Modelling of patient journey in chronic spontaneous urticaria: Increasing awareness and education by shorten patients' disease journey in Germany.

BACKGROUND: Chronic spontaneous urticaria (CSU) is both physically and emotionally stressful, and guideline recommendations are often not optimally implemented in clinical practice. The objective of this study was to provide an overview on the patient journey in CSU and to develop a mathematical model based on solid data. METHODS: The journey of CSU patients in Germany was traced through literature review and expert meetings that included medical experts, pharmacists and representatives of patient organizations. The current situation's main challenges in the patient journey (education, collaboration and disease management) were discussed in depth. Then, a probabilistic model was developed in a co-creation approach to simulate the impact of three potential improvement strategies: (1) patient education campaign, (2) medical professional education programme and (3) implementation of a disease management programme (DMP). RESULTS: Chronic spontaneous urticaria patients are severely burdened by delays in diagnosis and optimal medical care. Our simulation indicates that in Germany, it takes on average of 3.8 years for patients to achieve disease control in Germany. Modelling all three optimization strategies resulted in a reduction to 2.5 years until CSU symptom control. On a population level, the proportion of CSU patients with disease control increased from 44.2% to 58.1%. CONCLUSION: In principle, effective CSU medications and a disease-specific guideline are available. However, implementation of recommendations is lagging in practice. The approach of quantitative modelling of the patient journey validates obstacles and shows a clear effect of multiple interventions on the patient journey. The data generated by our simulation can be used to identify strategies for improving patient care. Our approach might helping in understanding and improving the management of patients beyond CSU.

Tolerability of sublingual versus vestibular allergy immunotherapy tablet administration: A randomized pilot study.

BACKGROUND: Local application site reactions are common with sublingual allergy immunotherapy (AIT)-tablets for the treatment of allergic rhinitis/conjunctivitis (AR/C) and occasionally lead to treatment discontinuation. Because of the lower mast cell density in the vestibular mucosa than the sublingual area, vestibular AIT-tablet administration may result in fewer adverse events (AEs). This pilot study evaluated the tolerability of the vestibular administration route of AIT-tablets compared with the sublingual route in adult subjects with AR/C. METHODS: Adults (n = 164) aged 18-65 years with AR/C treated with daily birch pollen, grass pollen, ragweed pollen or house dust mite AIT in tablet form were randomized 1:1 to vestibular or sublingual administration for 28 days, followed by 28 days of sublingual administration only. The primary endpoint was the severity (mild, moderate, severe) of local treatment-related adverse events (TRAEs) during the first 28 days of treatment. RESULTS: During the first 28 days, the percentage of subjects in the vestibular and sublingual groups reporting mild TRAEs were 55.6% versus 50.6%, respectively; moderate TRAEs were 27.2% versus 30.1%; and severe TRAEs were 12.3% versus 6.0% (p = .16). In the vestibular group, 95.1% of the subjects experienced at least one TRAE during the first period versus 81.9% in the sublingual group (p = .01) and discontinuation rates due to AEs were higher (12.3% vs. 3.6%). CONCLUSION: The frequencies of subjects experiencing severe TRAEs, at least one TRAE, and discontinuations due to AEs at the initiation of AIT-tablets were numerically higher with vestibular administration than sublingual administration. Sublingual administration should remain the standard of care for subjects treated with AIT-tablets for AR/C.

Differences in allergen-specific basophil activation and T cell proliferation in atopic dermatitis patients with comorbid allergic rhinoconjunctivitis treated with a monoclonal anti-IL-4Rα antibody or allergen-specific immunotherapy.

