Publications by authors named "Atsushi Fukunaga"

125 Publications

Genome-wide association study reveals an association between the HLA-DPB102:01:02 allele and wheat-dependent exercise-induced anaphylaxis.

Am J Hum Genet 2021 Jul 10. Epub 2021 Jul 10.

Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan. Electronic address:

Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a life-threatening food allergy triggered by wheat in combination with the second factor such as exercise. The identification of potential genetic risk factors for this allergy might help high-risk individuals before consuming wheat-containing food. We aimed to identify genetic variants associated with WDEIA. A genome-wide association study was conducted in a discovery set of 77 individuals with WDEIA and 924 control subjects via three genetic models. The associations were confirmed in a replication set of 91 affected individuals and 435 control individuals. Summary statistics from the combined set were analyzed by meta-analysis with a random-effect model. In the discovery set, a locus on chromosome 6, rs9277630, was associated with WDEIA in the dominant model (OR = 3.95 [95% CI, 2.31-6.73], p = 7.87 × 10). The HLA-DPB102:01:02 allele displayed the most significant association with WDEIA (OR = 4.51 [95% CI, 2.66-7.63], p = 2.28 × 10), as determined via HLA imputation following targeted sequencing. The association of the allele with WDEIA was confirmed in replication samples (OR = 3.82 [95% CI, 2.33-6.26], p = 3.03 × 10). A meta-analysis performed in the combined set revealed that the HLA-DPB102:01:02 allele was significantly associated with an increased risk of WDEIA (OR = 4.13 [95% CI, 2.89-5.93], p = 1.06 × 10). Individuals carrying the HLA-DPB102:01:02 allele have a significantly increased risk of WDEIA. Further validation of these findings in independent multiethnic cohorts is needed.
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http://dx.doi.org/10.1016/j.ajhg.2021.06.017DOI Listing
July 2021

X-chromosome inactivation patterns in females with Fabry disease examined by both ultra-deep RNA sequencing and methylation-dependent assay.

Clin Exp Nephrol 2021 Jun 14. Epub 2021 Jun 14.

Department of Nephrology, Kobe University Graduate School of Medicine, Kobe, Japan.

Background: Fabry disease is an X-linked inherited lysosomal storage disorder caused by mutations in the gene encoding α-galactosidase A. Males are usually severely affected, while females have a wide range of disease severity. This variability has been assumed to be derived from organ-dependent skewed X-chromosome inactivation (XCI) patterns in each female patient. Previous studies examined this correlation using the classical methylation-dependent method; however, conflicting results were obtained. This study was established to ascertain the existence of skewed XCI in nine females with heterozygous pathogenic variants in the GLA gene and its relationship to the phenotypes.

Methods: We present five female patients from one family and four individual female patients with Fabry disease. In all cases, heterozygous pathogenic variants in the GLA gene were detected. The X-chromosome inactivation patterns in peripheral blood leukocytes and cells of urine sediment were determined by both classical methylation-dependent HUMARA assay and ultra-deep RNA sequencing. Fabry Stabilization Index was used to determine the clinical severity.

Results: Skewed XCI resulting in predominant inactivation of the normal allele was observed only in one individual case with low ⍺-galactosidase A activity. In the remaining cases, no skewing was observed, even in the case with the highest total severity score (99.2%).

Conclusion: We conclude that skewed XCI could not explain the severity of female Fabry disease and is not the main factor in the onset of various clinical symptoms in females with Fabry disease.
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http://dx.doi.org/10.1007/s10157-021-02099-4DOI Listing
June 2021

A validation study of the Japanese version of the Angioedema Activity Score (AAS) and the Angioedema Quality of Life Questionnaire (AE-QoL).

Allergol Int 2021 May 19. Epub 2021 May 19.

Department of Dermatology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. Electronic address:

Background: Recurrent angioedema (RecAE) has a substantial impact on patients' daily lives. However, there have been no disease-specific patient-reported outcomes (PROs) available in Japan to measure disease activity and health-related QoL impairment in such patients.

Methods: Japanese versions of the Angioedema Activity Score (AAS) and the Angioedema Quality of Life Questionnaire (AE-QoL) were examined for their validity and reliability. By using these questionnaires, the relationship between disease activity and QoL impairment among the Japanese population of RecAE were analyzed in real-world setting.

