Definition, acronyms, nomenclature, and classification of angioedema (DANCE): AAAAI, ACAAI, ACARE, and APAAACI DANCE consensus.

BACKGROUND: Angioedema (AE) manifests with intermittent, localized, self-limiting swelling of the subcutaneous and/or submucosal tissue. AE is heterogeneous, can be hereditary or acquired, may occur only once or be recurrent, may exhibit wheals or not, and may be due to mast cell mediators, bradykinin, or other mechanisms. Several different taxonomic systems are currently used, making it difficult to compare the results of studies, develop multicenter collaboration, and harmonize AE treatment. OBJECTIVE: We developed a consensus on the definition, acronyms, nomenclature, and classification of AE (DANCE). METHODS: The initiative involved 91 experts from 35 countries and was endorsed by 53 scientific and medical societies, and patient organizations. A consensus was reached by online discussion and voting using the Delphi process over a period of 16 months (June 2021 to November 2022). RESULTS: The DANCE initiative resulted in an international consensus on the definition, classification, and terminology of AE. The new consensus classification features 5 types and endotypes of AE and a harmonized vocabulary of abbreviations/acronyms. CONCLUSION: The DANCE classification complements current clinical guidelines and expert consensus recommendations on the diagnostic assessment and treatment of AE. DANCE does not replace current clinical guidelines, and expert consensus algorithms and should not be misconstrued in a way that affects reimbursement of medicines prescribed by physicians using sound clinical judgment. We anticipate that this new AE taxonomy and nomenclature will harmonize and facilitate AE research and clinical studies, thereby improving patient care.

A Core Outcome Set for Efficacy of Acute Treatment of Hereditary Angioedema.

BACKGROUND: Clinical trials investigating drugs for the acute treatment of hereditary angioedema attacks have assessed many different outcomes. This heterogeneity limits the comparability of trial results and may lead to selective outcome reporting bias and a high burden on trial participants. OBJECTIVE: To achieve consensus on a core outcome set composed of key outcomes that ideally should be used in all clinical efficacy trials involving the acute treatment of hereditary angioedema attacks. METHODS: We conducted a Delphi consensus study involving all relevant parties: patients with hereditary angioedema, hereditary angioedema expert clinicians and clinical researchers, pharmaceutical companies, and regulatory bodies. Two Internet-based survey rounds were conducted. In round 1, panelists indicated the importance of individual outcomes used in clinical trials on a 9-point Likert scale. Based on these results, a core outcome set was developed and voted on by panelists in round 2. RESULTS: A total of 58 worldwide panelists completed both rounds. The first round demonstrated high importance scores and substantial agreement among the panelists. In the second round, a consensus of 90% or greater was achieved on a core outcome set consisting of five key outcomes: change in overall symptom severity at one predetermined time point between 15 minutes and 4 hours after treatment, time to end of progression of all symptoms, the need for rescue medication during the entire attack, impairment of daily activities, and treatment satisfaction. CONCLUSIONS: This international study obtained a high level of consensus on a core outcome set for the acute treatment of hereditary angioedema attacks, consisting of five key outcomes.

Berotralstat for long-term prophylaxis of hereditary angioedema in Japan: Parts 2 and 3 of the randomized APeX-J Phase III trial.

