Ocular surface disease in moderate-to-severe atopic dermatitis patients and the effect of biological therapy.

Atopic dermatitis (AD) is a chronic inflammatory skin disease for which new targeted therapies are currently available. Due to the increased rates of ocular surface disease (OSD) reported during treatment with these new targeted treatments, more insight into the occurrence and pathomechanism of OSD in moderate-to-severe AD patients is needed. Therefore, this review's first part highlights that most patients with moderate-to-severe AD already have characteristics of OSD before starting targeted treatment. Remarkably, not all AD patients with OSD report ocular symptoms. OSD in AD is associated with less conjunctival goblet cells (GC) compared to healthy controls. In addition, OSD severity in AD patients is associated with high AD activity, the presence of eyelid and/or facial eczema, and high levels of AD-related severity biomarkers in tear fluid. The second part of this review highlights that pre-existing ocular pathology (e.g. in combination with the use of ophthalmic medication or eyelid eczema) may be associated with the development of dupilumab-associated ocular surface disease (DAOSD). During dupilumab treatment, DAOSD (which can be new-onset OSD or worsening of pre-existing OSD) is observed in approximately one-third of the dupilumab-treated AD patients. Anti-inflammatory ophthalmic treatment improves DAOSD, and dose reduction of dupilumab may also be an effective treatment option. The pathomechanism of DAOSD is still not fully elucidated. In a prospective study low, but stable conjunctival GC numbers were observed in moderate-to-severe AD patients, before and during dupilumab treatment. However, the Mucin 5 AC (MUC5AC) expression of GCs decreased during dupilumab treatment, suggesting an impairment of the GC function by dupilumab treatment. In addition, higher dupilumab tear fluid levels were found in dupilumab-treated AD patients with moderate-to-severe OSD compared to patients with no or mild OSD, whereas the dupilumab serum levels are similar. Clinicians should be aware of the frequent occurrence of OSD in moderate-to-severe AD patients, and a low-threshold referral to an ophthalmologist is recommended.

Eosinophils-from cradle to grave: An EAACI task force paper on new molecular insights and clinical functions of eosinophils and the clinical effects of targeted eosinophil depletion.

Over the past years, eosinophils have become a focus of scientific interest, especially in the context of their recently uncovered functions (e.g. antiviral, anti-inflammatory, regulatory). These versatile cells display both beneficial and detrimental activities under various physiological and pathological conditions. Eosinophils are involved in the pathogenesis of many diseases which can be classified into primary (clonal) and secondary (reactive) disorders and idiopathic (hyper)eosinophilic syndromes. Depending on the biological specimen, the eosinophil count in different body compartments may serve as a biomarker reflecting the underlying pathophysiology and/or activity of distinct diseases and as a therapy-driving (predictive) and monitoring tool. Personalized selection of an appropriate therapeutic strategy directly or indirectly targeting the increased number and/or activity of eosinophils should be based on the understanding of eosinophil homeostasis including their interactions with other immune and non-immune cells within different body compartments. Hence, restoring as well as maintaining homeostasis within an individual's eosinophil pool is a goal of both specific and non-specific eosinophil-targeting therapies. Despite the overall favourable safety profile of the currently available anti-eosinophil biologics, the effect of eosinophil depletion should be monitored from the perspective of possible unwanted consequences.

EAACI guidelines on the diagnosis of IgE-mediated food allergy.

This European Academy of Allergy and Clinical Immunology guideline provides recommendations for diagnosing IgE-mediated food allergy and was developed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Food allergy diagnosis starts with an allergy-focused clinical history followed by tests to determine IgE sensitization, such as serum allergen-specific IgE (sIgE) and skin prick test (SPT), and the basophil activation test (BAT), if available. Evidence for IgE sensitization should be sought for any suspected foods. The diagnosis of allergy to some foods, such as peanut and cashew nut, is well supported by SPT and serum sIgE, whereas there are less data and the performance of these tests is poorer for other foods, such as wheat and soya. The measurement of sIgE to allergen components such as Ara h 2 from peanut, Cor a 14 from hazelnut and Ana o 3 from cashew can be useful to further support the diagnosis, especially in pollen-sensitized individuals. BAT to peanut and sesame can be used additionally. The reference standard for food allergy diagnosis is the oral food challenge (OFC). OFC should be performed in equivocal cases. For practical reasons, open challenges are suitable in most cases. Reassessment of food allergic children with allergy tests and/or OFCs periodically over time will enable reintroduction of food into the diet in the case of spontaneous acquisition of oral tolerance.