Results: The Japanese AAS and AE-QoL domains showed good internal consistency of 0.967 and > 0.835. For known group validity, AAS28 and AE-QoL total scores were higher in more severe patients than those with milder disease and QoL impairment, respectively. AAS28 showed strong correlation with indexes of disease activity, while the AE-QoL total score correlated with Dermatology Life Quality Index (DLQI). Sufficient reproductivity of the AAS and AE-QoL was shown by their intraclass correlation coefficients of 0.890 and 0.700. The Japanese population is characterized by the total score of AAS28, 34.3 ± 38.8 (mean ± SD); and AE-QoL, 38.7 ± 25.2. Each domain score of AE-QoL was 32.4 ± 29.7 in "Functioning", 35.0 ± 27.8 in "Fatigue/mood", 50.7 ± 30.6 in "Fears/shame", or 24.7 ± 29.8 in "Food". Changes in AAS28 and AE-QoL positively correlated to Patient global assessment of disease activity and DLQI, respectively.

Conclusions: The Japanese AAS and AE-QoL are valid and reliable instruments for Japanese patients with RecAE, and active disease affecting QoL. They help assess disease activity and QoL of RecAE in routine patient care and clinical trials.
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http://dx.doi.org/10.1016/j.alit.2021.04.006DOI Listing
May 2021

Activated steady status and distinctive FcεRI-mediated responsiveness in basophils of atopic dermatitis.

Allergol Int 2021 Jul 2;70(3):327-334. Epub 2021 Mar 2.

Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Kobe, Japan.

Background: Although basophils are considered to play an important role for maintenance of type 2 inflammation in atopic dermatitis (AD), studies on basophils in AD patients are limited. Some studies have reported the activation status, including CD203c and CD63, of peripheral blood basophils in AD patients.

Methods: We examined the features of circulating basophils in AD patients, assessed cell surface marker expressions and total serum IgE, and compared basophil responsiveness to stimulation between AD patients and healthy controls (HCs). In addition, the correlations among AD severity, laboratory factors, and features of basophils were examined. Blood samples from 38 AD patients and 21 HCs were analyzed. Basophil response markers CD203c and CD63, and expression of surface-bound IgE and FcεRI on basophils were measured. CD203c and CD63 expressions induced by stimulation with anti-IgE and anti-FcεRI antibodies were measured. Clinical/laboratory factors including total serum IgE were examined for correlations with these basophil parameters.

Results: Baseline CD203c and CD63 expression on basophils were significantly higher in AD patients compared with HCs. The CD203c/CD63 response ratio to anti-FcεRI stimulation was higher than that to anti-IgE stimulation in AD patients, but not HCs. FcεRI expression on basophils was higher in AD patients than in HCs, although surface-bound IgE on basophils was equivalent. Total serum IgE had negative correlations with surface-bound IgE and CD63 responsiveness to anti-IgE stimulation.

Conclusions: Basophils were spontaneously activated under steady-state conditions in AD patients and responsiveness to anti-IgE stimulation was lower than in HCs. Despite high serum IgE and high basophil FcεRI expression, surface-bound IgE on basophils remained relatively low. Basophils might be suppressed or exhausted regarding FcεRI signaling via IgE in severe AD.
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http://dx.doi.org/10.1016/j.alit.2021.01.005DOI Listing
July 2021

Multicenter 1-month follow-up study of the patch-test reaction to the gold sodium thiosulfate of the TRUE Test and its association with piercings and dental metal history.

Contact Dermatitis 2021 Mar 3. Epub 2021 Mar 3.

Japanese Contact Dermatitis Research Group, Nagoya, Japan.

Background: There is controversy over late and long-lasting reactions to gold sodium thiosulfate (GST).

Objectives: To study the GST patch-test reaction by observing the application site after 1 month, and to clarify the relevance of GST sensitization by piercings and dental metals.

Patients: A retrospective analysis was performed on 746 patients (143 male; 603 female) who were patch tested using GST of the TRUE Test. We conducted a questionnaire on the presence of piercings or dental metals in these patients.

Results: The GST positive rate was 27.9% at day (D)3 and/or D7 and 40.3% up to the 1-month reading. The positive rate was significantly higher in female patients and increased with age. Sixty-two percent of cases with a positive reaction at D7 continued to show a positive reaction after 1 month. Eleven percent of cases with a negative reaction at D3 and D7 showed a late reaction. Both piercings and dental metals were related to gold sensitization.

Conclusions: The GST of the TRUE Test had a high positive and low false-negative rate. The 1-month reading after the patch test was important for identifying late reactions. Piercing history and dental metal were associated with gold sensitization.
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http://dx.doi.org/10.1111/cod.13827DOI Listing
March 2021

Survey of actual conditions of erythema marginatum as a prodromal symptom in Japanese patients with hereditary angioedema.

World Allergy Organ J 2021 Feb 6;14(2):100511. Epub 2021 Feb 6.

Department of Nephrology, Internal Medicine, Saiyu Soka Hospital, Soka City, Saitama, Japan.