Background: Berotralstat is a once-daily oral inhibitor of plasma kallikrein for the prophylaxis of hereditary angioedema (HAE) in patients ≥12 years. APeX-J aimed to evaluate the efficacy and safety of berotralstat in Japan. Methods: APeX-J was a Phase III trial comprising 3 parts (NCT03873116). Part 1 was a randomized, placebo-controlled evaluation of berotralstat 150 or 110 mg over 24 weeks. Part 2 was a 28-week dose-blinded phase in which berotralstat-treated patients continued the same dose and placebo patients were re-randomized to berotralstat 150 or 110 mg. In Part 3, all patients remaining on study received berotralstat 150 mg in an open-label manner for up to an additional 52 weeks. The primary endpoint of Parts 2 and 3 was long-term safety and tolerability, and secondary endpoints examined effectiveness. Results: Seventeen patients entered Part 2, and 11 continued into Part 3. Treatment-emergent adverse events (TEAEs) were reported by 14/17 patients (82.4%) in Parts 2 or 3; the most common were nasopharyngitis, abdominal pain, cystitis, influenza, and vertigo. One patient (5.9%) experienced a drug-related TEAE (Grade 4 increased hepatic enzyme). No drug-related serious TEAEs were reported. For patients who completed 26 months of treatment with berotralstat 150 mg (n = 5), mean (standard error of the mean) monthly HAE attack rates and on-demand medication use decreased from baseline by 1.15 (0.09) attacks/month and 2.8 (0.64) doses/month, respectively. Sustained improvements were also observed in patient quality of life and treatment satisfaction. Conclusions: Long-term prophylaxis with berotralstat raised no new safety signals and was effective at reducing attacks and improving patient-reported outcomes. Trial registration: ClinicalTrials.gov NCT03873116. Registered March 13, 2019. Retrospectively registered.

A Staphylococcus epidermidis strain inhibits the uptake of Staphylococcus aureus derived from atopic dermatitis skin into the keratinocytes.

BACKGROUND: Various bacterial species form a microbiome in the skin. In the past, dead Staphylococcus aureus derived from atopic dermatitis (AD) are taken up by keratinocytes; however, whether live S. aureus can be taken up by keratinocytes is unknown. OBJECTIVE: This study aimed to examine whether live AD strains of S. aureus internalize into the keratinocytes and how the internalization changes under conditions in which other bacterial species including S. epidermidis are present. METHODS: HaCaT cells were cultured with live S. aureus and S. epidermidis (live or heat-treated) or their culture supernatants. After coculture, the change in the amount of S. aureus in the cytoplasm of HaCaT cells was analyzed using, a high-throughput imaging system, Opera Phenix™. RESULTS: Live S. aureus were taken up in the cytoplasm of HaCaT cells. Coculturing live S. aureus with live S. epidermidis or the culture supernatants decreased the abundance of S. aureus in the cytoplasm. The heat-treated culture supernatants of live S. epidermidis or culture supernatants of other S. strains did not decrease the abundance of S. aureus in the cytoplasm. CONCLUSION: Live S. aureus was internalized into the cytoplasm of HaCaT cells as does heat-treated S. aureus. In addition, the heat-sensitive substances secreted by coculture with S. epidermidis and keratinocytes inhibited the uptake of S. aureus by keratinocytes.

Analysis of questionnaire survey to determine worldwide trends in prescriptions of biologics for the treatment of unresponsive chronic urticaria.

Background: Chronic spontaneous urticaria (CSU) is a common condition treated by allergist/immunologists, but the only FDA-approved biologic medication, omalizumab, may be underutilized globally. Objective: This study was performed to determine the global prescription of omalizumab for treatment of CSU by allergists/immunologists. Methods: Anonymous questionnaire surveys were distributed online to World Allergy Organization (WAO) members worldwide. Categorical data were analyzed for descriptive analysis using one-way frequency tabulation in SAS 9.4. Results: There were 348 respondents (43 missing data); Average age 51 (range 28-90); M/F 48%/52%. 58% had > 15 years of clinical experience and 10% < 5; 42% worked in private clinics, 36% public hospitals, 24% academia, 18% private hospitals, and 4% in community practice. Eighty-two percent (82%) prescribed omalizumab for CSU patients and use of omalizumab was highest among young practitioners. The most significant barriers were cost (63%) and restricted formulary (24%). Drug safety (63%) and chances of adverse events (47%) were the most significant factors deciding treatment. Twenty-two percent (22%) reported 80-100% of CSU patients were complete responders to omalizumab; 34% preferred increasing frequency (q 2-weeks), and 18% preferred increasing dose (600 mg q 4-weeks) for partial or non-responders. UAS7, UCT, and CU-QoL were used to assess CSU by 55%, 29%, and 25% of respondents, respectively. Autoimmune thyroid disease (62%), thyroid abnormality (43%) and allergic rhinitis (35%) were the most frequent comorbidities reported. Conclusions: Most clinicians favored omalizumab over other potential treatments due to safety. Although younger clinicians were more likely to prescribe omalizumab, cost and formulary access were major barriers. Only 22% of respondents reported 80% or greater of their patients had complete response to omalizumab, indicating the need for novel CSU therapies.

