Allergen Immunotherapy: The Evidence Supporting the Efficacy and Safety of Subcutaneous Immunotherapy and Sublingual Forms of Immunotherapy for Allergic Rhinitis/Conjunctivitis and Asthma.

Allergen immunotherapy (AIT) is a recognized key therapeutic modality for the treatment of allergic respiratory disease. Definitive studies have provided evidence-based data to demonstrate its effectiveness in allergic rhinitis and asthma due to the inhalation of proteinaceous allergic substances from specific seasonal pollens, dust mites, animal allergens, and certain mold spores. Over the ensuing decades, laboratory investigations have provided objective evidence to demonstrate immunologic changes, including production of protective IgG antibody, suppression of IgE antibody, upregulation of regulatory T cells, and induction of a state of immune tolerance to the offending allergen(s). Tangential to this work were carefully designed clinical studies that defined allergen dose and duration of treatment, established the importance of preparing extracts with standardized allergens (or well-defined extracts) based on major protein moieties, and used allergen provocation models to demonstrate efficacy superior to placebo. In the United States, the use of subcutaneous immunotherapy extracts for AIT was grandfathered in by the Food and Drug Administration based on expert literature review. In contrast, sublingual tablet immunotherapy underwent formal clinical development programs (phase I-III clinical trials) that provided the necessary clinical evidence for safety and efficacy that led to regulatory agency approvals for the treatment of allergic rhinitis in properly characterized patients with allergy. The allergy specialist's treatment options currently include traditional subcutaneous AIT and specific sublingual tablets approved for grass, ragweed, house dust mites, trees belonging to the birch-homologous group, and Japanese cedar. Tangential to this are sublingual drops that are increasingly being used off-label (albeit not approved by the Food and Drug Administration) in the United States. This article will review the evidence-based literature supporting the use of these forms of AIT, as well as focus on several current controversies and gaps in our knowledge base that have relevance for the appropriate selection of patients for treatment with specific AIT.

Atopic Keratoconjunctivitis: Pathophysiology, Clinic, and Potential New Therapeutic Concepts. / Atopische Keratokonjunktivitis: Pathophysiologie, Klinik und potenzielle neue Therapiekonzepte.

Atopic dermatitis (AD) is a chronic recurrent inflammatory skin disease with a bipolar age distribution in childhood, adolescence and middle adulthood. Up to 50% of AD patients show ocular involvement, which can be potentially sight threatening. Clinically, the majority of cases present with atopic blepharo(kerato)conjunctivitis or atopic keratoconjunctivitis (AKC); other clinical variants from this group of inflammatory ocular surface diseases are keratoconjunctivitis vernalis in childhood and adolescence and allergic conjunctivitis. In addition to the aforementioned blepharitis, keratitis and conjunctivitis, AD is also associated with eyelid involvement with subsequent eyelid malposition, limbal insufficiency with the development of pseudopterygia, (chronic) cicatrizing conjunctivitis with symblephara formation and fornix shortening, as well as ocular surface malignancies such as conjunctival intraepithelial neoplasia (CIN) and squamous cell carcinoma. In addition, an association with AD or AKC has been described for keratoconus. Whereas the therapy of AD in dermatology has made revolutionary advances in recent years through the use of biologicals, the primary use of these biologicals in ophthalmological complications is still very hesitant. Treatment here is often provided using topical steroids and calcineurin inhibitors. The following article summarises recent developments in basic and clinical dermatological research and discusses them in the context of current concepts for ophthalmological therapy.

[Allergen-specific immunotherapy : A brief overview in association with allergic conjunctivitis]. / Allergenspezifische Immuntherapie : Ein kurzer Überblick im Zusammenhang mit der allergischen Konjunktivitis.

Allergen-specific immunotherapy (AIT) is the only causal and disease-modifying treatment for immunoglobulin E (IgE)-mediated type I allergies. Regular exposure to the causative allergen results in an immunomodulatory effect by which the predominant T­helper (Th) 2 lymphocyte response is shifted to a Th1 lymphocyte response and more allergen-specific blocking immunoglobulins are produced. The approval of substances for AIT is regulated by the Therapy Allergens Ordinance (TAV). There are subcutaneous and/or sublingual AITs for the following indications: allergic rhinitis, allergic conjunctivitis, allergic asthma and insect venom allergy. In this article the indications for allergic conjunctivitis are discussed in particular. Clinical symptoms and a relevant type 1 sensitization are the prerequisites for the indications for AIT. The assessment of the indications and carrying out an AIT should only be carried out by physicians who have been trained in allergology.