Unraveling heterogeneity in pediatric atopic dermatitis: Identification of serum biomarker based patient clusters.

BACKGROUND: Increasing evidence shows that pediatric atopic dermatitis (AD) differs from adult AD on a biologic level. Broad biomarker profiling across a wide range of ages of pediatric patients with AD is lacking. OBJECTIVE: Our aim was to identify serum biomarker profiles in children with AD aged 0 to 17 years and compare these profiles with those previously found in adults with AD. METHODS: Luminex multiplex immunoassays were used to measure 145 biomarkers in serum from 240 children with AD (aged 0-17 years). Principal components analysis followed by unsupervised k-means clustering were performed to identify patient clusters. Patients were stratified into age groups (0-4 years, 5-11 years, and 12-17 years) to assess association between age and cluster membership. RESULTS: Children aged 0 to 4 years had the highest levels of TH1 cell-skewing markers and lowest levels of TH17 cell-related markers. TH2 cell-related markers did not differ significantly between age groups. Similar to the pattern in adults, cluster analysis identified 4 distinct pediatric patient clusters (TH2 cell/retinol-dominant, skin-homing-dominant, TH1 cell/TH2 cell/TH17 cell/IL-1-dominant, and TH1 cell/IL-1/eosinophil-inferior clusters). Only the TH1 cell/TH2 cell/TH17 cell/IL-1-dominant cluster resembled 1 of the previously identified adult clusters. Although no association with age or age of onset seemed to be found, disease severity was significantly associated with the skin-homing-dominant cluster. CONCLUSION: Four distinct patient clusters based on serum biomarker profiles could be identified in a large cohort of pediatric patients with AD, of which 1 was similar to previously identified adult clusters. The identification of endotypes driven by distinct underlying immunopathologic pathways might be useful to define pediatric patients with AD who are at risk of persistent disease and may necessitate different targeted treatment approaches.

T-cell subsets in the skin and their role in inflammatory skin disorders.

T lymphocytes (T cells) are major players of the adaptive immune response. Naive T cells are primed in the presence of cytokines, leading to polarization into distinct T-cell subsets with specific functions. These subsets are classified based on their T-cell receptor profile, expression of transcription factors, surface cytokine and chemokine receptors, and their cytokine production, which together determine their specific function. This review provides an overview of the various T-cell subsets and their function in several inflammatory skin disorders ranging from allergic inflammation to skin tumors. Moreover, we highlight similarities of T-cell responses across different skin disorders, demonstrating the presence of similar and opposing functions for the different T-cell subsets. Finally, we discuss the effects of currently available and promising therapeutic approaches to harness T cells in inflammatory skin diseases for which efficacy next to unwanted side effects provide new insights into the pathophysiology of skin disorders.

Measurement of IgE to hazelnut allergen components cannot replace hazelnut challenge in Dutch adults.

BACKGROUND: Component-resolved diagnostics (CRD) help predict hazelnut allergy (HA) in children, but are of unknown diagnostic value in adults. This study aimed to evaluate the diagnostic accuracy of IgE to hazelnut extract and components in adults. METHODS: A Dutch population of consecutively presenting adults suspected of HA, who underwent a double-blind placebo-controlled food challenge, were included. Serum IgE to hazelnut extract and Cor a 1, 8, 9, and 14 was measured on ImmunoCAP. Diagnostic accuracy was assessed by area under the curve (AUC) analysis. RESULTS: Of 89 patients undergoing challenge, 46 had challenge-confirmed HA: 17 based on objective and 29 based on subjective symptoms. At commonly applied cutoffs 0.1 and 0.35 kUA /L, high sensitivity was observed for IgE to hazelnut extract and Cor a 1 (range 85-91%), and high specificity for IgE to Cor a 8, 9 and 14 (range 77-95%). However, the AUCs for hazelnut extract and components were too low for accurate prediction of HA (range 0.50-0.56). Combining hazelnut extract and component IgE measurements did not significantly improve accuracy. Higher IgE levels to Cor a 9 and 14 were tentatively associated with HA with objective symptoms, but the corresponding AUCs still only reached 0.68 and 0.63, respectively. CONCLUSIONS: Although hazelnut allergic adults are generally sensitized to hazelnut extract and Cor a 1, and hazelnut tolerant adults are usually not sensitized to Cor a 8, 9, or 14, challenge testing is still needed to accurately discriminate between presence and absence of HA in adults from a birch-endemic country.