BACKGROUND: Atopic dermatitis (AD), a chronic inflammatory disorder, is often accompanied by allergic rhinoconjunctivitis (ARC) as a co-morbidity. The use of a monoclonal anti-IL-4Rα antibody has been effective in controlling moderate to severe AD symptoms. Allergen-specific immunotherapy (AIT) is widely used for the treatment of ARC and asthma. The effects of AIT on basophil reactivity/effector functions have already been examined and used as indicators of the treatment efficacy. However, it is unclear, how an anti-IL-4Rα antibody can influence allergen-specific immune responses of basophils and T cells of AD patients with comorbid ARC. OBJECTIVE: To investigate the effect of a monoclonal anti-IL-4Rα antibody on the in vitro allergic responses of basophils and T cells deriving from AD patients with comorbid ARC. METHODS: Blood samples of 32 AD patients were obtained before, after 4 and 16 weeks of an anti-IL-4Rα antibody therapy (300 mg subcutaneously/2 weeks; n = 21) or AIT (daily sublingual application; n = 11). Patients treated with an anti-IL-4Rα antibody were grouped according to their serum specific immunoglobulin E levels and ARC symptoms, while patients receiving an AIT were additionally grouped according to the allergen specificity of their AIT. Basophil activation test and T cell proliferation assays were undertaken after an in vitro allergen stimulation. RESULTS: A significant reduction of the immunoglobulin E levels and the allergen-specific T cell proliferation was observed in AD patients treated with an anti-IL-4Rα -antibody, while the allergen-specific basophil activation/sensitivity were found to be significantly increased. In patients receiving an AIT, the in vitro allergen-specific basophil activation and the T cell proliferation were found to be significantly decreased in response to seasonal allergens. CONCLUSIONS: An IL-4Rα blockade induced by a monoclonal anti-IL-4Rα antibody leads to an increased activity/sensitivity of early effector cells (such as basophils), in contrast to a decreasing reactivity observed under an AIT. The late-phase T cell reaction to allergens did not differ between the herein assessed treatments.

IgE Depletion with Ligelizumab Does Not Significantly Improve Clinical Symptoms in Patients with Moderate-to-Severe Atopic Dermatitis.

BACKGROUND: The value, if any, of anti-IgE approaches in the treatment of atopic dermatitis has not been fully clarified. Studies using the anti-IgE omalizumab have yielded conflicting results. OBJECTIVE: Antibodies with an IgE-suppressive capacity stronger than omalizumab might be more efficacious. STUDY DESIGN: We assessed the safety and efficacy of the high-affinity anti-IgE antibody ligelizumab (280 mg, subcutaneous, every other week) in 22 adult patients with moderate-to-severe atopic dermatitis in a placebo and active (cyclosporine A) controlled, randomized, multicenter, double-blind clinical trial for 12 weeks. RESULTS: We found that ligelizumab treatment resulted in either complete (patients with baseline IgE < 1,500 IU/ml) or partial (baseline IgE > 1,500 IU/ml) suppression of serum and cell-bound IgE as well as of allergic skin prick tests. On the other hand, ligelizumab-as opposed to cyclosporine A-was not significantly superior to placebo in inducing Eczema Area and Severity Index 50 response or significantly reducing pruritus and sleep disturbance. Interestingly though, patients with high baseline IgE exhibited a slightly but not significantly better treatment response than those with low baseline IgE. CONCLUSION: Our study shows that an immunologically efficacious anti-IgE approach is not clearly superior to placebo in treating atopic dermatitis. Larger studies are needed to determine whether certain patient subgroups may benefit from this strategy. TRIAL REGISTRATION: The study was registered in 2011 at clinicaltrialsregister.eu, EudraCT Number 2011-002112-84.

A compilation answering 50 questions on monkeypox virus and the current monkeypox outbreak.