CRUSE® -An innovative mobile application for patient monitoring and management in chronic spontaneous urticaria.

BACKGROUND: Chronic spontaneous urticaria (CSU) is unpredictable and can severely impair patients' quality of life. Patients with CSU need a convenient, user-friendly platform to complete patient-reported outcome measures (PROMs) on their mobile devices. CRUSE® , the Chronic Urticaria Self Evaluation app, aims to address this unmet need. METHODS: CRUSE® was developed by an international steering committee of urticaria specialists. Priorities for the app based on recent findings in CSU were defined to allow patients to track and record their symptoms and medication use over time and send photographs. The CRUSE® app collects patient data such as age, sex, disease onset, triggers, medication, and CSU characteristics that can be sent securely to physicians, providing real-time insights. Additionally, CRUSE® contains PROMs to assess disease activity and control, which are individualised to patient profiles and clinical manifestations. RESULTS: CRUSE® was launched in Germany in March 2022 and is now available for free in 17 countries. It is adapted to the local language and displays a country-specific list of available urticaria medications. English and Ukrainian versions are available worldwide. From July 2022 to June 2023, 25,710 observations were documented by 2540 users; 72.7% were females, with a mean age of 39.6 years. At baseline, 93.7% and 51.3% of users had wheals and angioedema, respectively. Second-generation antihistamines were used in 74.0% of days. CONCLUSIONS: The initial data from CRUSE® show the wide use and utility of effectively tracking patients' disease activity and control, paving the way for personalised CSU management.

Efficacy and safety of ligelizumab in adults and adolescents with chronic spontaneous urticaria: results of two phase 3 randomised controlled trials.

BACKGROUND: Many patients with chronic spontaneous urticaria (CSU) do not achieve complete control of their symptoms with current available treatments. In a dose-finding phase 2b study, ligelizumab improved urticaria symptoms in patients with H1-antihistamine (H1-AH) refractory CSU. Here, we report the efficacy and safety outcomes from two ligelizumab phase 3 studies. METHODS: PEARL-1 and PEARL-2 were identically designed randomised, double-blind, active-controlled and placebo-controlled parallel-group studies. Patients aged 12 years or older with moderate-to-severe H1-AH refractory CSU were recruited from 347 sites in 46 countries and randomly allocated in a 3:3:3:1 ratio via Interactive Response Technology to 72 mg ligelizumab, 120 mg ligelizumab, 300 mg omalizumab, or placebo, dosed every 4 weeks, for 52 weeks. Patients allocated to placebo received 120 mg ligelizumab from week 24. The primary endpoint was change-from-baseline (CFB) in weekly Urticaria Activity Score (UAS7) at week 12, and was analysed in all eligible adult patients according to the treatment assigned at random allocation. Safety was assessed throughout the study in all patients who received at least one dose of the study drug. The studies were registered with ClinicalTrials.gov, NCT03580369 (PEARL-1) and NCT03580356 (PEARL-2). Both trials are now complete. FINDINGS: Between Oct 17, 2018, and Oct 26, 2021, 2057 adult patients were randomly allocated across both studies (72 mg ligelizumab n=614; 120 mg ligelizumab n=616; 300 mg omalizumab n=618, and placebo n=209). A total of 1480 (72%) of 2057 were female, and 577 (28%) of 2057 were male. Mean UAS7 at baseline across study groups ranged from 29·37 to 31·10. At week 12, estimated treatment differences in mean CFB-UAS7 were as follows: for 72 mg ligelizumab versus placebo, -8·0 (95% CI -10·6 to -5·4; PEARL-1), -10·0 (-12·6 to -7·4; PEARL-2); 72 mg ligelizumab versus omalizumab 0·7 (-1·2 to 2·5; PEARL-1), 0·4 (-1·4 to 2·2; PEARL-2); 120 mg ligelizumab versus placebo -8·0 (-10·5 to -5·4; PEARL-1), -11·1 (-13·7 to -8·5; PEARL-2); 120 mg ligelizumab versus omalizumab 0·7 (-1·1 to 2·5; PEARL-1), -0·7 (-2·5 to 1·1; PEARL-2). Both doses of ligelizumab were superior to placebo (p<0·0001), but not to omalizumab, in both studies. No new safety signals were identified for ligelizumab or omalizumab. INTERPRETATION: In the phase 3 PEARL studies, ligelizumab demonstrated superior efficacy versus placebo but not versus omalizumab. The safety profile of ligelizumab was consistent with previous studies. FUNDING: Novartis Pharma.