Proposal of 0.5 mg of protein/100 g of processed food as threshold for voluntary declaration of food allergen traces in processed food-A first step in an initiative to better inform patients and avoid fatal allergic reactions: A GA²LEN position paper.

BACKGROUND: Food anaphylaxis is commonly elicited by unintentional ingestion of foods containing the allergen above the tolerance threshold level of the individual. While labeling the 14 main allergens used as ingredients in food products is mandatory in the EU, there is no legal definition of declaring potential contaminants. Precautionary allergen labeling such as "may contain traces of" is often used. However, this is unsatisfactory for consumers as they get no information if the contamination is below their personal threshold. In discussions with the food industry and technologists, it was suggested to use a voluntary declaration indicating that all declared contaminants are below a threshold of 0.5 mg protein per 100 g of food. This concentration is known to be below the threshold of most patients, and it can be technically guaranteed in most food production. However, it was also important to assess that in case of accidental ingestion of contaminants below this threshold by highly allergic patients, no fatal anaphylactic reaction could occur. Therefore, we performed a systematic review to assess whether a fatal reaction to 5mg of protein or less has been reported, assuming that a maximum portion size of 1kg of a processed food exceeds any meal and thus gives a sufficient safety margin. METHODS: MEDLINE and EMBASE were searched until 24 January 2021 for provocation studies and case reports in which one of the 14 major food allergens was reported to elicit fatal or life-threatening anaphylactic reactions and assessed if these occurred below the ingestion of 5mg of protein. A Delphi process was performed to obtain an expert consensus on the results. RESULTS: In the 210 studies included, in our search, no reports of fatal anaphylactic reactions reported below 5 mg protein ingested were identified. However, in provocation studies and case reports, severe reactions below 5 mg were reported for the following allergens: eggs, fish, lupin, milk, nuts, peanuts, soy, and sesame seeds. CONCLUSION: Based on the literature studied for this review, it can be stated that cross-contamination of the 14 major food allergens below 0.5 mg/100 g is likely not to endanger most food allergic patients when a standard portion of food is consumed. We propose to use the statement "this product contains the named allergens in the list of ingredients, it may contain traces of other contaminations (to be named, e.g. nut) at concentrations less than 0.5 mg per 100 g of this product" for a voluntary declaration on processed food packages. This level of avoidance of cross-contaminations can be achieved technically for most processed foods, and the statement would be a clear and helpful message to the consumers. However, it is clearly acknowledged that a voluntary declaration is only a first step to a legally binding solution. For this, further research on threshold levels is encouraged.

Allergy: Type I, II, III, and IV.

Hypersensitivity reactions are overreactions of the immune system clinically seen as allergic and autoimmune diseases. Gell and Coombs originally described four different types of hypersensitivity reactions almost 60 years ago, and their description still applies in large parts. However, some modifications and extensions have been included in original definition. Especially in allergic diseases, it became clear that often, multiple types of hypersensitivity reaction can occur simultaneously. This improved insight is not only important for a better understanding of hypersensitivity disorders, but is especially of importance for improved diagnostics and directing therapeutic interventions.

Confirmation of multiple endotypes in atopic dermatitis based on serum biomarkers.

BACKGROUND: Atopic dermatitis (AD) is a highly heterogeneous disease, both clinically and biologically, whereas patients are still being treated according to a "one-size-fits-all" approach. Stratification of patients into biomarker-based endotypes is important for future development of personalized therapies. OBJECTIVE: Our aim was to confirm previously defined serum biomarker-based patient clusters in a new cohort of patients with AD. METHODS: A panel of 143 biomarkers was measured by using Luminex technology in serum samples from 146 patients with severe AD (median Eczema Area and Severity Index = 28.3; interquartile range = 25.2-35.3). Principal components analysis followed by unsupervised k-means cluster analysis of the biomarker data was used to identify patient clusters. A prediction model was built on the basis of a previous cohort to predict the 1 of the 4 previously identified clusters to which the patients of our new cohort would belong. RESULTS: Cluster analysis identified 4 serum biomarker-based clusters, 3 of which (clusters B, C, and D) were comparable to the previously identified clusters. Cluster A (33.6%) could be distinguished from the other clusters as being a "skin-homing chemokines/IL-1R1-dominant" cluster, whereas cluster B (18.5%) was a "TH1/TH2/TH17-dominant" cluster, cluster C (18.5%) was a "TH2/TH22/PARC-dominant" cluster, and cluster D (29.5%) was a "TH2/eosinophil-inferior" cluster. Additionally, by using a prediction model based on our previous cohort we accurately assigned the new cohort to the 4 previously identified clusters by including only 10 selected serum biomarkers. CONCLUSION: We confirmed that AD is heterogeneous at the immunopathologic level and identified 4 distinct biomarker-based clusters, 3 of which were comparable with previously identified clusters. Cluster membership could be predicted with a model including 10 serum biomarkers.