Sublingual Tablet Immunotherapy Improves Quality of Life in Adults With Allergic Rhinoconjunctivitis.

BACKGROUND: Allergic rhinitis with or without conjunctivitis can negatively impact many aspects of quality of life (QoL). The efficacy and safety of standardized quality (SQ) sublingual immunotherapy (SLIT) tablets have been confirmed across large clinical trials in adults with grass, tree, ragweed, and house dust mite (HDM) allergic rhinitis with or without conjunctivitis. OBJECTIVE: This pooled analysis investigates whether the reduction in symptom burden found across the clinical trials is supported by improvements in QoL. METHODS: A total of 11 phase II/III randomized placebo-controlled trials across the SQ grass, tree, ragweed, and HDM SLIT tablets (grass: N = 3179; ragweed: N = 767; tree: N = 634; HDM: N = 2221) were included. QoL was assessed using the standardized Rhinitis Quality of Life Questionnaire (RQLQ), with the exception of 3 grass trials, which used the nonstandardized version. The overall RQLQ scores were expressed as a mean of 7 domains. In the pooled analysis, treatment was used as fixed effect; and the trial, and the interaction between region/country and trial as random effects. RESULTS: The pooled analysis showed consistent and statistically significant improvements in overall RQLQ scores across all 4 SQ SLIT tablets versus placebo (pooled estimate [95% CI], P value-grass: -0.20 [-0.28 to -0.12], P < .001; tree: -0.42 [-0.58 to -0.26], P < .001; ragweed: -0.36 [-0.55 to -0.17], P < .001; HDM: -0.28 [-0.39 to -0.17], P < .001). Furthermore, significant improvements versus placebo for all 4 SQ SLIT tablets were seen across the 7 individual domains. CONCLUSIONS: The proven efficacy of SQ SLIT tablets to reduce symptoms across 4 of the most common respiratory allergens is supported by concurrent significant improvements in RQLQ scores overall and for all 7 domains.

Sublingual immunotherapy tablets in monosensitized and polysensitized adults with allergic rhinoconjunctivitis.

Background: Most patients with allergic rhinitis/conjunctivitis (AR/C) are sensitized to more than one allergen. An ongoing question is the efficacy of single-allergen immunotherapy in patients who are polysensitized. Objective: To evaluate the efficacy and safety of grass, ragweed, tree, and house-dust mite (HDM) sublingual immunotherapy (SLIT) tablets in adults with AR/C who are mono- or polysensitized. Methods: Data from adults (ages ≥ 18 years) with AR/C who participated in phase III double-blind, placebo controlled field trials (four grass, two ragweed, two HDM, one tree) were included in the post hoc analyses. Efficacy was assessed by the total combined score (TCS) (sum of AR/C daily symptom and medication scores) during the entire pollen season for grass and tree trials, and peak pollen season for ragweed trials versus placebo. Efficacy for the HDM SLIT-tablet was assessed by the total combined rhinitis score (TCRS) (sum of rhinitis daily symptom and medication scores) during the last 8 weeks of treatment versus placebo. Results: For the grass SLIT-tablet, TCS improved by 20% (mean difference 1.33 [95% confidence interval {CI}, 0.44-2.22]) in the subjects who were monosensitized (n = 442) and 20% (mean difference 1.28 [95% CI, 0.90-1.67]) in the subjects who were polysensitized (n = 1857). For the ragweed SLIT-tablet, TCS improved by 19% (mean difference 1.72 [95% CI, -0.20 to 3.63]) in the subjects who were monosensitized (n = 115) and 27% (mean difference 2.27 [95% CI, 1.28-3.27]) in the subjects who were polysensitized (n = 528). For the tree SLIT-tablet, TCS improved by 54% (mean difference 4.65 [95% CI, 2.48-6.82]) in the subjects who were monosensitized (n = 138) and 34% (mean difference 2.51 [95% CI, 1.34-3.69]) in the subjects who were polysensitized (n = 437). For the HDM SLIT-tablet, TCRS improved by 20% (mean difference 1.24 [95% CI, 0.48-1.99]) in the subjects who were monosensitized (n = 468) and 17% (mean difference 0.85 [95% CI, 0.43-1.28]) in the subjects who were polysensitized (n = 1294). The overall safety profile was not qualitatively different between the subjects who were monosensitized and the subjects who were polysensitized. Conclusion: Grass, ragweed, tree, or HDM SLIT-tablet treatment is effective for the specific allergen in question in adults with AR/C and who are monosensitized or polysensitized. Targeting one relevant allergen with SLIT-tablets induces a clinical effect for that allergen in patients who were polysensitized.

