunotherapy against HDM-induced AR.[9] The formulations of SLIT include drops and tablets, and there is a trend for the SLIT tablets to gradually replace the use of SLIT drops due to their more convenient transportation and safer and more effective outcomes.

However, the currently reported outcomes of SLIT tablets are highly variable while the outcomes of SLIT tablet in China have never been reported due to government regulations. Numerous randomized controlled studies (RCT) have been conducted worldwide, although the parameters and outcome measurement are still highly variable. In addition, the different efficacies of SLIT due to different drug formulations were varied according to clinical experience.[10111213] It is difficult to determine whether SLIT does or does not work overall. There has been no published meta-analysis concerning the efficacy of SLIT tablets on relieving AR patient symptoms. Our current meta-analysis aims to evaluate the outcome of SLIT tablets on HDM-induced AR patients to determine the efficacy of symptom relief and to provide the evidence for the further investigation and administration of SLIT tablet in China.

METHODS

Published literature was systematically reviewed through the PubMed, EMBASE, and Cochrane Library databases. Search items included “allergic,” “hypersensitive,” “anaphylactic,” “rhinitis,” “nasitis,” “SLIT,” etc., The articles were restricted to those published in English or Chinese and human studies.

The database search results were evaluated independently by two experienced researchers and strictly followed the inclusion and exclusion criteria and article quality evaluation protocol. If divergence occurred, a discussion was performed until a final consensus was reached. Next, full-text screening was conducted, and the included articles were identified for meta-analysis.

Inclusion criteria

(1) Reports should include patients with HDM-induced AR, with or without allergic asthma (AA). (2) Statistics should include Rhinitis Quality of Life Questionnaire scores (RQLQ), Rhinitis Total Symptom Scores (RTSS), and/or specific serum IgE level. (3) Only RCT and prospective controlled study were included. (4) Studies should be performed on adolescents, adults, or both. (5) Articles published in English or Chinese.

Exclusion criteria

(1) Experiment not performed on humans was excluded. (2) Main parameters were impossible to extract. (3) Reports recruited patients merely suffering from AA but not AR. (4) Statistics consisted of patients with SLIT and other immunotherapy combined, which cannot be separated. (5) Experiment administered non-SLIT therapy as the main treatment.

Data of the endpoint of each clinical study was then extracted and collected by the researchers using Microsoft Excel 2013 including RTSS and serum-specific IgE levels. Risk of bias, mean value, standardized mean deviation (SMD), and sample size were collected to perform a meta-analysis using Review Manager 5.3. The results are shown in forest plot and funnel plot format. Heterogeneity was considered high when I2> 50%, and a randomized model was conducted to pool these statistics; a fixed model was used if I2 is no more than 50%. Next, a meta-regression analysis was performed using STATA12.0 to determine the source of heterogeneity. P < 0.05 is considered to indicate a significant difference.

RESULTS

Study inclusion

Database screening included 1193 related articles identified by reviewing PubMed, EMBASE, Cochrane Library, and MEDLINE. In total, 972 articles were removed because the studies were not performed on human subjects. After full-text screening and quality evaluation conducted by our researchers, seven articles meeting the inclusion criteria were included. The selection process is illustrated in Figure 1.

Figure 1

Flow diagram of the meta-analysis study on house dust mite sublingual immunotherapy tablets relieve symptoms of adults allergic rhinitis.

Among the included seven articles, all of the studies were RCTs conducted on adult patients suffering from AR. RTSS was used to evaluate the symptom level, and specific IgEs were evaluated to elucidate the effect on the individual immune system. Study details are shown in Table 1.

Table 1

Characteristics of included studies on adult patients suffering from allergic rhinitis

Research	n	Type	Age (years)	Recruited patients	Formulation	Amount*	Duration	Primary endpoint	Secondary endpoint
Karl-Christian Bergmann 2014[14]	313	RCT	Drug 30.1 ± 8.43 Control 30 ± 8.96	Diameter of SPT >3 mm, or sIgE >0.7 kU/L, or ARTSS >4	Tablet	500 IR tablet QD	24 m	AAdSS	ARTSS, ARSS, ARMS
Hendrik Nolte 2015[20]	83	RCT	Drug 28 (18–58) Control 27 (19–43)	Diameter of SPT >3 mm, or sIgE >0.7 kU/L	Tablet	12 DU of MK-8237	24 w	Not reported	Not reported
Holger Mosbech 2015[19]	241	RCT	Drug 31.6 (15–68) Control 31.6 (14–74)	Diameter of SPT >3 mm, or sIgE >0.7 kU/L	Tablet	6 SQ-HDM	12 m	RTSS, RQLQ	Not reported
Kimihiro Okubo 2016[15]	633	RCT	Drug 26.8 ± 12.1 Control 26.8 ± 11.7	sIgE >3.5 kU/L	Tablet	12 SQ-HDM	12 m	TCRS	Symptoms and life quality scores
Michel Roux 2016[17]	180	RCT	Drug 32.8 ± 9.33 Control 31.3 ± 8.75	Diameter of SPT >3 mm, or sIgE >0.7 kU/L, or ARTSS >5	Tablet	500 IR tablet QD	6 m	ARTSS	ARSS, AVASS
Pascal Demoly 2016[16]	656	RCT	Drug 32.1 ± 10.6 Control 32.2 ± 10.9	Not reported	Tablet	12 SQ-HDM	12 m	TCRS	Symptoms and life quality scores
Y. Okamoto 2017[18]	612	RCT	Drug 30.5 ± 11.7 Control 30.2 ± 11.6	sIgE >0.7 kU/L, or ARTSS >5	Tablet	500 IR tablet QD	12 m	AASS	Nasal and ocular symptom scores, RQLQ

