[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 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.

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.

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.

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.

Knowledge mapping of immunotherapy for allergic rhinoconjunctivitis: a bibliometric study (2002–2021)

Background: Allergic rhinoconjunctivitis (ARC) is a common chronic inflammatory disease. Numerous studies on the treatment of ARC have been published. By contrast, there are few bibliometric studies on immunotherapy for ARC. The purpose of this article is to describe the current treatments for ARC and to identify the trends in immunotherapy for ARC. Methods: Publications were searched from the Web of Science (WOS) Core Collection on April 25, 2022. CiteSpace and Microsoft Excel software were used for further bibliometric analysis. Results: A total of 969 publications on immunotherapy for ARC in English were retrieved. The number of relevant publications has been continuously increasing over the past 20 years, with many of the publications coming from Germany and the United States of America. In terms of institutions, the ALK Company in Denmark, Imperial College London in United Kingdom, and Charite–Universitatsmedizin Berlin in Germany published the most articles on immunotherapy for ARC. Meanwhile, Allergy and Journal of Allergy and Clinical Immunology published the most number of studies, and Oliver Pfaar from Germany authored the most number of articles. “Subcutaneous immunotherapy,” “international consensus,” “allergen immunotherapy,” and “recommendation” were the most popular subjects. Thus, directions in research can be predicted as studies regarding mechanisms of ARC, clinical trials, and extracts have reported high-quality results. Conclusion: Over the past 20 years, the overall quality of research on immunotherapy for ARC has gradually improved, allowing the introduction of specific and targeted treatment. Currently, the main focus of ARC research is the novel routes of drug delivery and combined treatment with biological agents (AU)

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.].

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.

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.

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.

Ragweed sublingual immunotherapy (SLIT) tablets in allergic rhinoconjunctivitis: a systematic review and meta-analysis.

PURPOSE: Ragweed allergen causes Allergic rhinoconjunctivitis and sublingual immunotherapy is one of the treatment modalities to desensitize allergic individuals. This systematic review assesses the effectiveness and safety of sublingual immunotherapy for allergic rhinoconjunctivitis caused due to Ragweed. METHODS: The databases search was done through December 2020. English-language randomized controlled trials were included if they compared sublingual immunotherapy with placebo, pharmacotherapy, or other sublingual immunotherapy regimens, and reported clinical outcomes. The strength of the evidence for each comparison and outcome was graded based on the risk of bias, consistency, magnitude of effect, and the directness of the evidence. RESULTS: The searches performed according to the protocol identified 134 abstracts of which 67 were duplicates. A total of 37 full papers were therefore reviewed of which 5 were included for the final study. Participants' ages ranged from 4 to 58 years. The risk of bias was low in most studies. The review suggests that sublingual immunotherapy improves rhinoconjunctivitis symptoms, with 4 of 4 studies reporting efficacy showed improvement in the symptom score of SLIT groups compared to placebo. Local reactions were frequent, but anaphylaxis was not reported in any of the studies. Serious adverse events were very few in all the studies. CONCLUSIONS: The overall evidence showed the effectiveness of sublingual immunotherapy for the treatment of allergic rhinoconjunctivitis with or without asthma, but high-quality studies are still needed to answer questions regarding optimal dosing strategies.

Determining the minimal important differences in the RQLQ score with grass and tree allergy immunotherapy versus placebo in adults with moderate-to-severe allergy.

BACKGROUND: Pollen from grasses and trees can trigger allergic rhinitis (AR), where the symptoms and associated consequences can negatively affect quality of life (QoL). The Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) is frequently used in clinical trials of AR to assess QoL. To help interpret RQLQ data, the minimal important difference (MID) can be used to assess whether a mean difference in QoL between treatment groups is clinically meaningful. In seasonal allergy, an MID differs according to the allergen, pollen exposure, symptom severity, patient age and treatment; the same MID cannot be applied to all scenarios. METHODS: Using data from four Phase III clinical trials of SQ sublingual immunotherapy-tablets in adults with moderate-to-severe allergy, between-group MIDs were derived for the RQLQ in grass pollen allergy (during the peak [n = 501] and entire [n = 514] pollen seasons), and in tree pollen allergy (during the birch [n = 516] and tree [n = 518] pollen seasons), using anchor-based methodology, supported by distribution-based methods. RESULTS: For grass pollen allergy, anchor-based derived between-group MIDs were 0.22 for the entire pollen season (n = 343) and 0.10 for the peak pollen season (n = 335). For tree pollen allergy, anchor-based derived between-group MIDs were 0.26 for the tree pollen season (n = 306) and 0.16 for the birch pollen season (n = 305) (representative of peak season). Distribution-based derived MIDs were supportive of the anchor-based values. CONCLUSIONS: This analysis has derived between-group MIDs specific to the trial populations evaluated and to the conditions under which the data were obtained, and highlights the need for a range of MIDs to reflect the unique nature of seasonal allergic disease.