Vernal Keratoconjunctivitis: A Systematic Review.

Vernal keratoconjunctivitis (VKC) is a chronic, bilateral corneal and conjunctival problem which typically presents in young individuals. VKC is characterized by itching, photophobia, white mucous discharge, lacrimation, foreign body sensation, and pain due to corneal involvement of shield ulcers. Vernal keratoconjunctivitis is categorized within ocular diseases. The diagnosis is clinical, as no sure biomarkers pathognomonic of the disease have yet been identified. The VKC therapy relies on different types of drugs, from antihistamines and topical steroids to cyclosporine or tacrolimus eye drops. In extremely rare cases, there is also the need for surgical treatment for the debridement of ulcers, as well as for advanced glaucoma and cataracts, caused by excessive prolonged use of steroid eye drops. We performed a systematic review of the literature, according to PRISMA guideline recommendations. We searched the PubMed database from January 2016 to June 2023. Search terms were Vernal, Vernal keratoconjunctivitis, and VKC. We initially identified 211 articles. After the screening process, 168 studies were eligible according to our criteria and were included in the review. In this study, we performed a systematic literature review to provide a comprehensive overview of currently available diagnostic methods, management of VKC, and its treatments.

The use of environmental exposure chambers in studies related to ocular surface effects.

PURPOSE OF REVIEW: The potential of allergen challenges using environmental exposure facilities in allergic conjunctivitis drug development and more recently its implication on the diagnosis of the united airways concept have been emphasized in the recent literature. This study aims to present an overview of new and important data in this field. RECENT FINDINGS: Standardized methodologies for ocular surface assessment during allergen challenges were described. The Total Ocular Symptom Score (TOSS) is the main validated questionnaire used for the assessment of ocular surface during allergen challenges. It combines patient and investigator assessments for more accurate conjunctival response and was extensively used in clinical research and daily practice. Environmental Exposure Chambers (EECs) studies aim to conduct tight-controlled challenges to a stable and well defined allergen airborne concentration, closer to natural exposure to evaluate the efficacy of nonpharmaceutical and antiallergic treatments. Recent studies showed a good correlation between ocular symptoms elicited by EEC and those assessed during natural exposure. These validated methods allow to investigate the efficacy of novel pharmacotherapies for allergic conjunctivitis and allergen immunotherapy (AIT) in a real-world model of allergen exposure. SUMMARY: This study aims to summarize novel data regarding the impact of EECs in studying pathophysiology and drug efficacy in the context of existing clinical protocols related to ocular surface effects. In this regard, studies comparing conjunctival response during natural and EEC exposures in patients with pollen-induced conjunctivitis aimed to demonstrate better outcomes in tight-controlled exposures mimicking natural exposure. Because allergen challenges are widely implemented in allergy treatment, this article will focus on the most important outcomes and the evolution of treatments for allergic conjunctivitis.

Efficacy and safety of Artemisia annua sublingual immunotherapy in patients with seasonal allergic rhinoconjunctivitis over two pollen seasons.