*Amount is described as the highest does in a certain clinical trial. TCRS: Total combined rhinitis score; AASS: Average Adjusted Symptom Score; AAdSS: Average adjusted symptom score; ARTSS: Average Rhinitis Total Symptom Score; ARSS: Average Rhinitis Symptom Score; ARMS: Average Rescue Medication Score; AVASS: Average Visual Analog Scale Score; RQLQ: Rhinitis quality of life questionnaire score; SPT: Skin prick test; RCT: Randomized controlled studies; HDM: House dust mite; RTSS: Rhinitis Total Symptom Score.

Risk of bias

The methodological quality of selected trials was assessed using the Cochrane Collaboration's tool. All of the studies included suggested randomization, with the proper method of random sequences generation and six studies reported detailed allocation concealment. However, the risk was unclear regarding outcome assessment. The reasons for dropout between groups are similar in included studies. The risk of selective reporting bias is low. Six included studies had low risk of other bias while the other is unclear. Therefore, all studies were judged to be of a good methodological quality [Figures 2 and 3].

Figure 2

Risk of bias among included articles.

Figure 3

Risk of bias summary among included articles.

Efficacy of sublingual immunotherapy

Among the included seven articles, five of the studies that administered patients with SLIT tablets were eligible for meta-analysis of RTSS and consisted of 1490 patients.[1415161718] A randomized model was used due to the high heterogeneity (I2= 74%). Meta-analysis demonstrated a significant reduction in RTSS in patients receiving SLIT tablets compared to placebo (SMD = −0.33, 95% confidence interval [CI]: [−0.54, −0.13], P = 0.001) [Figure 4].

Figure 4

Efficacy of sublingual immunotherapy tablets on Rhinitis Total Symptom Score between experimental and placebo groups.

Two of the seven articles on SLIT tablets included descriptive data for meta-analysis on specific IgE levels. Data from these two articles consisted of 103 patients.[1920] A randomized model was used due to high heterogeneity (I2= 69%). There was no significant difference in IgE levels in the patients undergoing SLIT tablets compared to placebo (SMD = 0.14, 95% CI [−0.72, 1.07], P = 0.74) [Figure 5].

Figure 5

Efficacy of sublingual immunotherapy tablets on specific IgE levels between experimental and placebo groups.

Meta-regression analysis showed no association between SLIT dose, treatment duration, publication year, or patient age and the level of RTSS or specific IgE level (P > 0.05).

Adverse drug reaction

In general, most of the cases of adverse drug reaction (ADR) were mild-to-moderate local allergic reactions such as mouth edema, oral pruritus, and throat irritation, occurring in 5–20% of the cases in the therapeutic groups. Serious ADRs are not common; however, there were still nine serious ADRs reported among the three of the seven included studies such as respiratory distress, laryngeal edema, severe eczema, or vaginal laceration. However, among the included seven articles, no systemic anaphylactic reaction was reported, and only one case required epinephrine administration due to respiratory distress caused by laryngeal edema and followed by dysphonia, throat irritation, and dry cough. No case of death was reported.

DISCUSSION

Immunotherapy is considered to be the only approach with promising and long-term effects on allergic diseases. SLIT is one of the most commonly used therapies involving HDM-induced AR; however, the efficacy and outcome vary among the studies.

SLIT tablets combine two major species together[21] and may better target allergic diseases with high heterogeneity such as AR.[22] In addition, SLIT tablets ensure better modulation of the drug amount and higher compliance than SLIT drops due to its safety and convenience for transportation, administration, and follow-up.[23] A majority of current RCTs showed some benefit from immunotherapy on RQLQ and RTSS. SCIT and SLIT are two forms of immunotherapy on allergic rhinitis while SLIT has proven to be potentially safer than SCIT.[24] Although some of our included articles reported side effects, such as oral pruritus, resulting from SLIT tablets, none of the studies reported severe complications. However, the long-term efficacy of SLIT remains under investigation. For instance, a multicenter, large sample size RCT conducted in Europe revealed that SLIT reduces RTSS and RQLQ in patients suffering from allergic rhinitis.[16] Similar outcomes were shown in another meta-analysis studying AR patients treated with probiotics.[25]