ARIA-EAACI statement on severe allergic reactions to COVID-19 vaccines - An EAACI-ARIA Position Paper.

Further to the approval of the Coronavirus disease 2019 (COVID-19) vaccine BNT162b2, several severe anaphylaxis cases occured within the first few days of public vaccination. An investigation is taking place to understand the cases and their triggers. The vaccine will be administered to a large number of individuals worldwide and there are raising concerns that severe adverse events might occur. With the current information, the European Academy of Allergy and Clinical Immunology (EAACI) states its position for the following preliminary recommendations that are to be revised as soon as more data emerge. To minimize the risk of severe allergic reactions in vaccinated individuals, it is urgently required to understand the specific nature of the reported severe allergic reactions, including the background medical history of the individuals affected and the mechanisms involved. To achieve this goal, all clinical and laboratory information should be collected and reported. Mild and moderate allergic patients should not be excluded from the vaccine as this could have a significant impact on reaching the goal of population immunity. Healthcare practitioners vaccinating against COVID-19 are required to be sufficiently prepared to recognize and treat anaphylaxis properly with the ability to administer adrenaline. Further to vaccine administration, a mandatory observation period of at least 15 minutes should be followed for all individuals. The current data have not shown any higher risk for patients suffering from allergic rhinitis or asthma, and this message should be clearly stated by physicians to enable our patients to trust the vaccine. More than 30% of the population suffers from allergic diseases and the benefit of the vaccination clearly outweighs the risk of severe COVID-19 development.

Immune modulation via T regulatory cell enhancement: Disease-modifying therapies for autoimmunity and their potential for chronic allergic and inflammatory diseases-An EAACI position paper of the Task Force on Immunopharmacology (TIPCO).

Therapeutic advances using targeted biologicals and small-molecule drugs have achieved significant success in the treatment of chronic allergic, autoimmune, and inflammatory diseases particularly for some patients with severe, treatment-resistant forms. This has been aided by improved identification of disease phenotypes. Despite these achievements, not all severe forms of chronic inflammatory and autoimmune diseases are successfully targeted, and current treatment options, besides allergen immunotherapy for selected allergic diseases, fail to change the disease course. T cell-based therapies aim to cure diseases through the selective induction of appropriate immune responses following the delivery of engineered, specific cytotoxic, or regulatory T cells (Tregs). Adoptive cell therapies (ACT) with genetically engineered T cells have revolutionized the oncology field, bringing curative treatment for leukemia and lymphoma, while therapies exploiting the suppressive functions of Tregs have been developed in nononcological settings, such as in transplantation and autoimmune diseases. ACT with Tregs are also being considered in nononcological settings such as cardiovascular disease, obesity, and chronic inflammatory disorders. After describing the general features of T cell-based approaches and current applications in autoimmune diseases, this position paper reviews the experimental models testing or supporting T cell-based approaches, especially Treg-based approaches, in severe IgE-mediated responses and chronic respiratory airway diseases, such as severe asthma and COPD. Along with an assessment of challenges and unmet needs facing the application of ACT in these settings, this article underscores the potential of ACT to offer curative options for patients with severe or treatment-resistant forms of these immune-driven disorders.

COVID-19 pandemic and allergen immunotherapy-an EAACI survey.