OBJECTIVE: This study investigates the efficacy and safety of sublingual immunotherapy (SLIT) with A. annua allergens in patients with seasonal allergic rhinoconjunctivitis over two pollen seasons. METHODS: Seventy patients with moderate-severe seasonal allergic rhinoconjunctivitis were divided evenly into the SLIT and control groups. The SLIT last from 3 months before the summer-autumn pollen season in 2021 till the end of the summer-autumn pollen season in 2022. The daily individual symptom score, total rhinoconjunctivitis symptom score (dTRSS), total medication score (dTMS), combined score of medication and rhinoconjunctivitis symptom (dCSMRS), visual analog scale (VAS) score, and adverse events (AEs) were evaluated. RESULTS: The average pollen concentration in 2022 was twice that previous two-year during the pollen season. Fifty-six patients completed treatments (SLIT group: 29, control group: 27). Compared with baseline, the individual symptoms, dTRSS, dTMS, dCSMRS, and VAS scores of SLIT group declined in 2021. After 16 months of SLIT, all efficacy indexes in 2022 were still lower than baseline and equivalent to those in 2021. In control group, the efficacy indexes in 2022 were higher than that in 2020 and 2021. The efficacy indexes of SLIT group were lower than those of control group in 2021 and 2022. SLIT is effective for both mono- and poly-sensitized patients. AEs incidence in SLIT group was 82.7% without severe AEs. CONCLUSIONS: The A. annua-SLIT can obtain efficacy and safety over two pollen seasons for patients with moderate-severe seasonal allergic rhinoconjunctivitis.

Clinical efficacy and safety of coseasonal initiation of Artemisia annua sublingual immunotherapy on patients with Artemisia-induced rhinoconjunctivitis.

PURPOSE: Patients with seasonal allergic rhinoconjunctivitis (SARC) might seek evaluation and treatment when symptoms appear during the pollen season. It is unclear whether coseasonal-initiated sublingual immunotherapy (SLIT) would be effective and safe for SARC. This study aims to identify the feasibility of initiating Artemisia annua SLIT during the pollen season. MATERIALS AND METHODS: Sixty patients with Artemisia-induced SARC were equally recruited into the SLIT and control groups during the pollen season in 2021. The SLIT group was treated with standardized Artemisia annua SLIT drops using a modified dosing schedule combined with pharmacotherapy, while the control group only received pharmacotherapy. Diary cards for clinical symptoms, rescue medication use, and adverse events (AEs) were recorded during the pollen seasons. Objective measures, including average daily combined scores of medication and rhinoconjunctivitis symptoms (CSMRS), total rhinoconjunctivitis symptom score (TRSS), total medication score (TMS), and the score of visual analog scale (VAS) were calculated to evaluate the efficacy of SLIT. Safety was assessed through the occurrence and severity of AEs. RESULTS: In total, 80.0 % (24/30) patients in the SLIT group and 86.67 % (26/30) patients in the control group completed the study. The severity of SARC, which was assessed by objective measures including CSMRS, TRSS, TMS, and VAS of the SLIT group and the control group, was generally at the same level during the 2021 pollen season, except for the medical consumption, which the score of TMS was slightly higher in the SLIT group. After one year of treatment, the scores of CSMRS, TRSS, and VAS in the SLIT group were significantly improved compared with the control group (all P < 0.001), and the difference in the TMS between the two groups disappeared (P > 0.05). Moreover, clinical improvement of the four objective measures was also observed in the SLIT group compared with the baseline value (P < 0.001). Overall, 9/24 patients in the SLIT group experienced mild local AEs, and two patients experienced mild systemic AEs during the SLIT period. CONCLUSIONS: This controlled preliminary study identified that coseasonal-initiated Artemisia annua SLIT treatment for one year was generally safe and effective in improving the symptoms of SARC patients induced by Artemisia annua pollen.

Analysis of factors influencing the determination of indications for allergen-specific immunotherapy.

OBJECTIVE: To develop a questionnaire and a scoring system for evaluating physicians' knowledge of allergen immunotherapy (AIT). METHODS: Questionnaire was designed using the Questionnaire Star tool. A total of 1024 physicians were assessed, and based on the score divided into accurate judgment and inaccurate judgment groups. Statistical analysis was done, and counting data were expressed as frequencies and percentage values. Chi-square test and multi-factor logistic analysis were used to determine influencing factors on the indications for AIT. RESULTS: Physician's age, grade of the hospital, and pediatric specialty influenced the accurate judgment of AIT indication after adjustment for independent variables (P < 0.05). In all, 80.5% physicians exercised accurate assessment for allergic rhinitis. Allergic conjunctivitis was judged accurately by 47.0% physicians. Bronchial asthma was judged accurately by 71.0% physicians, and atopic dermatitis by 61.3% physicians, with a higher accuracy rate for pediatricians than nonpediatricians for all the mentioned conditions (P < 0.05). There was no significant difference in the accuracy of judgment between pediatricians and non-pediatricians in terms of AIT for food allergy and dust mite sensitization (P > 0.05). CONCLUSION: The results of our study demonstrated a high accuracy judgment rate among clinicians for rhinitis, asthma, and dermatitis, and a low accuracy rate for desensitization of healthy people with allergic conjunctivitis, food allergies, and allergen sensitization.