Our study illustrated a significant reduction of RTSS in patients undergoing treatment with SLIT tablets, and all the included patients were adults. These findings are consistent with our observation during clinical work that SLIT drops may not work at times.[1926] de Bot et al.[13] also noted that SLIT drops with HDM allergens are no better than placebo regarding the efficacy of reducing rhinitis symptoms in adolescents suffering from allergic rhinitis. The sample size was 251 patients. Allergic diseases are of high heterogeneity due to various molecular and age differences.[27] However, Ippoliti et al.[10] reported a significant reduction of RTSS in a sample of 86 adolescent patients suffering from allergic rhinitis and allergic asthma undergoing SLIT drops. However, the different immune system functions modulated by different drug formulations may serve as another reason for treatment response heterogeneity.[10] It is well known that environmental exposure levels affect immunotherapy outcomes. The model of environmental exposure chamber (EEC) enables a better assessment of AR outcomes.[1720] However, only two of the seven included studies were carried out following EEC guidelines, resulting in high heterogeneity in our meta-analysis. The limited number of recruited patients is likely to interfere with the conclusion and future multiple centers, and RCTs with large sample sizes are still needed, particularly in AR patients undergoing therapy with SLIT tablets.

Although the heterogeneity cannot currently be explained by SLIT tablet dose and treatment duration due to the results of the meta-regression, the different transmucosal concentration gradient may cause a significant difference even in patients undergoing a similar dose of SLIT tablets.[28] These findings suggest that in addition to the concentration of the extract, the biological activity of SLIT tablets, transmucosal diffusion gradient, and other parameters should also be evaluated as well as the SLIT tablets dose.[29] Moreover, the inclusion criteria of each RCT varied slightly from each other on characteristics, such as age range and dose of SLIT tablets, resulting in the relatively high heterogeneity.

The mechanism of SLIT is likely to be the modulatory effect on the immune system and cells.[30] However, we did not identify a significant reduction of specific IgE levels in AR patients after SLIT tablet administration. Interestingly, there is a trend toward a reduction of serum-specific IgE level in the placebo group, suggesting that the potential mechanism may be unrelated to the modulation of specific IgE. The mechanism through which SLIT tablets act on AR has not been completely defined.[25] The frequency and function of interleukin 10-secreting Tr1 cells are enhanced after immunotherapy on patients with allergic rhinitis; however, there was no significant reduction regarding serum-specific IgE levels[313233] regardless of the drug formulations. However, serum-specific IgE levels and the ratio of specific IgE to total IgE can potentially represent a mark for treatment response evaluation and evaluation of the prognosis.[1834] Collectively, these studies suggest that SLIT tablets may act as an adaptive modulator of the immune system. In addition, future translational investigations are still needed to further illustrate the mechanisms of SLIT tablets.

Our current study suggests that SLIT tablets are effective at reducing RTSS and relieving rhinitis symptoms and may be more efficacious than SLIT drops according to our clinical observations.[26] Positive outcomes of the effect of SLIT tablets have been reported in most of the RCTs; however, there are still some limitations preventing the formation of a complete guideline for the treatment of AR. Although our meta-analysis consisted of seven studies with more than 2000 patients, the heterogeneity is high, and the number of identified adolescent patients is still relatively small. Furthermore, the included studies lack the population of adolescents with AR undergoing SLIT tablet therapy. Moreover, the index indicating immunostate of the receivers such as Th1/Th2 and Treg is not extractable in all included studies as these are not regular clinical observing outcomes.[2233] The evidence for the level of serum sIgE is rather limited currently due to few articles reporting such outcomes. Despite these limitations, our study was able to synthesize the most current studies regarding the efficacy of SLIT tablets on AR patients. A majority of our identified articles showed a significant reduction in RTSS in AR patients undergoing SLIT tablets. Our meta-analysis also illustrated the improvement of rhinitis symptoms, although no significant improvement of serum-specific IgE level was observed.

SLIT tablet administration for allergic rhinitis patients is a widely adopted and safe immunotherapy.[263536] The current systematic review and meta-analysis suggest that SLIT tablets are effective in reducing RTSS in AR adults but are perhaps not as effective regarding the serum specific IgE level. However, the mechanism of SLIT tablets on AR patients has not been completely defined. Future RCTs and translational studies with larger sample sizes are still needed to provide a higher level of evidence regarding the efficacy of SLIT tablets in AR patients, particularly on adolescent AR patients. In addition, the outcomes in AR patients with or without allergic asthma should be evaluated independently to determine the potentially different outcomes between patients with or without comorbidities.

In conclusion, Our current meta-analysis suggests that SLIT tablets may serve as a safe and effective treatment in reducing rhinitis symptoms in patients suffering from HDM-induced allergic rhinitis, despite the limitation of high heterogeneity. However, the efficacy in adolescents is still under investigation. Future RCTs and translational studies with larger sample sizes are needed to provide further evidence.

Financial support and sponsorship

This work was supported by grants from the National Natural Science Foundation of China (No. 30671943 and No. 81771725) and CAMS Innovation Fund for Medical Sciences (No. 2016-I2M-1003).

Conflicts of interest

There are no conflicts of interest.