Background: Hereditary angioedema (HAE) is a rare but life-threatening condition. HAE types I and II (HAE-1/2) result from C1-inhibitor (C1-INH) deficiency. However, recent genetic analysis has established a new type of HAE with normal C1-INH (HAEnC1-INH). The mutations of factor XII, plasminogen, angiopoietin 1, and kininogen 1 genes may be the cause of HAEnC1-INH. Nevertheless, other causative molecules (HAE-unknown) may be involved. The Japanese therapeutic environment for HAE has been improving owing to the self-subcutaneous injection of icatibant, which was approved for the treatment of acute attack and enables early therapy. Erythema marginatum (EM) is a visible prodromal symptom which occasionally occurs prior to an angioedema attack; hence, recognizing the risk of an acute attack is important for early treatment. However, the detailed characteristics of EM remain unclear. In this study, we first investigated the clinical manifestations of EM in Japanese patients with HAE.

Methods: A 20-point survey was developed and distributed to 40 physicians to gather clinical data on EM from patients with HAE.

Results: Data on 68 patients with HAE (58 patients with HAE-1/2 and 10 patients with HAE-unknown) were collected. Of the patients with HAE-1/2, 53.4% experienced EM, whereas 43.1% did not. The forearm was the most frequent area of EM (64.5%), followed by the abdomen (29.0%) and upper arm and precordium (19.3%). Of the HAE-1/2 patients with EM, 41.9% always had angioedema following EM, while 29.0% always had colocalization of EM with angioedema. Moreover, 3.2% showed a correlation between the awareness of EM and severity of an angioedema attack. In 60.9% of HAE-1/2 patients with EM, the interval between the awareness of EM and appearance of angioedema was <3 h. Of the patients with HAE-unknown, 30.0% also experienced EM.

Conclusion: We confirmed that more than one-half of Japanese patients with HAE-1/2 and one-third of those with HAE-unknown develop EM as the prodromal symptom of an angioedema attack. Physicians should communicate the significance of EM to patients with HAE to prepare them for possible imminent attacks.
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http://dx.doi.org/10.1016/j.waojou.2021.100511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872976PMC
February 2021

Appropriate indication and procedure for random skin biopsy in the diagnosis of intravascular large B-cell lymphoma.

Australas J Dermatol 2021 May 18;62(2):225-227. Epub 2020 Dec 18.

Department of Dermatology, Kobe City Medical Centre General Hospital, Kobe, Japan.

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http://dx.doi.org/10.1111/ajd.13487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246572PMC
May 2021

The global impact of the COVID-19 pandemic on the management and course of chronic urticaria.

Allergy 2021 03 29;76(3):816-830. Epub 2020 Dec 29.

Urticaria Center of Reference and Excellence (UCARE), Department of Dermatology and Venereology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.

Introduction: The COVID-19 pandemic dramatically disrupts health care around the globe. The impact of the pandemic on chronic urticaria (CU) and its management are largely unknown.

Aim: To understand how CU patients are affected by the COVID-19 pandemic; how specialists alter CU patient management; and the course of CU in patients with COVID-19.

Materials And Methods: Our cross-sectional, international, questionnaire-based, multicenter UCARE COVID-CU study assessed the impact of the pandemic on patient consultations, remote treatment, changes in medications, and clinical consequences.

Results: The COVID-19 pandemic severely impairs CU patient care, with less than 50% of the weekly numbers of patients treated as compared to before the pandemic. Reduced patient referrals and clinic hours were the major reasons. Almost half of responding UCARE physicians were involved in COVID-19 patient care, which negatively impacted on the care of urticaria patients. The rate of face-to-face consultations decreased by 62%, from 90% to less than half, whereas the rate of remote consultations increased by more than 600%, from one in 10 to more than two thirds. Cyclosporine and systemic corticosteroids, but not antihistamines or omalizumab, are used less during the pandemic. CU does not affect the course of COVID-19, but COVID-19 results in CU exacerbation in one of three patients, with higher rates in patients with severe COVID-19.

Conclusions: The COVID-19 pandemic brings major changes and challenges for CU patients and their physicians. The long-term consequences of these changes, especially the increased use of remote consultations, require careful evaluation.
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http://dx.doi.org/10.1111/all.14687DOI Listing
March 2021

The diagnosis and treatment of hereditary angioedema patients in Japan: A patient reported outcome survey.

Allergol Int 2021 Apr 6;70(2):235-243. Epub 2020 Nov 6.

Department of Dermatology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; HAEJ Registered NPO, Japan. Electronic address:

Background: The rate at which patients are accurately diagnosed with hereditary angioedema (HAE), as well as diagnosed patients access to modern treatments differs greatly among countries. Moreover, the severity and burden of HAE on patients have been reported mostly on the basis of physician-reported surveys. To gain insight into the real-world conditions of patients with HAE through a patient-reported survey in Japan and identify any unmet needs.