The current monkeypox disease (MPX) outbreak constitutes a new threat and challenge for our society. With more than 55,000 confirmed cases in 103 countries, World Health Organization declared the ongoing MPX outbreak a Public Health Emergency of International Concern (PHEIC) on July 23, 2022. The current MPX outbreak is the largest, most widespread, and most serious since the diagnosis of the first case of MPX in 1970 in the Democratic Republic of the Congo (DRC), a country where MPX is an endemic disease. Throughout history, there have only been sporadic and self-limiting outbreaks of MPX outside Africa, with a total of 58 cases described from 2003 to 2021. This figure contrasts with the current outbreak of 2022, in which more than 55,000 cases have been confirmed in just 4 months. MPX is, in most cases, self-limiting; however, severe clinical manifestations and complications have been reported. Complications are usually related to the extent of virus exposure and patient health status, generally affecting children, pregnant women, and immunocompromised patients. The expansive nature of the current outbreak leaves many questions that the scientific community should investigate and answer in order to understand this phenomenon better and prevent new threats in the future. In this review, 50 questions regarding monkeypox virus (MPXV) and the current MPX outbreak were answered in order to provide the most updated scientific information and to explore the potential causes and consequences of this new health threat.

Diversity of T cells in the skin: Novel insights.

T cells populate the skin to provide an effective immunosurveillance against external insults and to maintain tissue homeostasis. Most cutaneous T cells are αß T cells, however, γδ T cells also exist although in much lower frequency. Different subsets of αß T cells can be found in the skin, such as short-lived effector T cells, central memory T cells, effector memory T cells, and tissue-resident memory T cells. Their differential biology, function, and location provide an ample spectrum of immune responses in the skin. Foxp3+ memory regulatory T cells have a pivotal role in maintaining homeostasis in the skin and their dysregulation has been linked with different skin pathologies. The skin also contains populations of non-classical T cells, such as γδ T cells, NK T cells, and MR1-restricted T cells. Their role in skin homeostasis and response to pathogens has been well established in the past years, however, there is also growing evidence of their role in mediating allergic skin inflammation and promoting sensitization to allergens. In this review, we provide an updated overview on the different subsets of T cells that populate the skin with a specific focus on their role in allergic skin inflammation.

Subcutaneous birch pollen allergen immunotherapy with a depigmented polymerized extract shows only sustained and long-term efficacy in a subgroup of monosensitized adults and adolescents with allergic rhinitis.

Background: Allergen immunotherapy (AIT) is an approved treatment for seasonal respiratory allergic diseases. A depigmented polymerized birch pollen extract for subcutaneous allergen immunotherapy (SCIT) has been demonstrated to be efficacious and safe in patients allergic to birch pollen and its homologous group. Objective: To determine whether SCIT with a birch pollen formulation (5000 depigmented polymerized (DPP) units/mL) shows sustained and long-term efficacy in adults and adolescents with birch-pollen induced allergic rhinitis with or without intermittent asthma. Methods: A multicentre (n = 66), double-blind, placebo-controlled Phase III clinical trial was performed in the Czech Republic, Finland, Germany, Latvia, Lithuania, Poland and Russia. Participants were randomized 2:1 to active treatment (birch 5000 DPP/ml) or placebo for three years of SCIT and followed up for two treatment-free years. The primary efficacy endpoint was the EAACI's combined symptom and medication score for rhinoconjunctivitis (CSMSEAACI). Results: A total of 973 participants were screened and 649 were randomized (active treatment: n = 434; placebo: n = 215). The intention-to-treat analysis of the CSMSEAACI in the overall study population did not demonstrate statistically significant differences in years 1, 2 and 3. In a post-hoc analysis, among the subgroup of patients monosensitized to birch pollen allergen only (n = 200), we observed a statistically significant difference (active treatment vs. placebo) in the CSMSEAACI in year 2, 3 and 5. The AIT's safety profile was good. Conclusions: SCIT with a depigmented polymerized birch pollen extract was safe. Sustained and long-term efficacy in years 2, 3 and 5 in monosensitized patients, but not in polysensitized patients was demonstrated.(EudraCT 2012-000414-11).

Atopic dermatitis and pregnancy.

