Moderate-to-severe allergic rhinitis (AR) may increase the risk of developing or worsening asthma, whereas treatment of AR with subcutaneously or sublingual allergen immunotherapy (SLIT) may slow this progression.

In a retrospective real-world analysis, prescription fulfilment data were gathered from French retail pharmacies between March 1st , 2012, and December 31st , 2016. Using linear regression analyses, patients having received at least two prescriptions of grass pollen SLIT tablets over at least two successive years were compared with control patients having received symptomatic medications only.

1,099 SLIT patients and 27,475 control patients were included in the main analysis. With regard to symptomatic AR medication dispensing, we observed a 50% decrease in the pre-index/follow-up ratio in the SLIT group, a 30% increase in the control group without age matching (p<0.0001 vs. SLIT), and a 20% increase in the control group with age matching (p<0.0001 vs. SLIT). During the follow-up, 11 (1.8%) and 782 (5.3%) patients initiated asthma treatment in the SLIT and control groups, respectively. The relative risk of medication dispensing for new asthma was lower in the SLIT group (by 62.5% [29.1%;80.1%] without age matching (p=0.0025), and by 63.7% [31.5%;80.7%] with age matching (p=0.0018)). SLIT was also associated with slower progression of asthma medication dispensing during the follow-up period, relative to the control group (regression coefficient: -0.58[-0.74;-0.42] without age matching (p<0.0001) and -0.61 [-0.76;-0.46] with age matching (p<0.0001)).

Prescription of grass pollen SLIT tablets reduced the dispensing of AR and asthma medications in real life.

In a recent trial of milk oral immunotherapy (MOIT) with or without omalizumab in 55 patients with milk allergy treated for 28 months, 44 of 55 subjects passed a 10-g desensitization milk protein challenge; 23 of 55 subjects passed the 10-g sustained unresponsiveness (SU) challenge 8 weeks after discontinuing MOIT.

We sought to determine whether IgE and IgG4 antibody binding to allergenic milk protein epitopes changes with MOIT and whether this could predict the development of SU.

By using a novel high-throughput Luminex-based assay to quantitate IgE and IgG4 antibody binding to 66 sequential epitopes on 5 milk proteins, serum samples from 47 subjects were evaluated before and after MOIT. Machine learning strategies were used to predict whether a subject would have SU after 8 weeks of MOIT discontinuation.

MOIT profoundly altered IgE and IgG4 binding to epitopes, regardless of treatment outcome. At the initiation of MOIT, subjects achieving SU exhibited significantly less antibody binding to 40 allergenic epitopes than subjects who were desensitized only (false discovery rate ≤ 0.05 and fold change > 1.5). Based on baseline epitope-specific antibody binding, we developed predictive models of SU. Using simulations, we show that, on average, IgE-binding epitopes alone perform significantly better than models using standard serum component proteins (average area under the curve, >97% vs 80%). The optimum model using 6 IgE-binding epitopes achieved a 95% area under the curve and 87% accuracy.

Despite the relatively small sample size, we have shown that by measuring the epitope repertoire, we can build reliable models to predict the probability of SU after MOIT. Baseline epitope profiles appear more predictive of MOIT response than those based on serum component proteins.

Previous clinical trials with birch pollen subcutaneous immunotherapy have been conducted over a 1-2 year treatment period and involved mostly a single geographic location.

This study (EudraCT-Number: 2005-000025-35) intended to evaluate the effect of subcutaneous immunotherapy with high-dose hypoallergenic birch pollen allergoid in patients with confirmed moderate to severe seasonal allergic rhinitis/rhinoconjunctivitis over a 3-year course in 19 European centers.

Adults with confirmed birch pollen allergy (n=253) were randomized to preseasonal placebo (n=129) or active treatment (n=124). Primary endpoint was change in Symptom Medication Score after 2 years treatment (2007).

The change in Symptom Medication Score of active- versus placebo-treated patients for the Full Analysis Set (n=227, 15.2% reduction, p=0.0710) and PerProtocol Set (n=216, 16.7% reduction, p=0.0523) showed a positive trend, although significance was not achieved. The primary endpoint, assessed in 2007, coincided with the lowest pollination during the study period. In a subgroup analysis of patients in the north-eastern region (n=102), where birch is the major tree and consequently patients’ exposure is higher, changes in Symptom Medication Score (32.7% reduction, p=0.0034) and median number of well days (p=0.0232) were highly significant in favor of the active group. During the open-label third year of treatment, the mean Symptom Medication Score of active-treated patients was further reduced despite an increased pollen count. Subcutaneous immunotherapy was well tolerated and consistent with the known safety profile.