Mathematical-based morphological classification of skin eruptions corresponding to the pathophysiological state of chronic spontaneous urticaria.

BACKGROUND: Chronic spontaneous urticaria (CSU) is one of the most intractable human-specific skin diseases. However, as no experimental animal model exists, the mechanism underlying disease pathogenesis in vivo remains unclear, making the establishment of a curative treatment challenging. METHODS: A novel approach combining mathematical modelling, in vitro experiments and clinical data analysis was used to infer the pathological state of CSU patients from geometric features of the skin eruptions. RESULTS: Based on our hierarchical mathematical modelling, the eruptions of CSU were classified into five categories, each with distinct histamine, basophils, mast cells and coagulation factors network signatures. The analysis of 105 real CSU patients with this classification by six individual dermatologists achieved 87.6% agreement. Furthermore, our network analysis revealed that the coagulation status likely determines boundary/area pattern of wheals, while the state of spontaneous histamine release from mast cells may contribute to the divergence of size and outline of the eruptions. CONCLUSIONS: Our multi-faceted approach was accurate in defining pathophysiological states of disease based on geometric features offering the potential to improve the accuracy of CSU diagnosis and better management of the disease in the clinic.

Chronic spontaneous urticaria (CSU) is a persistent skin disease that causes red itchy skin eruptions, called wheals, that are of various shapes. These wheals repeatedly appear and disappear daily for up to weeks or even decades, severely impacting the quality of life of those affected. The causes, consequences or disease processes are largely understudied. Here, we developed a novel approach using mathematical modelling to analyse the geometric measurements of patients' wheals alongside laboratory experiments on human skin samples with eruptions to improve CSU diagnosis and clinical management. We find that geometric measurements of these skin eruptions can be classified into five categories, which could facilitate accurate diagnosis and consequently better clinical management of CSU and may be more widely applied to other skin diseases.

Enhancing evidence-informed policymaking in medicine and healthcare: stakeholder involvement in the Commons Project for rare diseases in Japan.

BACKGROUND: Although stakeholder involvement in policymaking is attracting attention in the fields of medicine and healthcare, a practical methodology has not yet been established. Rare-disease policy, specifically research priority setting for the allocation of limited research resources, is an area where evidence generation through stakeholder involvement is expected to be effective. We generated evidence for rare-disease policymaking through stakeholder involvement and explored effective collaboration among stakeholders. METHODS: We constructed a space called 'Evidence-generating Commons', where patients, family members, researchers, and former policymakers can share their knowledge and experiences and engage in continual deliberations on evidence generation. Ten rare diseases were consequently represented. In the 'Commons', 25 consecutive workshops were held predominantly online, from 2019 to 2021. These workshops focused on (1) clarification of difficulties faced by rare-disease patients, (2) development and selection of criteria for priority setting, and (3) priority setting through the application of the criteria. For the first step, an on-site workshop using sticky notes was held. The data were analysed based on KJ method. For the second and third steps, workshops on specific themes were held to build consensus. The workshop agendas and methods were modified based on participants' feedback. RESULTS: The 'Commons' was established with 43 participants, resulting in positive effects such as capacity building, opportunities for interactions, mutual understanding, and empathy among the participants. The difficulties faced by patients with rare diseases were classified into 10 categories. Seven research topics were identified as priority issues to be addressed including 'impediments to daily life', 'financial burden', 'anxiety', and 'burden of hospital visits'. This was performed by synthesising the results of the application of the two criteria that were particularly important to strengthen future research on rare diseases. We also clarified high-priority research topics by using criteria valued more by patients and family members than by researchers and former policymakers, and criteria with specific perspectives. CONCLUSION: We generated evidence for policymaking in the field of rare diseases. This study's insights into stakeholder involvement can enhance evidence-informed policymaking. We engaged in comprehensive discussions with policymakers regarding policy implementation and planned analysis of the participants' experiences in this project.