BACKGROUND: As in many fields of medical care, the coronavirus disease 2019 (COVID-19) resulted in an increased uncertainty regarding the safety of allergen immunotherapy (AIT). Therefore, the European Academy of Allergy and Clinical Immunology (EAACI) aimed to analyze the situation in different countries and to systematically collect all information available regarding tolerability and possible amendments in daily practice of sublingual AIT (SLIT), subcutaneous AIT (SCIT) for inhalant allergies and venom AIT. METHODS: Under the framework of the EAACI, a panel of experts in the field of AIT coordinated by the Immunotherapy Interest Group set-up a web-based retrospective survey (SurveyMonkey® ) including 27 standardized questions on practical and safety aspects on AIT in worldwide clinical routine. RESULTS: 417 respondents providing AIT to their patients in daily routine answered the survey. For patients (without any current symptoms to suspect COVID-19), 60% of the respondents informed of not having initiated SCIT (40% venom AIT, 35% SLIT) whereas for the maintenance phase of AIT, SCIT was performed by 75% of the respondents (74% venom AIT, 89% SLIT). No tolerability concern arises from this preliminary analysis. 16 physicians reported having performed AIT despite (early) symptoms of COVID-19 and/or a positive test result for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). CONCLUSIONS: This first international retrospective survey in atopic diseases investigated practical aspects and tolerability of AIT during the COVID-19 pandemic and gave no concerns regarding reduced tolerability under real-life circumstances. However, the data indicate an undertreatment of AIT, which may be temporary, but could have a long-lasting negative impact on the clinical care of allergic patients.

COVID-19 pandemic: Practical considerations on the organization of an allergy clinic-An EAACI/ARIA Position Paper.

BACKGROUND: The coronavirus disease 2019 (COVID-19) has evolved into a pandemic infectious disease transmitted by the severe acute respiratory syndrome coronavirus (SARS-CoV-2). Allergists and other healthcare providers (HCPs) in the field of allergies and associated airway diseases are on the front line, taking care of patients potentially infected with SARS-CoV-2. Hence, strategies and practices to minimize risks of infection for both HCPs and treated patients have to be developed and followed by allergy clinics. METHOD: The scientific information on COVID-19 was analysed by a literature search in MEDLINE, PubMed, the National and International Guidelines from the European Academy of Allergy and Clinical Immunology (EAACI), the Cochrane Library, and the internet. RESULTS: Based on the diagnostic and treatment standards developed by EAACI, on international information regarding COVID-19, on guidelines of the World Health Organization (WHO) and other international organizations, and on previous experience, a panel of experts including clinicians, psychologists, IT experts, and basic scientists along with EAACI and the "Allergic Rhinitis and its Impact on Asthma (ARIA)" initiative have developed recommendations for the optimal management of allergy clinics during the current COVID-19 pandemic. These recommendations are grouped into nine sections on different relevant aspects for the care of patients with allergies. CONCLUSIONS: This international Position Paper provides recommendations on operational plans and procedures to maintain high standards in the daily clinical care of allergic patients while ensuring the necessary safety measures in the current COVID-19 pandemic.

Response of FcεRI-bearing leucocytes to omalizumab in chronic spontaneous urticaria.

BACKGROUND: The pathogenesis of chronic spontaneous urticaria (CSU) and the mechanism of action of omalizumab in CSU remain unclear. OBJECTIVE: In this study, we assessed the responsiveness and FcεRI expression of various subsets of leucocytes in patients with CSU treated with omalizumab. METHODS: In this prospective cohort study, 30 patients were treated with 6 administrations of 300 mg omalizumab every 4 weeks, followed by a follow-up period of 12 weeks. FcεRI expression and the percentage of basophils, monocytes, and dendritic cell subsets were analysed before and during treatment, and after follow-up. In addition, anti-IgE- and C5a-induced basophil degranulation was measured. The results were correlated with disease activity and response to omalizumab. RESULTS: In addition to a rapid and significant reduction in FcεRI on basophils, we demonstrated a reduction in FcεRI on plasmacytoid dendritic cells during omalizumab treatment, which persisted until 3 months after discontinuation. FcεRI expression on basophils and its reduction did not correlate with the treatment response. Omalizumab led to an increased percentage of basophils in blood but not of the other FcεRI-bearing leucocytes. Basophil responsiveness was differentially affected; anti-IgE-, but not C5a-induced basophil degranulation increased during the treatment. Apart from clinical non-responders showing a stronger increase in anti-IgE-induced basophil degranulation over a period time, no differences were found in omalizumab responders vs non-responders. CONCLUSIONS/CLINICAL RELEVANCE: FcεRI expression on basophils decreased rapidly, while anti-IgE-induced degranulation significantly increased due to omalizumab treatment in patients with CSU, persisting at least for 3 months after stopping the treatment. None of the markers were able to predict the effectiveness of treatment. Whether basophils play a role in omalizumab responsiveness in CSU remains unclear.