Management of Vernal Keratoconjunctivitis in Children in the United Kingdom: A Review of the Literature and Current Best Practice Across Six Large United Kingdom Centers.

Vernal keratoconjunctivitis (VKC) is a form of ocular allergy primarily affecting children. Considered a rare disease in Europe, its prevalence varies by geographic region and is poorly studied in the United Kingdom. There is considerable national variation in the management of VKC within the United Kingdom, risking misdiagnosis and delays to treatment for some children. This can significantly impact their quality of life, with the potential for lasting negative consequences. Based on discussions between experienced clinicians from six large centers across the United Kingdom, this article describes best practice recommendations for United Kingdom settings, including principles for diagnosis, referral, initial and long-term management, and supportive care. Recommendations include guidance on referral timing, which should depend on VKC severity, and a stepwise approach to treatment. Joint management by primary care and secondary care is recommended and the importance of supportive care, including emotional support and outreach to schools, is highlighted. Because frequent flareups are common in VKC, it is essential that families have access to the information they need to manage the disease and routes to access rapid care if needed. A thorough understanding of the nature of VKC, its triggers, and how best to manage it, by both patients and their families, is critical to ensuring appropriate management and to improving patient outcomes. [J Pediatr Ophthalmol Strabismus. 2023;60(1):6-17.].

Topical cyclosporine versus allergen specific immunotherapy in perennial allergic conjunctivitis.

PURPOSE: Symptom control in the long-term with less side effects is important in perennial allergic conjunctivitis, since would improve quality of life. This study aimed to assess the clinical efficacies of topical cyclosporin A and subcutaneous allergen immunotherapy (SCIT) in terms of sign control in perennial allergic conjunctivitis. METHODS: This retrospective study included 20 adult patients with perennial allergic conjunctivitis and confirmed sensitization to house dust mites with skin prick test. Patients were assigned to either topical cyclosporine A treatment or SCIT. The participants were followed for 6 months, and signs scores were recorded at 1, 3 and 6 months. RESULTS: Overall, both cyclosporine and immunotherapy groups showed significant improvements in papillary reaction (p = 0.011 and 0.003, respectively), limbal involvement (p = 0.031 and 0.001), and conjunctival hyperemia (p = 0.001 and p < 0.001) scores during the 6-month follow-up. However, only cyclosporine group showed a significant improvement in corneal involvement scores (p = 0.015) during the study period. When scores at different time points were compared, significant improvement in conjunctival hyperemia was evident at 6 months in both groups when compared to baseline (cyclosporine group, 0.7 ± 0.68 vs. 2.4 ± 0.84, 70.8% decrease, p = 0.01; immunotherapy group, 0.3 ± 0.48 vs. 2.3 ± 0.95, 87.0% decrease, p = 0.004), whereas for limbal involvement such an improvement was only evident in the immunotherapy group (0.1 ± 0.32 vs. 1.3 ± 0.95, 92.3% decrease, p = 0.01). CONCLUSIONS: Allergen immunotherapy and cyclosporin A treatment may provide effective sign relief in perennial allergic conjunctivitis. It may represent an encouraging treatment option particularly for cases with perennial allergic conjunctivitis refractive to other treatments and positive skin prick test to a specific allergen (house dust in the present study). Long-term relief by SCIT would reduce the side effects of polypharmacotherapy. Larger studies with longer follow-up are warranted to confirm our findings.

Off-label Use of Oral Immunotherapy for Rhinoconjunctivitis and Asthma due to Grass Pollen: A Safe and Effective Alternative in Patients over 65 Years Old: A Series of Case Reports.

