Baseline Severity and Disease Duration Can Predict the Response to Allergen-specific Immunotherapy in Allergic Rhinitis.

Allergen-specific immunotherapy (AIT) has confirmed its efficacy in improving the symptoms of allergic rhinitis. However, no reliable biomarkers have been identified to predict the efficacy of AIT were found. We aimed to find clinical and immunological markers to predict efficacy in children after 2 years of sublingual immunotherapy (SLIT). A total of 285 children diagnosed with allergic rhinitis were recruited. The clinical efficacy was evaluated by comparing endpoint and baseline symptom and medication scores (SMS). Baseline clinical and immunological markers (serum total and specific immunoglobulin [Ig]E) and their correlation with clinical efficacy were analyzed. Of the 285 children recruited, 249 completed the 2-year SLIT program. After 2 years of SLIT, 68.3% of the children showed a significant response. Children in the Remarkable Response Group had the highest baseline SMS and most extended disease duration, followed by the Effective Relief and Unresponsive Group. Correlation analysis demonstrated that SMS improvement was positively correlated with baseline SMS (r=0.67) and disease duration (r=0.35). SMS improvement was not correlated with age, body mass index, total or specific IgE levels, or their ratios. Our results show that baseline SMS and disease duration can predict the efficacy of SLIT. Our study can guide the selection of suitable candidates for SLIT.

Immune Cell Alterations and PI3K-PKB Pathway Suppression in Patients with Allergic Rhinitis Undergoing Sublingual Immunotherapy.

INTRODUCTION: Our prior clinical study assessed the efficacy and safety of sublingual immunotherapy (SLIT) with standardized Dermatophagoides farina drops on patients with allergic rhinitis (AR) while analyzing the characteristics of adverse reactions. This study was conducted to evaluate the immune cell composition alterations in AR patients before and after SLIT, and to comprehensively investigate the role and changes of antigen-specific immune cells associated with treatment efficacy. METHODS: A total of 68 AR patients who completed 12 months of SLIT were included in the study. Before the trial's initiation and after 1 year of SLIT, 10 ml of venous blood was collected. Peripheral blood mononuclear cells were isolated using the Ficoll gradient method. The mRNA transcriptome was analyzed using an Affymetrix microarray. The proportions of 22 immune cell types were calculated via the CIBERSORTx platform. Correlations between each immune cell type and SLIT were analyzed. PI3K-PKB pathway dysregulation were analyzed using quantitative PCR and Western blot. Flow cytometry was utilized to assess the percentages of Th1 and Th2 cells. RESULTS: Mono-sensitized AR patients exhibited marked increases in plasma cells, activated memory T cells, regulatory T cells, and activated dendritic cells, while experiencing decreased neutrophils and resting dendritic cells. In poly-sensitized AR patients, the most notable change was an increase in regulatory T cells, coupled with decreased T follicular helper cells, resting dendritic cells, and activated mast cells. These findings indicated that SLIT reshaped immune cell profiles in AR patients, and, notably, the specific changes differed between mono-sensitized and poly-sensitized individuals. Furthermore, SLIT appeared to shift the immune response towards a Th2 decrease profile in both groups. Importantly, suppression of the PI3K-PKB pathway was evidenced as inhibition of PKB phosphorylation and the decrease of glycogen synthase kinase 3 ß (GSKß) and mammalian target of rapamycin (mTOR) expression after SLIT. CONCLUSION: Our study has demonstrated that SLIT treatment led to distinct changes in immune cell profiles between mono-sensitized and poly-sensitized AR patients. Furthermore, SLIT appeared to reduce a Th2 immune response, highlighting its efficacy in AR treatment. Importantly, the study revealed the suppression of the PI3K-PKB pathway, shedding light on the immunological mechanisms underlying SLIT's effectiveness.