Dupilumab is very effective in a large cohort of difficult-to-treat adult atopic dermatitis patients: First clinical and biomarker results from the BioDay registry.

INTRODUCTION: Dupilumab has recently been approved for the treatment of moderate to severe atopic dermatitis (AD) in adults. Daily practice data on dupilumab treatment are scarce. OBJECTIVE: To study the effect of 16-week treatment with dupilumab on clinical response and serum biomarkers in adult patients with moderate-severe AD in daily practice. METHODS: Data were extracted from the BioDay registry, a prospective multicenter registry. Sixteen-week clinical effectiveness of dupilumab was expressed as number of patients achieving EASI-50 (Eczema Area and Severity Index) or EASI-75, as well as patient-reported outcomes measures (Patient-Oriented Eczema Measure, Dermatology Life Quality Index, Numeric Rating Scale pruritus). Twenty-one biomarkers were measured in patients treated with dupilumab without concomitant use of oral immunosuppressive drugs at five different time points (baseline, 4, 8, 12, and 16 weeks). RESULTS: In total, 138 patients treated with dupilumab in daily practice were included. This cohort consisted of patients with very difficult-to-treat AD, including 84 (61%) patients who failed treatment on ≥2 immunosuppressive drugs. At week 16, the mean percent change in EASI score was 73%. The EASI-50 and EASI-75 were achieved by 114 (86%) and 82 (62%) patients after 16 weeks of treatment. The most reported side effect was conjunctivitis, occurring in 47 (34%) patients. During dupilumab treatment, disease severity-related serum biomarkers (TARC, PARC, periostin, and IL-22), eotaxin-1, and eotaxin-3 significantly decreased. CONCLUSION: Treatment with dupilumab significantly improved disease severity and decreased severity-related serum biomarkers in patients with very difficult-to-treat AD in a daily practice setting.

Immunology of COVID-19: Mechanisms, clinical outcome, diagnostics, and perspectives-A report of the European Academy of Allergy and Clinical Immunology (EAACI).

With the worldwide spread of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) resulting in declaration of a pandemic by the World Health Organization (WHO) on March 11, 2020, the SARS-CoV-2-induced coronavirus disease-19 (COVID-19) has become one of the main challenges of our times. The high infection rate and the severe disease course led to major safety and social restriction measures worldwide. There is an urgent need of unbiased expert knowledge guiding the development of efficient treatment and prevention strategies. This report summarizes current immunological data on mechanisms associated with the SARS-CoV-2 infection and COVID-19 development and progression to the most severe forms. We characterize the differences between adequate innate and adaptive immune response in mild disease and the deep immune dysfunction in the severe multiorgan disease. The similarities of the human immune response to SARS-CoV-2 and the SARS-CoV and MERS-CoV are underlined. We also summarize known and potential SARS-CoV-2 receptors on epithelial barriers, immune cells, endothelium and clinically involved organs such as lung, gut, kidney, cardiovascular, and neuronal system. Finally, we discuss the known and potential mechanisms underlying the involvement of comorbidities, gender, and age in development of COVID-19. Consequently, we highlight the knowledge gaps and urgent research requirements to provide a quick roadmap for ongoing and needed COVID-19 studies.

Pegvaliase: Immunological profile and recommendations for the clinical management of hypersensitivity reactions in patients with phenylketonuria treated with this enzyme substitution therapy.