Stakeholder involvement is significant for effective policymaking in the field of rare diseases. However, practical methods for this involvement have not yet been established. Therefore, we developed the 'Commons project' to generate valuable policymaking information and explore effective ways for stakeholders' collaboration. This article explains the process and results of 25 continuous workshops, held from 2019 to 2021 with 43 participants, including patients, family members, researchers, and former policymakers. The main achievements of the discussion that took place in the 'Commons' included a presentation of the overview of the difficulties faced by patients with rare diseases and formulation of high priority research topics.First, the difficulties faced by patients with rare diseases were grouped into 10 categories. Second, seven research topics were identified as priority issues including 'impediments to daily life', 'financial burden', 'anxiety', and 'burden of hospital visits'. During the project process, positive effects such as capacity building, opportunities for interactions, mutual understanding, and empathy among the participants, were identified. Beyond the context of the field of rare diseases and science of policy, these findings are useful for the future of society, including co-creation among stakeholders and patient and public involvement. Based on this study's results, we have initiated communications with policy stakeholders in the field of rare diseases, with the aim of policy implementation.

A concept for integrated care pathways for atopic dermatitis-A GA2 LEN ADCARE initiative.

INTRODUCTION: The integrated care pathways for atopic dermatitis (AD-ICPs) aim to bridge the gap between existing AD treatment evidence-based guidelines and expert opinion based on daily practice by offering a structured multidisciplinary plan for patient management of AD. ICPs have the potential to enhance guideline recommendations by combining interventions and aspects from different guidelines, integrating quality assurance, and describing co-ordination of care. Most importantly, patients can enter the ICPs at any level depending on AD severity, resources available in their country, and economic factors such as differences in insurance reimbursement systems. METHODS: The GA2 LEN ADCARE network and partners as well as all stakeholders, abbreviated as the AD-ICPs working group, were involved in the discussion and preparation of the AD ICPs during a series of subgroup workshops and meetings in years 2020 and 2021, after which the document was circulated within all GAL2 EN ADCARE centres. RESULTS: The AD-ICPs outline the diagnostic procedures, possible co-morbidities, different available treatment options including differential approaches for the pediatric population, and the role of the pharmacists and other stakeholders, as well as remaining unmet needs in the management of AD. CONCLUSION: The AD-ICPs provide a multidisciplinary plan for improved diagnosis, treatment, and patient feedback in AD management, as well as addressing critical unmet needs, including improved access to care, training specialists, implementation of educational programs, assessment on the impact of climate change, and fostering a personalised treatment approach. By focusing on these key areas, the initiative aims to pave the way for a brighter future in the management of AD.

Efficacy and safety of lanadelumab in Japanese patients with hereditary angioedema: A phase 3 multicenter, open-label study.