Efficacy and safety of intratonsillar immunotherapy for allergic rhinitis: A randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: A lower adherence rate existed in patients receiving allergen-specific immunotherapy due to its lengthy period and adverse effects even though it is the only curative treatment for IgE-mediated allergies. Therefore, exploring innovative allergen-specific immunotherapy routes is necessary. OBJECTIVE: To explore the efficacy and safety of the intratonsillar injection of house dust mite (HDM) extract in patients with HDM-induced allergic rhinitis (AR). METHODS: A randomized, double-blind, placebo-controlled clinical trial was conducted. A total of 80 patients with HDM-induced AR were randomized to receive 6 intratonsillar injections with HDM extract or placebo in 3 months. The total nasal symptom score (TNSS), visual analogue scale of nasal symptoms, combined symptom and medication score, mini rhinoconjunctivitis quality of life questionnaire, and serum allergen-specific IgG4 to Dermatophagoides pteronyssinus were all monitored at baseline and 3 months, 6 months, and 12 months after the treatment was finished. The intent-to-treat and per-protocol set (PPS) are both analyzed. RESULTS: The primary end points TNSS and ΔTNSS were improved significantly at 3 months after the patients with AR finished a 3-month 6-injection intratonsillar immunotherapy compared with those in the placebo treatment in both intent-to-treat and PPS. Results of visual analogue scale, combined symptom and medication score, and mini rhinoconjunctivitis quality of life questionnaire were also improved significantly at 3 months after the treatment in PPS. However, the improvement effect of intratonsillar immunotherapy at 6 and 12 months was limited and uncertain based on the data. The increase of serum Der p IgG4 in the active group was significantly higher than that in the placebo group at 3, 6, and 12 months after the treatment was finished. Adverse events were monitored, and no systemic adverse reactions were observed. CONCLUSION: The clinical trial revealed that intratonsillar injection with HDM extract was safe and effective in patients with AR. Optimizing the protocol and allergen formulations is expected to increase and maintain the efficacy of this novel approach. TRIAL REGISTRATION: https://www.chictr.org.cn/index.html, identifier: ChiCTR-TRC-13003600.

Anaphylaxis in Clinical Trials of Sublingual Immunotherapy Tablets.

BACKGROUND: There is no consensus method to identify anaphylaxis in sublingual immunotherapy (SLIT) trials. Standardized Medical Dictionary for Regulatory Activities (MedDRA) queries (SMQs) are standardized groupings of MedDRA terms used in drug safety monitoring. OBJECTIVE: To develop a method to identify potential anaphylaxis in SLIT-tablet trials using SMQ searches and case definitions of anaphylaxis adopted from the National Institute of Allergy and Infectious Disease. METHODS: The SMQ search tool contained 2 criteria including treatment-emergent adverse events (AEs): (1) narrow MedDRA terms related to anaphylaxis and (2) all AEs with broad MedDRA terms from at least 2 of 3 categories (respiratory/skin/cardiovascular) occurring on the same day. Criteria were applied to a pooled data set of all subjects from 48 timothy grass, ragweed, house dust mite, and tree SLIT-tablet trials (SLIT-tablet, N = 8200; placebo, N = 7033). Additional search strategies were any treatment-emergent AE with MedDRA preferred term "hypersensitivity" and epinephrine administrations. Identified potential cases underwent blinded independent medical expert review. Nonanaphylaxis cases were designated local AEs or mild to moderate systemic reactions. RESULTS: Using the SMQ search tool and after subsequent medical review, 8 anaphylaxis cases were identified; 3 were considered treatment-related, resulting in a proportion of anaphylaxis cases/subject of 0.02% (2 of 8200) with SLIT-tablet and 0.01% (1 of 7033) with placebo. One additional anaphylaxis case related to SLIT-tablet was identified by the preferred term "hypersensitivity." The 3 anaphylaxis cases associated with SLIT-tablet treatment were not life-threatening. The epinephrine administration rate was 17 of 8200 (0.2%) with SLIT-tablet treatment and 2 of 7033 (0.03%) with placebo. CONCLUSIONS: SMQ search criteria for identifying potential anaphylaxis related to SLIT were developed. Anaphylaxis was rare for SLIT-tablets.

Prevention Is Better than Cure: Impact of Allergen Immunotherapy on the Progression of Airway Disease.

Allergen immunotherapy is highly effective for seasonal pollinosis. Three years of treatment results in long-term efficacy. This disease modification is accompanied by downregulation of allergen-specific Th2 responses and the induction of persistent specific IgG- and IgA-associated IgE-blocking activity. In children with seasonal rhinitis, both subcutaneous and sublingual pollen immunotherapy have been shown to reduce the development of asthma symptoms and asthma medication requirements. House dust mite tablet allergen immunotherapy has been shown to be effective for perennial mite-driven rhinitis in adults and children and may suppress asthma exacerbations, whereas its long-term efficacy has yet to be explored. The success of primary prevention of peanut allergy in childhood by introduction of peanut into the diet during infancy provides a strong rationale to explore whether primary prevention of inhalant allergies and asthma may also be possible. House dust mite allergy is a major risk factor for developing asthma. Preliminary data in at-risk children suggest that sublingual house dust mite immunotherapy initiated during infancy could reduce the onset of multiple allergen sensitizations and prevent the development of asthma at age 6 years. This possibility should now be explored in an adequately powered, prospectively randomized controlled trial.