OBJECTIVE: To provide recommendations for managing hypersensitivity adverse events (HAEs) to an injectable enzyme substitution therapy (pegvaliase, a PEGylated phenylalanine ammonia lyase enzyme) in adult patients with phenylketonuria (PKU). METHODS: Eight European academic immunology experts with a broad range of experience in hypersensitivity, anaphylaxis, and/or drug reactions, and two geneticists from the USA with pegvaliase experience convened for two advisory board meetings. Efficacy, safety, and immunological profile of pegvaliase were discussed with the objective of developing recommendations for the clinical management of HAEs associated with pegvaliase treatment. RESULTS: Based on available immunogenicity data, it was concluded that pegvaliase induces a Type III hypersensitivity reaction, causing HAEs with peak event rates during induction/titration and a decline over time during maintenance therapy. The decline in HAEs with longer duration of therapy was considered to likely be driven by anti-drug antibody affinity maturation, reduced immune complex formation, and decreased complement activation over time. Immunology and PKU experts unanimously supported that the use of an induction, titration, and maintenance dosing regimen and implementation of several risk mitigation strategies contributed to the improvement of tolerability over time. Key risk mitigation strategies utilized in the Phase 3 clinical trials such as premedication with H1-receptor antagonists, allowance for a longer titration period after an HAE, patient education, and requirement to carry auto-injectable adrenaline (epinephrine) should be continued in clinical practice. A tool for administration of auto-injectable adrenaline in patients using pegvaliase was suggested. It was added that after the occurrence of a severe HAE a temporary dose reduction is more likely to improve tolerability than treatment interruption. CONCLUSIONS: Overall, it was agreed that pegvaliase has a generally tolerable safety profile in adults with PKU. Importantly, the risk mitigation strategies utilized in the clinical trials were considered to support the continued use of key strategies for management in the commercial setting, such as a slow induction/titration dosing paradigm and premedication with H1-receptor antagonists. However, physicians and patients need to be aware of the risk of HAEs associated with pegvaliase; presence of a trained observer during early treatment may be beneficial in certain circumstances, and a requirement to carry auto-injectable adrenaline is recommended. Because pegvaliase offers the possibility to normalize diet, while maintaining blood phenylalanine within the recommended therapeutic range, safe use of this medication in the clinical setting is important. Ongoing monitoring of long-term clinical safety of patients on pegvaliase treatment in the commercial setting was recommended.

Comparing biologicals and small molecule drug therapies for chronic respiratory diseases: An EAACI Taskforce on Immunopharmacology position paper.

Chronic airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), together with their comorbidities, bear a significant burden on public health. Increased appreciation of molecular networks underlying inflammatory airway disease needs to be translated into new therapies for distinct phenotypes not controlled by current treatment regimens. On the other hand, development of new safe and effective therapies for such respiratory diseases is an arduous and expensive process. Antibody-based (biological) therapies are successful in treating certain respiratory conditions not controlled by standard therapies such as severe allergic and refractory eosinophilic severe asthma, while in other inflammatory respiratory diseases, such as COPD, biologicals are having a more limited impact. Small molecule drug (SMD)-based therapies represent an active field in pharmaceutical research and development. SMDs expand biologicals' therapeutic targets by reaching the intracellular compartment by delivery as either an oral or topically based formulation, offering both convenience and lower costs. Aim of this review was to compare and contrast the distinct pharmacological properties and clinical applications of SMDs- and antibody-based treatment strategies, their limitations and challenges, in order to highlight how they should be integrated for their optimal utilization and to fill the critical gaps in current treatment for these chronic inflammatory respiratory diseases.

Biomarkers and clinical characteristics of autoimmune chronic spontaneous urticaria: Results of the PURIST Study.

BACKGROUND: Autoimmune chronic spontaneous urticaria (aiCSU) is an important subtype of chronic spontaneous urticaria (CSU) in which functional IgG autoantibodies to IgE or its high-affinity receptor (FcεRI) induces mast cell degranulation and subsequent symptom development. However, it has not been tightly characterized. This study aimed to better define the clinical and immunological features and to explore potential biomarkers of aiCSU. METHODS: This was a multinational, multicenter study of 182 CSU patients. The clinical features studied included: urticaria activity and impact (UAS7 and quality of life); autologous serum skin test (ASST); IgG anti-FcεRI and IgG anti-IgE; IgG-anti-thyroperoxidase (IgG anti-TPO); total serum IgE; and basophil reactivity (BASO) using the basophil activation test (BAT) and basophil histamine release assay (BHRA). RESULTS: Of the 182 patients, 107 (59%) were ASST+, 46 (25%) were BASO+, and 105 (58%) were IgG anti-FcεRI+/IgE+. Fifteen patients (8%) fulfilled all three criteria of aiCSU. aiCSU patients appeared more severe (UAS7 21 vs 9 P < 0.016) but showed no other clinical or demographic differences from non-aiCSU patients. aiCSU patients also had markedly lower total IgE levels (P < 0.0001) and higher IgG anti-TPO levels (P < 0.001). Of biomarkers, positive BAT and BHRA tests were 69% and 88% predictive of aiCSU, respectively. CONCLUSIONS: aiCSU is a relatively small but immunologically distinct subtype of CSU that cannot be identified by routine clinical parameters. Inclusion of BHRA or BAT in the diagnostic workup of CSU patients may aid identification of aiCSU patients, who may have a different prognosis and benefit from specific management.