Methods: A questionnaire was distributed to 121 patients with HAE via a Japanese HAE patient organization during 2016-2017. Responses were collected from 70 patients (57.9%) and subjected to analysis.

Results: The average periods from the initial appearance of symptoms (e.g. edema) to a HAE diagnosis was 15.6 years (min-max, 0-53). Patients visited an average of 4.6 different departments until receiving a definitive diagnosis. The average age at the first visit was 25.6 years (3-73) and at diagnosis 32.8 years (0-73). Patients reported an average of 15.7 (0-100) attacks per year, but only 53.1% of attacks were treated. The days of hospitalization due to severe attacks was 14.3 (0-200) before diagnosis, but these declined to 4.3 (0-50) after diagnosis. In the treatment for attacks, 82% of the patients were treated with the plasma-derived C1 inhibitor concentrate, and 69% of the patients reported experiencing a therapeutic effect.

Conclusions: There is a long gap between first attack and diagnosis of HAE, and the number of non-treated attacks is high in Japan. Steps are needed to improve the diagnostic and treatment environments to address these issues.
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http://dx.doi.org/10.1016/j.alit.2020.09.008DOI Listing
April 2021

Progress in the mechanism and targeted drug therapy for COPD.

Signal Transduct Target Ther 2020 10 27;5(1):248. Epub 2020 Oct 27.

Department of Basic Medicine, Medical College, Shaoxing University, Shaoxing, 312000, China.

Chronic obstructive pulmonary disease (COPD) is emphysema and/or chronic bronchitis characterised by long-term breathing problems and poor airflow. The prevalence of COPD has increased over the last decade and the drugs most commonly used to treat it, such as glucocorticoids and bronchodilators, have significant therapeutic effects; however, they also cause side effects, including infection and immunosuppression. Here we reviewed the pathogenesis and progression of COPD and elaborated on the effects and mechanisms of newly developed molecular targeted COPD therapeutic drugs. Among these new drugs, we focussed on thioredoxin (Trx). Trx effectively prevents the progression of COPD by regulating redox status and protease/anti-protease balance, blocking the NF-κB and MAPK signalling pathways, suppressing the activation and migration of inflammatory cells and the production of cytokines, inhibiting the synthesis and the activation of adhesion factors and growth factors, and controlling the cAMP-PKA and PI3K/Akt signalling pathways. The mechanism by which Trx affects COPD is different from glucocorticoid-based mechanisms which regulate the inflammatory reaction in association with suppressing immune responses. In addition, Trx also improves the insensitivity of COPD to steroids by inhibiting the production and internalisation of macrophage migration inhibitory factor (MIF). Taken together, these findings suggest that Trx may be the ideal drug for treating COPD.
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http://dx.doi.org/10.1038/s41392-020-00345-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588592PMC
October 2020

Management of hereditary angioedema in Japan: Focus on icatibant for the treatment of acute attacks.

Allergol Int 2021 Jan 9;70(1):45-54. Epub 2020 Sep 9.

Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Hyogo, Japan.

Hereditary angioedema (HAE) is characterized by unpredictable, recurring and painful swelling episodes that can be disabling or even life-threatening. Awareness of HAE has progressively grown worldwide, and options for treatment of acute attacks and prevention of future attacks continue to expand; however, unmet needs in diagnosis and treatment remain. In Japan, recognition of HAE within the medical community remains low, and numerous obstacles complicate diagnosis and access to treatment. Importance of timely treatment of HAE attacks with on-demand therapies is continually demonstrated; recommended agents per the WAO/EAACI treatment guidelines published in 2018 include C1 inhibitor (C1-INH) concentrate, ecallantide, and icatibant. In Japan, multiple factors contribute to delayed HAE treatment (potentially leading to life-threatening consequences), including difficulties in finding facilities at which C1-INH agents are readily available. Recognition of challenges faced in Japan can help promote efforts to address current needs and expand access to effective therapies. Icatibant, a potent, selective bradykinin B receptor antagonist, has demonstrated inhibition of various bradykinin-induced biological effects in preclinical studies and has shown efficacy in treating attacks in various clinical settings (e.g. clinical trials, real-world studies), and HAE patient populations (e.g. with C1-INH deficiency, normal C1-INH). Icatibant was approved in Japan for the treatment of HAE attacks in September 2018; its addition to the HAE treatment armamentarium contributes to improved patient care. In Japan, disease awareness and education campaigns are warranted to further advance the management of HAE patients in light of the unmet needs and the emerging availability of modern diagnostic approaches and therapies.
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http://dx.doi.org/10.1016/j.alit.2020.07.008DOI Listing
January 2021

Improved FcεRI-Mediated CD203c Basophil Responsiveness Reflects Rapid Responses to Omalizumab in Chronic Spontaneous Urticaria.