INTRODUCTION: Allergic rhinoconjunctivitis and asthma are the most common IgE-mediated diseases worldwide. Allergen-specific immunotherapy (AIT) is currently the only modifying treatment for these IgE-mediated diseases in both children and adults. Subcutaneous immunotherapy is widely used, but in patients over 65 years old, there may be an increased risk of adverse reactions and a worse response to treatment. Oral immunotherapy (OIT) has been proven to be effective and safe, but currently, in most countries, it has been licensed only for patients up to 65 years old based on its technical datasheet. So far, no studies on the efficacy and safety of this type of immunotherapy in patients older than 65 years old have been published. CASE PRESENTATION: We present four patients older than 65 years old with a diagnosis of moderate seasonal rhinoconjunctivitis and moderate-persistent seasonal pollen-induced asthma. Off-label use of oral immunotherapy (OIT) for grass pollen was prescribed due to the severity of their rhinoconjunctivitis symptoms and the worsening of asthma symptoms during the spring. Improvement in the rhinoconjunctivitis and asthma symptoms was reported by all patients since the first spring season and was maintained during the following two years of follow-up. There were no systemic reactions, and only two patients initially had self-limiting oral pruritus. CONCLUSION: Oral immunotherapy for pollens appears to be a convenient, effective, and safe option in older patients (>65 years) with comorbidities after a three-year treatment. This is, to the best of our knowledge, the first report on the off-label use of OIT in patients over 65 years old with symptoms of allergic rhinoconjunctivitis and asthma.

Executive summary: Japanese guidelines for allergic conjunctival diseases 2021.

Allergic conjunctival disease (ACD) is an inflammatory disease of the conjunctiva that is mainly caused by type I hypersensitivity response to allergens and accompanied by subjective symptoms and other findings induced by antigens. ACD is classified as allergic conjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, and giant papillary conjunctivitis. This article summarizes the third edition of the Japanese guidelines for allergic conjunctival diseases published in 2021 and outlines the diagnosis, pathogenesis, and treatment of ACD. Since the introduction of immunosuppressive eye drops, the treatment strategies for severe ACDs have significantly changed. To clarify the recommended standard treatment protocols for ACD, the advantages and disadvantages of these treatments were assessed using clinical questions, with a focus on the use of steroids and immunosuppressive drugs. This knowledge will assist healthcare providers and patients in taking an active role in medical decision making.

The multifaceted aspects of ocular allergies: Phenotypes and endotypes.

Like the lung, skin, and nose, the external eye is a common target of allergic inflammation. Ocular allergy (OA) represents a collection of underestimated diseases of the eye observed in children and adults. The ocular manifestations are the expression of multifactorial immune mechanisms that generally have a good prognosis, but for a few patients, long term inflammation may remarkably reduce the visual function. Evidence suggests that other co-participant systems, including epigenetic, genetic, environmental, individual factors, sex hormones, and the central and autonomic nervous systems may influence the ocular response from distant sites. This is consistent with the concept that the eye is an organ fully integrated with the rest of the body and that the therapeutic approach should be holistic, dynamic, and personalized. For instance, androgens and estrogens binding to receptors on the ocular surface and the continuous cross-talking of neuromediators and growth factors with immune cells act to maintain the ocular surface homeostasis in response to environmental challenges. The immune system links and regulates the response of the ocular surface. Complex and incompletely understood mechanisms influence the innate and adaptive immune responses and generate different OA phenotypes and endotypes discussed in the present review.

Role of Damage-Associated Molecular Patterns (DAMPs/Alarmins) in Severe Ocular Allergic Diseases.

Severe ocular allergic diseases, such as atopic keratoconjunctivitis and vernal keratoconjunctivitis, cause severe allergic inflammation in the conjunctiva and corneal epithelial damage, resulting in visual disturbances. The involvement of damage (danger)-associated molecular patterns (DAMPs/alarmins) in the pathogenesis of these diseases has been recognized. Alarmins released from damaged corneal epithelial cells or eosinophils play a critical role in the induction of corneal lesions, vicious loop of corneal injury, and exacerbation of conjunctival allergic inflammation. Alarmins in the conjunctiva also play an essential role in the development of both allergic inflammation, based on the acquired immune system, and type 2 inflammation by innate immune responses in the ocular surface. Therefore, alarmins may be a potentially important therapeutic target in severe refractory ocular allergic diseases.