Fascinating immunologic mechanisms that are crucial for pregnancy can, however, lead to the development of different skin conditions, of which atopic dermatitis (AD) is the most frequent one. AD in pregnancy may occur de novo or as a recurrence or exacerbation of known chronic AD. The changes in hormone levels that occur during pregnancy influence the cytokine balance and can lead to manifestation of eczematous lesions, currently classified as atopic eruption of pregnancy. The diagnosis of atopic eruption of pregnancy may be challenging, especially in patients who developed this skin disease de novo during gestation. The treatment is another challenge, because it needs to be safe for both the mother and especially the unborn child. Emollients make up the basis of the therapy. Topical corticosteroids and calcineurin inhibitors are also safe treatment options, and ultraviolet therapy can be added, if required. Use of cyclosporin A is possible for systemic therapy during pregnancy, whereas safety data on new drugs such as biologics approved for AD are limited to small case series. This review is aimed at summarizing available data on the mechanisms that lead to AD during gestation, differential diagnostic evaluations, and treatment options.

Adverse rare events to vaccines for COVID-19: From hypersensitivity reactions to thrombosis and thrombocytopenia.

Vaccines for the prevention of coronavirus disease 2019 (COVID-19) started to be developed since the initiation of the COVID-19 pandemic. Up to now, four vaccines have been authorized by international agencies such as European Medicines Agency (EMA). Two are DNA vaccines (ChAdOx1 nCov-19 and Ad26.COV2.S) and two mRNA vaccines (BNT162b2 and mRNA-1273). The administration of the vaccines has been associated with a strong decrease in the infections by SARS-CoV-2 and deaths associated with it. However, in parallel to these results, some rare adverse events have also been described. In that sense, events of thrombosis, thrombocytopenia, and hemorrhage have been described in close temporal proximity to the administration of the DNA vaccines ChAdOx1 nCov-19 and Ad26.COV2.S, but also mRNA vaccines. Recent scientific reports have been released with updated information on the possible association of thrombotic thrombocytopenia and COVID-19 vaccines. On the other hand, since the initiation of the vaccination campaigns, adverse hypersensitivity reactions have been described after mRNA and DNA vaccines administration for COVID-19. Although globally these adverse events are rare, a high proportion of the world population will be exposed to these vaccines. For that reason, their safety and tolerance should be carefully considered. In this review, we provide an updated review of the last scientific findings that can explain the rare side effects that the vaccines for COVID-19 can produce.

White paper on peanut allergy - part 1: Epidemiology, burden of disease, health economic aspects.

Peanuts are Leguminosae, commonly known as the legume or pea family, and peanut allergy is among the most common food allergies and the most common cause of fatal food reactions and anaphylaxis. The prevalence of peanut allergy increased 3.5-fold over the past two decades reaching 1.4-2% in Europe and the United States. The reasons for this increase in prevalence are likely multifaceted. Sensitization via the skin appears to be associated with the development of peanut allergy and atopic eczema in infancy is associated with a high risk of developing peanut allergy. Until recently, the only possible management strategy for peanut allergy was strict allergen avoidance and emergency treatment including adrenaline auto-injector in cases of accidental exposure and reaction. This paper discusses the various factors that impact the risks of peanut allergy and the burden of self-management on peanut-allergic children and their caregivers.

COVID-19 vaccination and allergen immunotherapy (AIT) - A position paper of the German Society for Applied Allergology (AeDA) and the German Society for Allergology and Clinical Immunology (DGAKI).

BACKGROUND: Vaccinations against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) are intended to induce an immune response to protect against infection/disease. Allergen immunotherapy (AIT) is thought to induce a (different) immune response, e.g., to induce tolerance to allergens. In this position paper we clarify how to use AIT in temporal relation to COVID-19 vaccination. Four SARS-CoV-2 vaccines are currently approved in the EU, and their possible immunological interactions with AIT are described together with practical recommendations for use. MATERIALS AND METHODS: Based on the internationally published literature, this position paper provides specific recommendations for the use of AIT in temporal relation to a SARS-CoV-2 vaccination. RESULTS: AIT is used in 1) allergic rhinitis, 2) allergic bronchial asthma, 3) insect venom allergy, 4) food allergy (peanut). CONCLUSION: For the continuation of an ongoing AIT, we recommend an interval of 1 week before and after vaccination for subcutaneous immunotherapy (SCIT). For sublingual immunotherapy (SLIT) and oral immunotherapy (OIT), we recommend taking them up to the day before vaccination and a break of 2 - 7 days after vaccination. Initiation of a new SCIT, SLIT, or OIT should be delayed until 1 week after the day of the second vaccination. For SCIT, we generally recommend an interval of ~ 1 week to COVID-19 vaccination.