J Allergy Clin Immunol Pract 2021 03 6;9(3):1166-1176.e8. Epub 2020 Sep 6.

Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Kobe, Japan.

Background: Omalizumab is effective in patients with chronic spontaneous urticaria (CSU) although its mechanism of action is poorly understood. Several studies reported that decreased high-affinity IgE receptor (FcεRI)-mediated histamine release and/or responsiveness was characteristic of basophils in patients with CSU. However, few studies have focused on the relationship between changes in basophil responsiveness via FcεRI after omalizumab treatment and the therapeutic effect in patients with CSU.

Objective: To assess basophil responsiveness via FcεRI stimulation, as well as FcεRI expression and IgE binding on blood basophils from patients with CSU before and after omalizumab treatment and its possible association with the clinical response.

Methods: We analyzed 34 patients with CSU treated with omalizumab who were categorized as fast responders (FRs) (n = 20) and non or slow responders (N/SRs) (n = 14). CD203c expression induced by FcεRI stimulation, and IgE and FcεRI expressions on blood basophils from patients with CSU before and after omalizumab treatment were analyzed. Basophil responsiveness via FcεRI stimulation was observed in vitro using basophils pretreated with omalizumab.

Results: FRs had increased CD203c responsiveness after treatment with omalizumab compared with N/SRs. This improvement of basophil responsiveness via FcεRI stimulation in FRs was not observed in peripheral blood basophils preincubated with omalizumab in vitro, suggesting that omalizumab does not directly affect circulating pre-existing abnormal basophils.

Conclusion: Increased basophil responsiveness via FcεRI after omalizumab treatment is associated with the therapeutic effect and mechanism of action of omalizumab.
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http://dx.doi.org/10.1016/j.jaip.2020.08.048DOI Listing
March 2021

Acquired idiopathic partial anhidrosis successfully treated with adapalene gel.

J Dermatol 2020 Sep 22;47(9):e314-e315. Epub 2020 Jun 22.

Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Kobe, Japan.

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http://dx.doi.org/10.1111/1346-8138.15474DOI Listing
September 2020

Occupational respiratory allergy to lettuce in lettuce farmers.

Clin Exp Allergy 2020 08 1;50(8):932-941. Epub 2020 Jul 1.

Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.

Background: Lettuce-associated respiratory allergy has never been reported before. The aim of this study was to clarify the clinical condition of lettuce-associated respiratory allergy and to identify the lettuce antigen which induces allergic symptoms.

Methods: We distributed questionnaires to 1168 lettuce farmers and performed medical examinations in those who exhibited respiratory symptoms related to occupational exposure to lettuce. We analysed specific IgE-binding proteins in the sera of patients through immunoblotting analysis and determined molecular characterization of the IgE-binding bands using liquid chromatography-mass spectrometry.

Results: A total of 932 farmers (80%) responded to the questionnaire. Of those, 7% exhibited lettuce-associated respiratory symptoms, during harvesting and packaging. Thirteen patients were diagnosed with allergy to lettuce and agreed to undergo further examinations. The percentage of activated basophils in these patients was significantly higher compared with that reported in negative controls (P < .05). Lettuce-specific IgE (ImmunoCAP ) and skin prick testing was positive in 46% and 62% of patients, respectively. Notably, occupational lettuce-allergic asthma was detected in one patient through specific bronchial provocation testing. The IgE-binding bands recognized in the sera of >50% of patients were identified as epidermis-specific secreted glycoprotein EP1-like (51 kDa).

Conclusion: The present analysis identified a novel lettuce allergen. This allergen may have clinically useful applications, such as specific IgE testing and allergen-specific immunotherapy.
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http://dx.doi.org/10.1111/cea.13682DOI Listing
August 2020

High prevalence of epilepsy in HAE with normal C1-INH.

Allergol Int 2020 Oct 19;69(4):630-632. Epub 2020 May 19.

Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Kobe, Japan.

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http://dx.doi.org/10.1016/j.alit.2020.04.008DOI Listing
October 2020

[EFFICACY, PHARMACOKINETICS, PHARMACODYNAMICS, AND SAFETY OF INTRAVENOUS C1 INHIBITOR FOR LONG-TERM PROPHYLAXIS AND TREATMENT OF BREAKTHROUGH ATTACKS IN JAPANESE SUBJECTS WITH HEREDITARY ANGIOEDEMA: A PHASE 3 OPEN-LABEL STUDY].