A successful linkage of a named patient products of sublingual immunotherapy-dispensing registry to French healthcare insurance database (SNDS): methodological constitution of the EfficAPSI cohort.

BACKGROUND: The only causal treatment for allergic rhinitis (AR) is allergen immunotherapy (AIT) including personalized liquid sublingual AIT (SLIT). We present the methodology for establishing the EfficAPSI cohort to further evaluate the real-life effectiveness and use of SLIT liquid. RESEARCH DESIGN AND METHODS: The EfficAPSI cohort was constituted by deterministic linkage of Stallergenes Greer dispensing and nationwide French healthcare insurance system (SNDS) databases. Data from 2006 to 2018 were extracted. All patients who initiated Stallergenes Greer SLIT liquid between 2010 and 2013 were considered as exposed and those dispensed with AR symptomatic treatment only as control. To limit the impact of confounding, the models will be weighted using the inverse probability of treatment weighting (IPTW). RESULTS: A total of 445,574 patients were included; median age was 38 years; 59.1% were female. Exposed patients (n = 112,492) were significantly younger, more frequently males, and less likely to have comorbidities than controls (n = 333,082). After IPTW, patients' characteristics from both groups were similar. CONCLUSIONS: To date, the EfficAPSI cohort has the largest number of person-years of follow-up in the field of AIT. The completeness of the data allows to evaluate SLIT liquid effectiveness with rigorous methodology, leading to important insights on personalized medicine in real-life.

A novel dose-adjustment protocol for interrupted subcutaneous immunotherapy for allergic rhinitis.

Background: This study aimed to develop a novel dose strategy for subcutaneous immunotherapy to reduce medical waste and financial burdens for patients who are required to restart subcutaneous immunotherapy. Patients & methods: A prospective, nonrandomized concurrent controlled trial was performed to assess the safety and advantages of the novel dose-adjustment protocol compared with the conventional one. 76 subjects were grouped to receive novel or conventional dose-adjustment protocols. Results: The injections, visits and time needed to reach the pre-established dose with the novel regimen were decreased. Furthermore, there were no differences in side reactions between the two groups. Conclusion: The novel protocol seemed safe and well tolerated, offering the advantages of time efficiency and reduced healthcare costs.

A common sickness people can acquire from house dust mites is called allergic rhinitis. One way to treat it is with regular shots of a special medicine made from dust mite allergens. This is termed subcutaneous immunotherapy. Patients need to take these shots in their arm for about 3­5 years. Initially, the shot is given once a week for at least 15 weeks; then the frequency can be reduced to every 4­8 weeks. However, if a patient misses their scheduled shot, they may have to start getting weekly shots again. This can lead to a lot of medical waste and can be expensive for patients. Therefore we developed a new way to give these shots. In this study, patients who needed to start weekly shots again were administered this new treatment plan. The new plan significantly reduced the number of doctor's visits and shots. This new and improved treatment regimen is convenient and saves patients time and money. The side effects of this new treatment method were not higher compared with the traditional treatment. Therefore this new treatment method is safe, cost-effective and patient-friendly. It also saves time and reduces both medical waste and financial costs.

The relationship between sublingual immunotherapy for allergic rhinitis and the risk of symptoms in patients with COVID-19 infection.