Although the primary endpoint was not reached for the Full Analysis Set, a significant and clinically relevant effect on Symptom Medication Score was clearly demonstrated for the subgroup of patients in the north-eastern region of Europe, where birch is the predominant tree species. Proving efficacy of birch allergen subcutaneous immunotherapy is challenging due to the numerous factors influencing birch pollen allergen exposure in field studies.

Currently, there is no FDA-approved therapy for food allergy. Several new potential treatments are under investigation, including food allergen immunotherapy via various routes of administration, such as oral immunotherapy, epicutaneous therapy, subcutaneous immunotherapy, and sublingual immunotherapy. The double-blind, placebo-controlled food challenge has traditionally been used for diagnostic purposes, but extrapolation of the specific terminology used in food allergy diagnosis to interpretation of efficacy in clinical trials is incongruent and difficult to apply. There is a need for standardization of the terminology used in food allergy clinical trials, as inconsistencies can lead to potential misinterpretation of endpoints. The reactive dose, previously referred to as the eliciting dose, is defined as the dose given that induces the onset of unequivocal allergic symptoms, or the dose that stops the challenge based on physician discretion. Conversely, the single highest tolerated dose is defined as the highest dose given during a food challenge that elicits either no symptoms or symptoms that do not meet stopping criteria per the study protocol. The evolving field of food allergy provides a novel opportunity to define those endpoints that are most meaningful for patients, which is fundamental for successful implementation, education, and safety.

The prevalence of food allergy is increasing, and allergen avoidance continues to be the main standard of care. There is a critical need for safe and effective forms of immunotherapy for patients with food allergy as well as other allergic diseases.

The skin is a multifunctional organ with unique immunologic properties, making it a favorable administration route for allergen-specific immunotherapy. Epicutaneous immunotherapy (EPIT) takes advantage of the skin’s immune properties to modulate allergic responses and is thus one of the allergenspecific immunotherapy approaches currently being investigated for food allergy. Advances made in the understanding of how epicutaneously applied proteins interact with the immune system and in the technology for facilitating such interactions offer many opportunities for clinical application. Research has shown that allergen delivered to intact skin via EPIT is taken up in the superficial layers of the skin by Langerhans cells, avoiding passive movement of allergen through the dermis and limiting systemic circulation. EPIT brings about allergen desensitization by activating a population of regulatory T cells (Tregs) with unique properties and the potential for inducing a sustained effect as well as the possibility (seen in animal models) for protection against further sensitizations. Several clinical trials investigating the therapeutic efficacy of EPIT for treatment of peanut allergy have been completed, as well as a Phase 2 trial for treatment of milk allergy.

Taken together, the reviewed literature supports the concept that EPIT activates the natural desensitization pathway of the skin, offering a progressive, possibly sustained response. EPIT offers a potential alternative for allergen immunotherapy that is less invasive and carries a lower risk for systemic reactions than oral immunotherapy.

Japanese cedar (JC) pollinosis is a common allergic rhinitis in Japan. The JC pollen SLIT tablet was developed using the highest concentration of JC pollen extract.

This was a randomized, double-blind, placebo-controlled phase II/III trial to investigate the optimal dose of the JC pollen SLIT tablet and examine long-term efficacy and safety for 3 years with the selected dose, and 2-year follow-up.

A total 1,042 patients with JC pollinosis (aged 5-64 years) were equally randomized into four groups and received daily treatment with 2,000, 5,000, or 10,000 Japanese allergy unit (JAU) or placebo. The primary endpoint was the total nasal symptom and medication score (TNSMS) during the peak symptom period in the first season. Key secondary endpoints were TNSMS for the JC pollen dispersion season and total nasal and ocular symptom and medication score (TNOSMS) for the peak symptom period and JC pollen dispersion season.

For the primary endpoint, absolute reductions and relative mean reductions in TNSMS compared with placebo were 1.50 and 21.4%, 2.24 and 32.1%, and 2.18 and 31.2% for 2,000, 5,000, and 10,000 JAU, respectively (P < .001 in all groups). For all key secondary endpoints, efficacy was confirmed for all doses (P < .001 in all groups). The treatment was well tolerated. Long-term efficacy of 5,000 JAU was shown over the 3 years.