Arerugi 2020 ;69(3):192-203

Department of Dermatology, Graduate School of Biomedical and Health Sciences, Hiroshima University.

Background: Hereditary angioedema (HAE) is associated with recurrent, painful, and potentially lifethreatening attacks characterized by swelling of subcutaneous or submucosal tissues.

Purpose: To investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of repeat-use C1 inhibitor (C1-INH) replacement therapy for long-term prophylaxis and treatment of breakthrough attacks in the management of Japanese patients with HAE type I or II.

Methods: An open-label, single-arm, Phase 3 study was conducted in Japanese patients with HAE (NCT02865720). For patients 6 years of age or older, 1000U were administered biweekly (by a healthcare professional or self-administered) via intravenous infusion.

Results: In 8 enrolled patients, the mean number of attacks normalized per month was lower during C1-INH treatment than during the 3 months prior (1.826 vs. 3.375). Clinically meaningful mean change from baseline in the angioedema-quality of life (AE-QoL) total score was shown during treatment with C1-INH. Pharmacokinetic data showed markedly higher and enduring post-baseline plasma levels of C1-INH functional activity and C1-INH antigen concentration, starting from 0.5h after first dose of C1-INH and lasting up to 72 hours. C1-INH was well tolerated with no new safety signals identified in this population of Japanese patients with HAE.

Conclusion: C1-INH was effective for long-term prophylaxis and treatment of breakthrough attacks with favourable safety profile in Japanese patients with HAE.
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http://dx.doi.org/10.15036/arerugi.69.192DOI Listing
August 2020

Establishment of the basophil activation test to detect photoallergens in solar urticaria.

J Allergy Clin Immunol Pract 2020 09 26;8(8):2817-2819.e1. Epub 2020 Apr 26.

Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Kusunoki-cho, Chuo-ku, Kobe, Japan.

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http://dx.doi.org/10.1016/j.jaip.2020.04.042DOI Listing
September 2020

Reply.

J Allergy Clin Immunol Pract 2020 02;8(2):826-827

Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan.

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http://dx.doi.org/10.1016/j.jaip.2019.11.033DOI Listing
February 2020

Hepatitis B Virus Reactivation after Receiving Cancer Chemotherapy under Administration of Leuprorelin Acetate.

Intern Med 2020 May 17;59(9):1163-1166. Epub 2020 Jan 17.

Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan.

An 88-year-old man was admitted for elevated liver enzyme levels. Nine years earlier, the patient had been diagnosed with diffuse large B-cell lymphoma (DLBCL) and undergone rituximab, cyclophosphamide, doxorubicin hydrochloride, oncovin, prednisone (R-CHOP) therapy. This patient previously had had a hepatitis B virus (HBV) infection before chemotherapy. After the chemotherapy, he was administered an luteinizing hormone-releasing hormone (LHRH) agonist for prostate cancer. We diagnosed him with HBV reactivation because of positive serum HBV-DNA. HBV reactivation can occur a long time after chemotherapy, particularly if another treatment with immunity-altering drugs is added. In such cases, additional surveillance may be required to detect HBV reactivation.
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http://dx.doi.org/10.2169/internalmedicine.3805-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270765PMC
May 2020

Efficacy of switching to bilastine, a histamine H1 receptor antagonist, in patients with chronic spontaneous urticaria (H1-SWITCH): study protocol for a randomized controlled trial.

Trials 2020 Jan 6;21(1):23. Epub 2020 Jan 6.

Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.

Background: Chronic spontaneous urticaria (CSU) is characterized by the spontaneous appearance of wheals, angioedema, or both for > 6 weeks. Continuous treatment with H1-antihistamines is used as a first-line treatment for CSU. However, H1-antihistamine treatment leads to absence of symptoms in less than 50% of patients with CSU. Although Japanese guidelines for the diagnosis and treatment of urticaria recommend an increase in the H1-antihistamine dose or a switch to other H1-antihistamines, there is no evidence supporting a switch to other H1-antihistamines in patients with refractory CSU who are unresponsive to H1-antihistamines at the licensed dose.

Methods: We will conduct a multicenter, open-label, non-inferiority, randomized, parallel, comparison study to determine if the efficacy of bilastine 20 mg is not inferior to that of a twofold H1-antihistamine dose increase in patients with refractory CSU who are unresponsive to H1-antihistamines at the licensed dose. This study will be performed at 15 academic hospitals in Japan, and the administration period (increasing the H1-antihistamine dose twofold vs. switching to bilastine 20 mg) will be 7 days. Participants (n = 150) will be randomized to either an increased H1-antihistamine dose or a switch to bilastine 20 mg at a 1:1 ratio. The primary endpoint, mean of the total symptom score of 5-7 days after the intervention, will be evaluated. The secondary objective is to determine if the safety of bilastine 20 mg regarding somnolence is superior to that of a twofold dose increase of H1-antihistamines. This will be measured by a change in the Japanese version of the Epworth Sleepiness Scale from baseline to 7 days after starting the intervention.