To evaluated the risk ratio of Allergic rhinitis (AR) people on the symptoms after COVID-19 infection, and explored the relationship between AR and the symptoms after COVID-19 infection. An observational study was performed of people from outpatient department of the Hospital of Chengdu University of Chinese Medicine. Participants completed an electronic survey and between January 10 to January 20, 2023. We divided the participants into three groups according to the disease information of the population: non-AR people group (AR-N), AR patients with sublingual immunotherapy group (AR-S), and AR patients with conventional therapy group (AR-C). A total of 1116 participants were included in the study, with an average age of 21.76 ± 8.713, women accounted for 62.5%, men accounted for 37.5%. The final results showed that the risk of most symptoms after AR-C infection was not different from that of AR-N, except for sore throat, dry and itchy, chest distress, shortness of breath, and dyspnea. AR-S could effectively reduce the risk of post-infection symptoms including: dry and itchy (OR = 0.484, 95%CI: 0.335-0.698), pain (OR = 0.513, 95%CI:0.362-0.728), cough (OR = 0.506, 95% CI:0.341-0.749), expectoration (OR = 0.349, 95% CI:0.244-0.498), fever (OR = 0.569, 95% CI:0.379-0.853), head and body pain (OR = 0.456, 95% CI:0.323-0.644), fatigue (OR = 0.256, 95% CI:0.177-0.371), cold limbs (OR = 0.325, 95%CI:0.227-0.465), diarrhea (OR = 0.246, 95% CI:0.132-0.457), constipation (OR = 0.227, 95%CI:0.100-0.513), hyposmia (OR = 0.456, 95% CI:0.296-0.701), hypogeusia (OR = 0.397, 95% CI:0.259-0.607), chest distress (OR = 0.534, 95% CI:0.343-0.829), shortness of breath (OR = 0.622, 95% CI:0.398-0.974), palpitations (OR = 0.355, 95% CI:0.206-0.613). The risk of symptoms after COVID-19 infection in allergic rhinitis population receiving sublingual immunotherapy is lower.

Efficacy of Sublingual Immunotherapy in Allergic Rhinitis Patients with Asthma: A Systematic Review and Meta-Analysis.

OBJECTIVE: Sublingual immunotherapy (SLIT) has been widely applied to treat patients with allergic rhinitis (AR). However, meta-analyses on the efficacy of SLIT in AR patients with asthma are still limited. METHODS: Literature without language limitation published before October 28, 2022, were retrieved from PubMed, EMBASE, and Cochrane Library. STATA 16.0 software was used for the meta-analysis of the extracted data. The results reported were symptom scores, drug scores, adverse effects rates, and cost of treatment. RESULTS: Ten studies involving 1722 patients met the inclusion criteria. The total rhinitis score (TRSS) (weighted mean difference [WMD] = -1.23, 95% CI: -1.39--1.06, P < .001) and total asthma symptom score (TASS) (WMD = -1.00, 95% CI: -1.12-0.89, P < .001) were significantly lower in the SLIT group than the placebo group. The SLIT group had higher rates of treatment-related adverse events (relative risk [RR] = 2.82, 95% CI: 1.77-4.48, P < .001) and total costs of treatment (standardized mean difference [SMD] = 0.71, 95% CI: 0.45-0.97, P < .001). There was no significant difference in inhaled corticosteroids (ICS) dose (P = .195), fractional exhaled nitric oxide (FeNO) (P = .158), forced expiratory volume in 1 s (FEV1) (P = .237), and direct costs of treatment (P = .630) between the SLIT and placebo groups. CONCLUSION: SLIT may be a therapeutic method for improving rhinitis symptoms and asthma symptoms in AR patients with asthma. However, as there was significant heterogeneity in results, more high-quality and well-designed studies are needed in the future to elucidate the efficacy of SLIT.

Evaluation of the quality of guidelines for sublingual immunotherapy of allergic rhinitis.

BACKGROUND: Guidelines are intended to facilitate evidence-based clinical decision-making and knowledge translation; however, the quality and rigor of the guidelines are different. This study was conducted to assess the quality of sublingual immunotherapy guidelines for allergic rhinitis, in order to provide a reference for evidence-based clinical treatment and management of sublingual immunotherapy. METHODS: Using both Chinese and English search methods, articles were obtained from PubMed, Cochrane, Web of Science, CNKI, CBM, WanFang Data, VIP, and other databases from the construction of the database to September 2020. The AGREE II instrument was used by two researchers to independently evaluate the quality of the extracted articles, and the consistency of the researchers was evaluated using the inter-group correlation coefficient. RESULTS: Ten articles were included in this study, of which two articles ranked A level, six articles ranked B level, and two articles ranked C level. The six sections of AGREE II included scope and aim, clarity, participant, applicability, rigor, and editorial independence, with standardized scores of 78.06%, 45.83%, 42.81%, 77.50%, 50.42%, and 46.25%, respectively. CONCLUSION: The quality of the current guidelines for sublingual immunotherapy is average. The formulation methodology and reporting standards of these guidelines must be developed. By standardizing the treatment of sublingual immunotherapy properly, it is recommended that guideline makers refer to the AGREE II to formulate high-quality guidelines and promote their wide application.

Nasal and blood transcriptomic pathways underpinning the clinical response to grass pollen immunotherapy.