The safety and efficacy of lanadelumab for the prevention of hereditary angioedema (HAE) attacks have not been studied in Japanese patients. We report outcomes from a phase 3, multicenter, open-label study (NCT04180163) of lanadelumab in Japanese patients with HAE. Japanese patients with HAE aged ≥12 years with ≥1 investigator-confirmed HAE attack during the 4-week run-in baseline period were enrolled into the study and received lanadelumab 300 mg every 2 weeks subcutaneously for 52 weeks. Dosing could be reduced to 300 mg every 4 weeks during the second 26-week treatment period if patients had well-controlled symptoms (e.g., attack-free) for 6 months. The primary efficacy endpoint was no investigator-confirmed HAE attacks (attack-free status) during days 0-182. Other outcomes included the rate of investigator-confirmed HAE attacks per month (28 days) and lanadelumab safety. Twelve patients (mean ± SD age 41.9 ± 12.4 years) were enrolled. During the first 26 weeks (days 0-182), five (41.7%) patients were attack-free. The mean ± SD HAE attack rate per month decreased by 74.0%, from 3.8 ± 2.4 during baseline to 1.2 ± 2.6 during the overall 52-week treatment period. There were no deaths or discontinuations due to treatment-emergent adverse events (TEAEs), no severe or serious TEAEs related to lanadelumab, and no positive anti-drug antibody results. The most frequent TEAEs were injection-site reactions (37 events in six patients). Most of the injection-site reaction adverse events were mild in severity. Results of this study support the findings from two global phase 3 studies for lanadelumab use as prophylactic therapy in Japanese patients with HAE.

Time Course of Priming Effect of TF Inducers on Synergistic TF Expression and Intra-Cellular Gap Formation of Human Vascular Endothelial Cells via the Extrinsic Coagulation Cascade.

Chronic spontaneous urticaria (CSU) is characterized by daily recurring wheal and flare with itch for more than 6 weeks. The extrinsic coagulation system has been shown to be activated in correlation with CSU severity. We have reported that tissue factor (TF), a trigger of the extrinsic coagulation cascade, is synergistically expressed on vascular endothelial cells by simultaneous stimulation with TF inducers (TFI), followed by activation of the extrinsic coagulation cascade and hyper permeability in vitro. However, vascular endothelial cells are not likely to be simultaneously stimulated by multiple TFIs under physiological conditions. Therefore, in order to know whether sequential, rather than simultaneous, stimuli with interval may induce synergistic activation of TF, we investigated the time course of the priming effects of each TFI for synergistic TF expression in vascular endothelial cells (HUVECs). We stimulated HUVECs with a TFI (first stimulation) and then stimulated cells with another TFI at indicated time points (second stimulation) and detected TF expression and activity. The TF expression induced by simultaneous stimulation diminished in a few hours. However, both synergistic enhancement of TF expression and activation level of the coagulation cascade were detected even when the second stimulation was added 18 or 22 h after the first stimulation. Thus, the priming effect of TFI for synergistic TF expression may persist for a half day or longer.

English version of Japanese guidance for biologics in treating atopic dermatitis.

This is the English version of the Japanese guidance for biologics in treating atopic dermatitis (AD). The signaling pathway mediated by interleukin (IL)-4 and IL-13 contributes to type 2 inflammatory responses and plays an important role in the pathogenesis of AD. IL-31 is a cytokine mainly produced by activated T cells and is known to be involved in the pruritus of AD. Biologics for AD have been approved, including dupilumab, an anti-IL-4 receptor α antibody that was approved for expanded use in AD in 2018. In 2022, nemolizumab, an anti-IL-31 receptor α antibody, was approved for pruritus of AD, and tralokinumab, an anti-IL-13 antibody, was approved for AD. Physicians who intend to use these drugs should sufficiently understand and comply with the contents of the guidelines prepared by the Japanese Ministry of Health, Labour, and Welfare to promote the optimal use of the drugs. In treatment with biologics, it is important to consider disease factors (activity and severity), treatment factors (dosage and administration as well as the efficacy and safety), and patients' background characteristics (age and comorbidities) and share this information with patients when choosing treatment options. This guidance was developed for board-certified dermatologists who specialize in treating AD, and for promoting the proper use of biologics, taking into account the variety of factors in individual patients.

A single-blind, randomized, crossover study on the efficacy of icatibant for sweating-induced dermal pain (icatibant for sweating-induced dermal pain).