Discussion: This multicenter, open-label, non-inferiority, randomized, parallel, comparison study will be, to our knowledge, the first well-designed clinical study to evaluate the efficacy of a switch to other H1-antihistamines in patients with refractory CSU who are unresponsive to H1-antihistamines at the licensed doses. This trial will provide evidence of the efficacy and safety of bilastine when treatment is switched in patients with refractory CSU who are unresponsive to H1-antihistamines at the licensed dose.

Trial Registration: Japan Registry of Clinical Trials (jRCT), jRCTs051180105. Registered on 8 March 2019.
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http://dx.doi.org/10.1186/s13063-019-3878-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945582PMC
January 2020

Anti-Allergic and Anti-Inflammatory Effects and Molecular Mechanisms of Thioredoxin on Respiratory System Diseases.

Antioxid Redox Signal 2020 04 28;32(11):785-801. Epub 2020 Jan 28.

Department of Basic Medicine, Medical College, Shaoxing University, Shaoxing, China.

The pathogenesis and progression of allergic inflammation in the respiratory system are closely linked to oxidative stress. Thioredoxin (TRX) is an essential redox balance regulator in organisms and is induced by various oxidative stress factors, including ultraviolet rays, radiation, oxidation, viral infections, ischemia reperfusion, and anticancer agents. We demonstrated that systemic administration and transgenic overexpression of TRX is useful in a wide variety of inflammatory respiratory diseases models, such as viral pneumonia, interstitial lung disease, chronic obstructive pulmonary disease, asthma, acute respiratory distress syndrome, and obstructive sleep apnea syndrome, by removing reactive oxygen species, blocking production of inflammatory cytokines, inhibiting migration and activation of neutrophils and eosinophils, and regulating the cellular redox status. In addition, TRX's anti-inflammatory mechanism is different from the mechanisms associated with anti-inflammatory agents, such as glucocorticoids, which regulate the inflammatory reaction in association with suppressing immune responses. Understanding the molecular mechanism of TRX is very helpful for understanding the role of TRX in respiratory diseases. In this review, we show the protective effect of TRX in various respiratory diseases. In addition, we discuss its anti-allergic and anti-inflammatory molecular mechanism in detail. The application of TRX may be useful for treating respiratory allergic inflammatory disorders. . 32, 785-801.
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http://dx.doi.org/10.1089/ars.2019.7807DOI Listing
April 2020

[JAPANESE GUIDELINES FOR DIAGNOSIS AND TREATMENT OF URTICARIA 2018].

Authors:
Atsushi Fukunaga

Arerugi 2019;68(10):1181-1187

Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine.

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http://dx.doi.org/10.15036/arerugi.68.1181DOI Listing
December 2019

Real-world clinical practices for spontaneous urticaria and angioedema in Japan: A nation-wide cross-sectional web questionnaire survey.

Allergol Int 2020 Apr 8;69(2):300-303. Epub 2019 Nov 8.

Department of Dermatology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.alit.2019.10.003DOI Listing
April 2020

Structural and Functional Basis for LILRB Immune Checkpoint Receptor Recognition of HLA-G Isoforms.

J Immunol 2019 12 6;203(12):3386-3394. Epub 2019 Nov 6.

Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan;

Human leukocyte Ig-like receptors (LILR) LILRB1 and LILRB2 are immune checkpoint receptors that regulate a wide range of physiological responses by binding to diverse ligands, including HLA-G. HLA-G is exclusively expressed in the placenta, some immunoregulatory cells, and tumors and has several unique isoforms. However, the recognition of HLA-G isoforms by LILRs is poorly understood. In this study, we characterized LILR binding to the β2-microglobulin (β2m)-free HLA-G1 isoform, which is synthesized by placental trophoblast cells and tends to dimerize and multimerize. The multimerized β2m-free HLA-G1 dimer lacked detectable affinity for LILRB1, but bound strongly to LILRB2. We also determined the crystal structure of the LILRB1 and HLA-G1 complex, which adopted the typical structure of a classical HLA class I complex. LILRB1 exhibits flexible binding modes with the α3 domain, but maintains tight contacts with β2m, thus accounting for β2m-dependent binding. Notably, both LILRB1 and B2 are oriented at suitable angles to permit efficient signaling upon complex formation with HLA-G1 dimers. These structural and functional features of ligand recognition by LILRs provide novel insights into their important roles in the biological regulations.
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http://dx.doi.org/10.4049/jimmunol.1900562DOI Listing
December 2019

Long-term dynamics of omega-5 gliadin-specific IgE levels in patients with adult-onset wheat allergy.