The optimal dose of the JC pollen SLIT tablet was 5,000 JAU, with good efficacy and safety over a 3-year treatment period. This sustained effect was dependent on treatment duration.

Dermatophagoides pteronyssinus (DP) and Blomia tropicalis (BT) are the dominant house dust mites inducing allergic diseases in tropical climates. It is not known whether the efficacy of DP subcutaneous immunotherapy (SCIT) is similar in patients sensitized to DP alone or to both DP and BT.

Ninety-five children (5-17 years old) affected by asthma with rhinitis and sensitized to both DP and BT received 3 years of DP-SCIT. Clinical symptom and medication scores, serum-specific IgE and IgG4 were evaluated during DP-SCIT. Patients were grouped based on DP and BT co-sensitization or crossreactivity, according to positive or negative IgE to BT major allergen (BTMA).

After 3 years of DP-SCIT, all patients had significant reductions in symptoms and medication use. In all, 65% of the patients were free of asthma symptoms and medication use; in addition, 3% was free of rhinitis symptoms. FEV1 in all patients were greater than 95% of predicted. DP-SCIT induced significant increases in DP- and BT-specific IgG4. In 50% of patients, DP-specific IgG4 increased more than 67-fold. BT-specific IgG4 increased more than 2.5 fold. A moderate correlation (r = 0.48-0.61, p < 0.01) was found between specific IgE against DP and BT in the BTMA- group (n = 34) before and after DP-SCIT, whereas no correlation was found in the BTMA+ group (n = 61). The 2 BTMA groups responded similarly with regard to clinical improvement and increase in specific IgG4 to both DP and BT. No safety finding of concern were reported in either group.

DP-SCIT may be of clinical benefit to patients with IgE sensitizations to both DP and BT. DP-SCIT induces IgG4 that cross-react with BT allergens.

Forkhead box P3-positive regulatory T (Treg) cells are essential mediators of tolerance against self-antigens and harmless exogenous antigens. Treg cell deficiencies result in multiple autoimmune and allergic syndromes in neonates. How Treg cells affect conventional allergies against aeroantigens, which are restricted to a few specific proteins released from inhaled particles, remains controversial. The hallmarks of antigen-specific loss of tolerance are allergenspecific TH2 cells and IgE. However, difficulties in identifying the rare allergen-specific Treg cells have obscured the cellular basis of tolerance to aeroallergens, which is also a major obstacle for the rational design of novel and more efficient allergen-specific immunotherapies. Recent technological progress allowing characterization of allergen-specific effectors and Treg cells with minimal in vitro manipulation revealed their detailed contribution to tolerance. The data identified inhaled particles as immunodominant Treg cell targets in healthy and allergic subjects. Conversely, the supposed immunodominant major allergens being rapidly released from inhaled particles apparently do not actively induce tolerance but are ignored by the immune system. Here, the partially contradictory data on various allergen-specific T-cell types in healthy subjects, allergic patients, and patients undergoing allergen-specific immunotherapy are discussed and integrated into one model, postulating Treg cell-dependent and Treg cell-independent checkpoints of tolerance and allergy development.

This review paper aims to provide an overview of recent developments in the field of allergic and non-allergic rhinitis, as well as allergen immunotherapy. Recent advances in phenotyping and endotyping various forms of rhinitis have brought us one step closer towards tailoring treatment more appropriately for a given patient. Updates on local allergic rhinitis are also covered. Allergen immunotherapy (AIT) is an area of significant interest, with multiple original papers and recent position papers and guidelines published. Evidence related to the application of AIT in seasonal and perennial allergic rhinitis (AR), local allergic rhinitis and novel and expanded applications is discussed in the publication.

Allergen immunotherapy (AIT) is the only disease-modifying treatment option for patients with IgE-mediated inhalant allergies. Though used in clinical practice for more than 100 years, most innovations in AIT efficacy and safety have been developed in the last two decades. This expert review aimed to highlight the recent progress in AIT for both application routes, the sublingual (SLIT) and subcutaneous (SCIT) forms. As such, it covers recent aspects regarding efficacy and safety in clinical trials and real-life data and outlines new concepts in consensus and position papers as well as in guidelines for AIT. Potential clinical and nonclinical biomarkers are discussed. This review also focuses on potential future perspectives in AIT, such as alternative application routes, immune-modulating adjuvants, and recombinant vaccines. In conclusion, this state of the art review provides a comprehensive overview of AIT and highlights unmet needs for the future.