Cutaneous Adverse Reactions to COVID-19 Vaccines: Insights from an Immuno-Dermatological Perspective.

(1) Background: Numerous vaccines are under preclinical and clinical development for prevention of severe course and lethal outcome of coronavirus disease 2019 (COVID-19). In light of high efficacy rates and satisfactory safety profiles, some agents have already reached approval and are now distributed worldwide, with varying availability. Real-world data on cutaneous adverse drug reactions (ADRs) remain limited. (2) Methods: We performed a literature research concerning cutaneous ADRs to different COVID-19 vaccines, and incorporated our own experiences. (3) Results: Injection site reactions are the most frequent side effects arising from all vaccine types. Moreover, delayed cutaneous ADRs may occur after several days, either as a primary manifestation or as a flare of a pre-existing inflammatory dermatosis. Cutaneous ADRs may be divided according to their cytokine profile, based on the preponderance of specific T-cell subsets (i.e., Th1, Th2, Th17/22, Tregs). Specific cutaneous ADRs mimic immunogenic reactions to the natural infection with SARS-CoV-2, which is associated with an abundance of type I interferons. (4) Conclusions: Further studies are required in order to determine the best suitable vaccine type for individual groups of patients, including patients suffering from chronic inflammatory dermatoses.

Immunologically relevant aspects of the new COVID-19 vaccines-an ÖGAI (Austrian Society for Allergology and Immunology) and AeDA (German Society for Applied Allergology) position paper.

BACKGROUND: The vaccines against the coronavirus disease 2019 (COVID-19) approved in the European Union represent a decisive step in the fight against the pandemic. The application of these available vaccines to patients with pre-existing immunological conditions leads to a multitude of questions regarding efficacy, side effects and the necessary patient information. RESULTS: This review article provides insight into mechanisms of action of the currently available severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines and summarises the current state of science as well as expert recommendations regarding tolerability of the vaccines. In addition, the potential to develop protective immune responses is determined. A special focus is given on patients under immunosuppression or in treatment with immunomodulatory drugs. Special groups of the population such as children, pregnant women and the elderly are also considered. CONCLUSION: Despite the need for a patient-specific risk-benefit assessment, the consensus among experts is that patients with immunological diseases in particular benefit from the induced immune protection after COVID-19 vaccination and do not have an increased risk of side effects.

Novel therapies and the potential for a personalized approach to atopic dermatitis.

PURPOSE OF REVIEW: To provide a cutting-edge overview of recent developments in topical and systemic therapeutic approaches for the treatment of atopic dermatitis (AD). RECENT FINDINGS: Growing knowledge about key pathways in AD and stratification of patient's subgroups have set the basis for a new era of targeted topical and systemic therapy in AD.Different aspects have to be considered in the decision process for topical versus systemic therapy. Further on, co-factors from the patient's side as well as the side of the substances determine the choice of a particular drug/drug type.Tailored medicine in AD treatment comprises drugs of the group of small molecules such as topical Janus kinases-signal transducer and activator of transcription (JAK-STAT) inhibitors or phosphodiesterase 4 inhibitors, and JAK-STAT inhibitors for oral use, as well as monoclonal antibodies for subcutaneous use, which target key cytokines or cytokine receptors in AD pathogenesis. SUMMARY: The current stepwise treatment approaches, which are settled on basic therapy and structured patient education and gradually expanded depending on the severity of the disease by stronger topical or even systemic measures, will have to be adapted to the rapid development in the therapeutic field, mirrored by an impressive high number of ongoing clinical studies as well as novel drugs at late stages of clinical trials with so far quite promising results.