BACKGROUND: Allergen immunotherapy (AIT) is a well-established disease-modifying therapy for allergic rhinitis, yet the fundamental mechanisms underlying its clinical effect remain inadequately understood. Gauging Response in Allergic Rhinitis to Sublingual and Subcutaneous Immunotherapy was a randomized, double-blind, placebo-controlled trial of individuals allergic to timothy grass who received 2 years of placebo (n = 30), subcutaneous immunotherapy (SCIT) (n = 27), or sublingual immunotherapy (SLIT) (n = 27) and were then followed for 1 additional year. OBJECTIVE: We used yearly biospecimens from the Gauging Response in Allergic Rhinitis to Sublingual and Subcutaneous Immunotherapy study to identify molecular mechanisms of response. METHODS: We used longitudinal transcriptomic profiling of nasal brush and PBMC samples after allergen provocation to uncover airway and systemic expression pathways mediating responsiveness to AIT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01335139, EudraCT Number: 2010-023536-16. RESULTS: SCIT and SLIT demonstrated similar changes in gene module expression over time. In nasal samples, alterations included downregulation of pathways of mucus hypersecretion, leukocyte migration/activation, and endoplasmic reticulum stress (log2 fold changes -0.133 to -0.640, false discovery rates [FDRs] <0.05). We observed upregulation of modules related to epithelial development, junction formation, and lipid metabolism (log2 fold changes 0.104 to 0.393, FDRs <0.05). In PBMCs, modules related to cellular stress response and type 2 cytokine signaling were reduced by immunotherapy (log2 fold changes -0.611 to -0.828, FDRs <0.05). Expression of these modules was also significantly associated with both Total Nasal Symptom Score and peak nasal inspiratory flow, indicating important links between treatment, module expression, and allergen response. CONCLUSIONS: Our results identify specific molecular responses of the nasal airway impacting barrier function, leukocyte migration activation, and mucus secretion that are affected by both SCIT and SLIT, offering potential targets to guide novel strategies for AIT.

Updates in food allergen immunotherapy.

PURPOSE OF REVIEW: Food allergies are on the rise. Though allergen avoidance and management of acute reactions have been the backbone of therapy, complete avoidance and timely acute care is often not feasible. Food allergen immunotherapy (FAIT) is a novel and evolving treatment option intended to induce desensitization and potential sustained unresponsiveness (SU) to food allergens. This review addresses the methods, mechanisms, efficacy, and adverse effects of oral immunotherapy (OIT), sublingual immunotherapy (SLIT), and epicutaneous immunotherapy (EPIT) for food allergens in the published literature. RECENT FINDINGS: Single FAIT has been most extensively studied in peanut, milk, and hen's egg allergic patients and has been successful in achieving desensitization in treated individuals through various modalities. Long-term data regarding SU is limited; however, current data suggests subsets of patients may be more likely to achieve SU compared to others. Other studies are actively assessing multifood AIT and novel FAIT protocols with adjunctive therapies. SUMMARY: Food allergy constitutes a prevalent problem with far-reaching consequences. The emergence of FAIT may mitigate the burden of food allergy. Current evidence is promising for specific allergens and pediatric patient populations. Future studies are needed to further assess efficacy between different modalities of immunotherapy for food allergens across an age continuum.

Pharmacotherapy and immunotherapy of allergic rhinitis induced by house dust mite, grass, and birch pollen allergens: a meta-analysis of randomized clinical trials.

BACKGROUND: The aim of this study was to assess the efficacy and safety of oral antihistamines (AHs), intranasal antihistamines (INAH) intranasal glucocorticosteroids (INCS), subcutaneous immunotherapy (SCIT), and sublingual immunotherapy (SLIT) in the management of allergic rhinitis (AR). The authors focused on the division into selected AR's triggers: house dust mites (HDMs), grass pollen, and birch pollen. METHODS: For each drug and allergen class, a meta-analysis of the efficacy and adverse events (AEs) was performed. The obtained results were presented as a therapeutic index (TIX-Score). RESULTS: Twenty-seven randomized clinical trials (RCTs) were included. The best total efficacy was observed for: HDMs for INCS and grass pollen for combination of INCS with INAH in a single device and for INAH. Considering the data that was obtained for birch pollen, SLIT showed statistically significant total efficacy. Summation scores for efficacy and AEs showed highest TIX-Score for combination of INCS and INAH in a single device in grass pollen. CONCLUSIONS: Treatment methods selected for this review may serve as an effective and safe treatment in reducing perennial and seasonal AR's symptoms. However, due to high heterogeneity probably associated with potential confounders existence in control in some cases, results should be interpreted with caution.