INTRODUCTION: Severe dermal pain triggered by sweating stimuli, such as bathing, exercise, and mental stress, significantly affects patients' daily lives. The pathomechanism underlying the sweating-induced dermal pain remains poorly understood and there exists no standard treatment for such pain. This study aims to evaluate the effectiveness of icatibant as an analgesic, a bradykinin B2 receptor antagonist, in treating sweating-induced dermal pain, and to establish the role of bradykinin in pain induction. METHODS/DESIGN: A multicenter, exploratory, crossover, single-blinded, placebo-controlled randomized, comparative study will be conducted to evaluate the efficacy of subcutaneous icatibant injection (30 mg) in treating sweating-induced dermal pain. Ten patients will be enrolled and assigned randomly in a 1:1 ratio to either the icatibant-placebo or placebo-icatibant groups. The primary endpoint is the change in the visual analog scale scores for dermal pain induced by thermal load before and after treatment with icatibant or placebo. Secondary endpoints include changes in the duration of dermal pain, blood and plasma histamine levels, serum angiotensin-converting enzyme levels, and histological evaluation of skin tissue samples at the site of dermal pain. DISCUSSION: The effectiveness of icatibant against sweating-induced dermal pain would provide clear evidence for the involvement of the bradykinin-bradykinin B2 receptor pathway in the pathogenesis of this condition. This finding may contribute to a better understanding of the underlying mechanisms of dermal pain associated with sweating stimuli and has the potential to improve patients' quality of life by suggesting potential treatment options, specifically, using drugs that inhibit bradykinin or suppress its production.

Basophil Characteristics as a Marker of the Pathogenesis of Chronic Spontaneous Urticaria in Relation to the Coagulation and Complement Systems.

Chronic spontaneous urticaria (CSU) is a common skin disorder characterized by daily or almost daily recurring skin edema and flare with itch and pruritus anywhere on the body for more than 6 weeks. Although basophil- and mast cell-released inflammatory mediators, such as histamine, play important roles in the pathogenesis of CSU, the detailed underlying mechanism is not clear. Since several auto-antibodies, IgGs which recognize IgE or the high-affinity IgE receptor (FcεRI) and IgEs against other self-antigens, are detected in CSU patients, they are considered to activate both mast cells in the skin and basophils circulating in the blood. In addition, we and other groups demonstrated that the coagulation and complement system also contribute to the development of urticaria. Here, we summarized the behaviors, markers and targets of basophils in relation to the coagulation-complement system, and for the treatment of CSU.

Safety, efficacy, and pharmacokinetics of icatibant treatment in Japanese pediatric patients with hereditary angioedema: A phase 3, open-label study.

We evaluated the safety, efficacy, and pharmacokinetics of subcutaneous weight-adjusted icatibant for the treatment of acute hereditary angioedema attacks in Japanese pediatric patients. Two patients (aged 10-13 and 6-9 years) received icatibant for a total of four attacks. Each attack was abdominal and/or cutaneous and was treated with a single icatibant injection. Mild or moderate injection-site reactions were the only adverse events reported. Time to onset of symptom relief was 0.9-1.0 h. Icatibant was rapidly absorbed, with a pharmacokinetic profile consistent with previous studies. Simulated exposure levels were consistent with non-Japanese pediatric patients. These results support the safety and efficacy of icatibant in Japanese pediatric patients.

The expression of prolyl isomerase Pin1 is expanded in the skin of patients with atopic dermatitis and facilitates IL-33 expression in HaCaT cells.