Comparison of evidence of treatment effects in randomized and nonrandomized studies on allergen immunotherapy.

Nonrandomized studies (NRS) on allergen immunotherapy (AIT) particularly lend themselves to evaluate outcomes that are insufficiently addressed in randomized controlled studies (RCTs). However, NRS are prone to several sources of bias, which limit their validity. We aimed at comparing AIT effects between RCTs and NRS and evaluate the reasons for discrepancies in study results. In this analysis, we compared NRS on AIT (including subcutaneous and sublingual immunotherapy, SCIT and SLIT, respectively) with SLIT and SCIT RCTs from published meta-analyses, assessing the Risk of Bias (RoB) for each study and the certainty of evidence from NRS and RCTs using the GRADE approach. We found: (1) very serious RoB in the 7 NRS included in the meta-analysis showing a large difference between AIT and controls (standardized mean difference [SMD] for symptom score [SS], -1.77; 95% CI, -2.30, -1.24; p < .001; I2 = 95%) with very low certainty evidence; (2) serious RoB in the 13 SCIT-RCTs reporting a moderate-to-high difference between SCIT and controls (SMD for SS, -0.81; 95% CI, -1.12, -0.49; p < .001; I2 = 88%) with moderate certainty evidence; (3) low RoB in the 13 SLIT-RCTs reporting a small benefit (SMD for SS, -0.28; 95% CI, -0.37, -0.19; p < .001; I2 = 54.2%) with high certainty evidence. Similar results were reported for medication score. Our evidence is sufficient to conclude that the magnitude of effect estimates of NRS and RCTs directly correlate with the degree of RoB and inversely with the overall evidence certainty. NRS, which are more affected than RCTs by bias resulting in low certainty evidence, showed the largest effect size. Sound NRS are needed to complement RCTs.

Efficacy and safety of sublingual immunotherapy for allergic rhinitis: A network meta-analysis.

Background: To systematically evaluate the clinical efficacy and safety of sublingual immunotherapy for allergic rhinitis (AR) and provide evidence for clinical treatment. Methods: A literature search was performed on the China National Knowledge Infrastructure (CNKI), Wanfang database, PubMed, Web of Science, Cochrane Library, and Embase database. Data from randomized controlled trials (RCTs) of sublingual immunotherapy for AR were screened and extracted from the establishment of those databases to November 2022. Subsequently, a network meta-analysis was performed using a statistical software R 4.2. Results: Totally 22 RCTs that met the inclusion and exclusion criteria and screened from 1,164 literature were included. A total of 4,941 AR patients were involved in the 22 trials, as well as five interventions including placebo, pharmacotherapy, subcutaneous immunotherapy_dust mite, sublingual immunotherapy_dust mite, and sublingual immunotherapy_ grass mix plus pollen extract. The results of network meta-analysis showed that, based on symptom scores after different interventions for AR, the most effective treatments for AR were in order as follows: sublingual immunotherapy_dust mite, subcutaneous immunotherapy_dust mite, sublingual immunotherapy_ grass mix plus pollen extract, placebo, and pharmacotherapy. Importantly, sublingual immunotherapy had fewer adverse reactions and higher safety. Conclusion: Sublingual immunotherapy_dust mite for AR has the best efficacy, whereas traditional medicine has the worst. More high-quality studies with a large sample and multiple centers are needed to verify this conclusion in the future, so as to further provide more reliable evidence-based medical evidence for the clinical treatment options of AR patients.

House dust mite sublingual immunotherapy tablet safety in adolescents with allergic rhinoconjunctivitis: Worldwide clinical trial results.

BACKGROUND: The house dust mite (HDM) sublingual immunotherapy (SLIT)-tablet is a treatment option for allergic rhinitis with/without conjunctivitis (AR/C) approved in adults worldwide and in adolescents in some countries. OBJECTIVE: To supplement existing adolescent HDM SLIT-tablet safety data by conducting the MT-18 trial in adolescents. METHODS: MT-18 (EudraCT:2020-000446-34) was a phase 3, open-label, single-arm, 28-day safety trial of daily HDM SLIT-tablet (12 SQ-HDM dose) in European adolescents (12-17 years) with HDM AR/C, with or without asthma. The primary end point was at least 1 treatment-emergent adverse event (TEAE). MT-18 results were compared with 12 SQ-HDM adolescent subpopulation data from previously described 1-year phase 3 trials conducted in North America (P001; clinicaltrials.gov:NCT01700192) or Japan (TO-203-3-2; JapicCTI:121848). RESULTS: No treatment-related anaphylaxis, epinephrine administrations, severe local swellings, severe mouth or throat edema, or eosinophilic esophagitis occurred in the trials. For MT-18 (N = 253), P001 (N adolescents = 189), and TO-203-3-2 (N adolescents = 206), the percentage of adolescents treated with 12 SQ-HDM reporting any TEAE was 88%, 95%, and 93%, respectively, and the percentage reporting any treatment-related AE (TRAE) was 86%, 93%, and 66%, respectively. The most common TRAEs were local application site reactions. Most TRAEs were mild in intensity and were typically experienced the first 1 to 2 days of treatment. There were no asthma-related TEAEs with the HDM SLIT-tablet. The safety profile appears similar between adolescents with or without asthma at baseline. CONCLUSION: The HDM SLIT-tablet was well tolerated in European, North American, and Japanese adolescents with HDM AR/C, indicating safety of the HDM SLIT-tablet is insensitive to age or geographic region. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: (P001: NCT01700192); EudraCT: (MT-18; 2020-000446-34); JapicCTI: (TO-203-3-2; 121848).

Real-world, long-term effectiveness of allergy immunotherapy in allergic rhinitis: Subgroup analyses of the REACT study.

BACKGROUND: Randomized controlled trials have demonstrated the efficacy of allergy immunotherapy (AIT) in allergic rhinitis (AR) and the disease-modifying effects of the SQ grass sublingual immunotherapy (SLIT) tablet. OBJECTIVE: We sought to assess real-world, long-term effectiveness and safety across AIT subgroups: route of administration, therapeutic allergen, persistence to AIT, and SQ grass SLIT tablet. METHODS: The primary outcome of AR prescriptions from a retrospective cohort study (REAl-world effeCtiveness in allergy immunoTherapy; 2007-2017) was assessed across prespecified AIT subgroups in subjects with AR with and without AIT prescriptions (controls). Safety was assessed as anaphylaxis for 2 days or less of the first AIT prescription. Subgroup follow-up continued until samples were fewer than 200 subjects. RESULTS: Subcutaneous immunotherapy (SCIT) and SLIT tablets showed similarly greater reductions in AR prescriptions than controls (SCIT vs SLIT tablets: year 3, P = .15; year 5, P = .43). Comparably greater reductions in AR prescriptions were observed for grass- and house dust mite-specific AIT than for controls, but significantly smaller reductions were observed for tree-specific AIT (tree vs house dust mite, and vs grass: years 3 and 5, P < .0001). Persistence to AIT was associated with greater reductions in AR prescriptions versus nonpersistence (persistence vs nonpersistence: year 3, P = .09; year 5, P = .006). SQ grass SLIT tablet showed sustained reductions versus controls for up to 7 years (year 3, P = .002; year 5, P = .03). Rates of anaphylactic shock were low (0.000%-0.092%), with no events for SQ SLIT tablets. CONCLUSIONS: These results demonstrate real-world, long-term effectiveness of AIT, complement disease-modifying effects observed in SQ grass SLIT-tablet randomized controlled trials, and highlight the importance of using newer evidence-based AIT products for tree pollen AR.

Open-label study of the efficacy, safety, and durability of peanut sublingual immunotherapy in peanut-allergic children.

BACKGROUND: Studies on the efficacy of peanut sublingual immunotherapy (SLIT) are limited. The durability of desensitization after SLIT has not been well described. OBJECTIVE: We sought to evaluate the efficacy and safety of 4-mg peanut SLIT and persistence of desensitization after SLIT discontinuation. METHODS: Challenge-proven peanut-allergic 1- to 11-year-old children were treated with open-label 4-mg peanut SLIT for 48 months. Desensitization after peanut SLIT was assessed by a 5000-mg double-blind, placebo-controlled food challenge (DBPCFC). A novel randomly assigned avoidance period of 1 to 17 weeks was followed by the DBPCFC. Skin prick test results immunoglobulin levels, basophil activation test results, TH1, TH2, and IL-10 cytokines were measured longitudinally. Safety was assessed through patient-reported home diaries. RESULTS: Fifty-four participants were enrolled and 47 (87%) completed peanut SLIT and the 48-month DBPCFC per protocol. The mean successfully consumed dose (SCD) during the DBPCFC increased from 48 to 2723 mg of peanut protein after SLIT (P < .0001), with 70% achieving clinically significant desensitization (SCD > 800 mg) and 36% achieving full desensitization (SCD = 5000 mg). Modeled median time to loss of clinically significant desensitization was 22 weeks. Peanut skin prick test; peanut-specific IgE, IgG4, and IgG4/IgE ratio; and peanut-stimulated basophil activation test, IL-4, IL-5, IL-13, IFN-γ, and IL-10 changed significantly compared with baseline, with changes seen as early as 6 months. Median rate of reaction per dose was 0.5%, with transient oropharyngeal itching being the most common, and there were no dosing symptoms requiring epinephrine. CONCLUSIONS: In this open-label, prospective study, peanut SLIT was safe and induced clinically significant desensitization in most of the children, lasting more than 17 weeks after discontinuation of therapy.