Atopic dermatitis (AD) is attributable to both a genetic predisposition and environmental factors. Among numerous cytokines involved in the pathogenesis of AD, interleukin-33 (IL-33), reportedly escaping exocytotically in response to a scratch, is abundantly expressed in the skin tissues of patients with AD and is postulated to induce inflammatory and autoimmune responses. In this study, we first demonstrated that peptidylprolyl cis/trans isomerase, NIMA-interacting 1 (Pin1), a unique enzyme which isomerizes the proline residues of target proteins, is abundantly expressed in keratinocytes, and that the areas where it is present in the skin tissues of AD patients became expanded due to hyperkeratosis. Thus, we investigated the effects of Pin1 on the regulation of IL-33 expression using the human keratinocyte cell line HaCaT. Interestingly, silencing of the Pin1 gene or treatment with Pin1 inhibitors dramatically reduced IL-33 expressions in HaCaT cells, although Pin1 overexpression did not elevate it. Subsequently, we showed that Pin1 binds to STAT1 and the nuclear factor-kappaB (NF-κB) subunit p65. Silencing the Pin1 gene with small interfering RNAs significantly reduced the phosphorylation of p65, while no marked effects of Pin1 on the STAT1 pathway were detected. Thus, it is likely that Pin1 contributes to increased expression of IL-33 via the NF-κB subunit p65 in HaCaT cells, at least modestly. Nevertheless, further study is necessary to demonstrate the pathogenic roles of Pin1 and IL-33 in AD development.

Burden of illness seen in hereditary angioedema in Japanese patients: Results from a patient reported outcome survey.

Hereditary angioedema (HAE) is a potentially life-threatening rare disease, which is mainly caused by the deficiency or dysfunction of C1-esterase inhibitor, and characterized by spontaneous, recurrent episodes of edema in various parts of the body including internal organs and the laryngeal area. Delayed diagnosis and treatment increase the burdens and risks of this condition. The current study aimed to understand the burden of illness for HAE patients in Japan before and after diagnosis through a patient reported outcome survey. A survey instrument was distributed to 121 adult patients with HAE by a patient organization via HAE treating physicians between July and November in 2016. Seventy patients (57.9%) returned the questionnaire. Patients reported high levels of medical resource utilization, including emergency procedures and services. Episodes of receiving laparotomy were somewhat less after diagnosis with HAE than before, but no apparent difference in episodes of tracheotomy between before and after the diagnosis. The economic burden, including direct and indirect medical costs, was highest before diagnosis, but still perceived as substantial after diagnosis. Patients reported disruption of work and school life, with 40% reporting that they miss 10 or more days from work or education per year. Sixty percent of patients reported that HAE affected their daily activities. We concluded that HAE is associated with considerable physical, social, economic and psycho-social burdens even after diagnosis, and that higher attack frequency is associated with a heavy disease burden for patients in Japan.

Efficacy, pharmacokinetics, and safety of subcutaneous C1-esterase inhibitor as prophylaxis in Japanese patients with hereditary angioedema: Results of a Phase 3 study.

BACKGROUND: Hereditary angioedema (HAE) is a rare and potentially life-threatening genetic disorder characterized by recurrent attacks of angioedema. HAE types I and II result from deficient or dysfunctional C1-esterase inhibitor (C1-INH). This Phase 3 study assessed the efficacy, pharmacokinetics (PK), and safety of subcutaneous (SC) C1-INH in Japanese patients with HAE. METHODS: The prospective, open-label, multicenter, single-arm Phase 3 study recruited patients with HAE types I or II to an initial run-in period, followed by a 16-week treatment period where patients received 60 IU/kg C1-INH (SC) twice weekly. The two primary endpoints were the time-normalized number of HAE attacks per month and C1-INH functional activity at Week 16. RESULTS: Nine patients entered the treatment period and completed the study. Treatment with C1-INH (SC) significantly reduced the mean monthly attack rate from 3.7 during the run-in period to 0.3 during treatment (exploratory p value of within-patient comparison = 0.004). After the last dose of C1-INH (SC) at Week 16, the mean trough concentration of C1-INH was 59.8%, and the mean area under the plasma concentration-time curve to the end of the dosing period and to the last sample were 5317.1 and 13,091.5 h•%, respectively. During the study, there were no deaths, serious adverse events, or adverse events leading to study discontinuation. CONCLUSIONS: C1-INH (SC) (60 IU/kg twice weekly) was efficacious and well tolerated as a prophylaxis against HAE attacks in Japanese patients with HAE types I or II, which was supported by the increased and maintained C1-INH functional activity. EudraCT Number 2019-003921-99; JapicCTI-205273.