Changes in type 2 innate lymphoid cells and serum cytokines in sublingual immunotherapy in pediatric patients with allergic rhinitis.

BACKGROUND: Type 2 innate lymphoid cells (ILC2) are upregulated in childhood allergic rhinitis (AR) and are associated with AR severity. This study aimed to investigate changes in the ILC2 milieu in pediatric patients with AR after sublingual immunotherapy (SLIT). METHODS: Forty- pediatric patients with AR received house dust mite (HDM) allergen extract for SLIT group and thirty pediatric patients received placebo in the study, respectively. The levels of ILC2, ILC2-related cytokines (IL-5/IL-13) and their transcription factors (GATA binding protein 3, retinoic acid-related orphan receptor α) in the circulation were assessed after 1- and 2-year SLIT. Moreover, peripheral blood mononuclear cells (PBMCs) in patients were prepared and stimulated by recombinant thymic stromal lymphopoietin, IL-25, and IL-33 after 2-year SLIT. Subsequently, the levels of ILC2, IL-5, and IL-13 were tested. RESULTS: The frequency of ILC2 and the levels of their transcription factors in the circulation were significantly decreased after SLIT in the SLIT group. The levels of ILC2-related cytokines in the SLIT group showed the same trend. The frequency of ILC2 was positively correlated with transcription factors and cytokines after SLIT. SLIT was observed to reduce the ability of HDM sensitization to generate the ILC2 milieu in PBMCs. CONCLUSIONS: Changes in the ILC2 milieu may be correlated with the curative effect and immune regulation function of SLIT. Our results suggested that the regulatory effect on ILC2 is part of the therapeutic mechanism of SLIT.

Extraction, Purification, and Development of Sublingual Film (SLIT Films) Comprising Cockroach Allergen for Treatment of Allergy.

AIM: Allergy associated with cockroaches are mostly from the American cockroach (Periplaneta americana) and German cockroach (Blattella germanica). The effective and safe treatment for cockroach allergy is Sublingual immunotherapy (SLIT). In this study, SLIT Films containing purified allergen extract of Periplaneta americana were prepared by solvent casting and were evaluated for their efficiency in delivery. METHODOLOGY: Cockroach allergen extract was prepared and purified by ultrafiltration and chromatography. The molecular weight of protein content was identified and estimated by SDS- PAGE and ELISA. SLIT films were developed by the Quality by Design (QbD) approach and were evaluated for allergen- excipient compatibility, swelling index, taste, diffusion, in vitro dissolution, local toxicity, and stability analysis. RESULTS: Cockroach allergen protein extracts (cut-off 25-71KDa) were identified by SDS-PAGE and quantified by indirect ELISA and further selected for sublingual film preparation. The indirect ELISA results show a higher optical density (OD) value compared to crude extract. The weight uniformity and thickness of the film were between 13-18 mg and 0.04-0.06 mm. The disintegration time was found to be less than 1 min. The cumulative percentage release was also found to be satisfactory. The local toxicity study indicated no signs of irritation in the buccal mucosa of rabbits. The optimised F3 film had uniform thickness, faster disintegration and drug content within pharmacopeial limits. Ex vivo study revealed better permeability with 90% release of allergen in 7 minutes. The formulation was also stable at room temperature during the study period. CONCLUSION: SLIT Film containing cockroach allergen from Periplaneta americana was successfully developed and evaluated. SLIT films of cockroach allergen could be more beneficial and convenient for emergency use in patients when compared to subcutaneous immunotherapy. SLIT films provide dose accuracy and are a promising alternative for SCIT and SLIT drops and tablets.