J Allergy Clin Immunol Pract 2020 03 31;8(3):1149-1151.e3. Epub 2019 Oct 31.

Department of Dermatology, Shimane University Faculty of Medicine, Shimane, Japan.

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http://dx.doi.org/10.1016/j.jaip.2019.10.008DOI Listing
March 2020

Efficacy, pharmacokinetics, and safety of icatibant for the treatment of Japanese patients with an acute attack of hereditary angioedema: A phase 3 open-label study.

Allergol Int 2020 Apr 28;69(2):268-273. Epub 2019 Oct 28.

Department of Palliative Care Internal Medicine, Niigata City General Hospital, Niigata, Japan.

Background: Hereditary angioedema (HAE) is a genetic disease characterized by recurrent swelling episodes affecting the skin, gastrointestinal mucosa, and upper respiratory tract.

Methods: A phase 3, single-arm, open-label study was performed to evaluate a selective bradykinin B receptor antagonist, icatibant, for the treatment of acute attacks in Japanese patients with HAE Type I or II. After the onset of an acute attack, icatibant 30 mg was administered by the patient or a healthcare professional via subcutaneous injection in the abdomen.

Results: Eight patients who had an attack affecting the skin (n = 4), abdomen (n = 3), or larynx (n = 1) were treated with icatibant (3 of the injections were self-administered). The median time to onset of symptom relief was 1.75 h (95% confidence interval, 1.00-2.50), and all patients had symptom relief within 5 h after administration. The time to maximum plasma concentration of icatibant was 1.79 h, and the maximum plasma concentration was 405 ng/ml. Seven patients experienced an injection site reaction, and 3 patients had adverse events (2 patients had a worsening or repeat HAE attack 29.0 and 18.3 h after icatibant administration, respectively, and 1 had headache).

Conclusions: Although the number of patients is small, the efficacy and tolerability of icatibant for acute attacks were demonstrated in Japanese patients with HAE, regardless of self-administration or administration by healthcare professional.
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http://dx.doi.org/10.1016/j.alit.2019.08.012DOI Listing
April 2020

Clinical utility of the basophil activation test in the diagnosis of sweat allergy.

Allergol Int 2020 Apr 12;69(2):261-267. Epub 2019 Oct 12.

Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Kobe, Japan.

Background: Many patients with atopic dermatitis and cholinergic urticaria display an immediate-type allergy to autologous sweat. Although the histamine release test (HRT) using semi-purified sweat antigen (QR) was available for the detection of immediate sweat allergy, the existence of HRT low responders could not be disregarded. Furthermore, it has not been established whether the results of the HRT are consistent with the autologous sweat skin test (ASwST). We aimed to compare the HRT and basophil activation test (BAT) for the diagnosis of immediate sweat allergy.

Methods: The HRT and BAT were performed on 47 subjects (35 ASwST positive, 12 negative) whose symptoms had worsened on sweating. For the BAT, blood was incubated with QR or crude sweat and CD203c upregulation was assessed. A commercial HRT was performed and histamine release induced by QR was quantified.

Results: When excluding non-responders for anti-IgE antibody, the BAT using QR and the HRT had a sensitivity of 100% and 44% and specificity of 75% and 100%, respectively. The BAT and HRT had a positive predictive value of 91.3% and 100% and negative predictive value of 100% and 30%, respectively. The BAT detected 0% non-responders, whereas the HRT identified 22.5%. When using crude sweat for the BAT, the false-positives observed when using QR were not detected.

Conclusions: The BAT using QR displayed a higher sensitivity and negative predictive value and a lower number of non-responders compared with the HRT. Furthermore, the BAT using crude sweat can also be an alternative tool for the ASwST.
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http://dx.doi.org/10.1016/j.alit.2019.09.003DOI Listing
April 2020

HLA-DQ and RBFOX1 as susceptibility genes for an outbreak of hydrolyzed wheat allergy.

J Allergy Clin Immunol 2019 11 10;144(5):1354-1363. Epub 2019 Jul 10.

Department of Dermatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Background: Food allergy is a growing health problem worldwide because of its increasing prevalence, life-threatening potential, and shortage of effective preventive treatments. In an outbreak of wheat allergy in Japan, thousands of patients had allergic reactions to wheat after using soap containing hydrolyzed wheat protein (HWP).

Objectives: The aim of the present study was to investigate genetic variation that can contribute to susceptibility to HWP allergy.

Methods: We conducted a genome-wide association study of HWP allergy in 452 cases and 2700 control subjects using 6.6 million genotyped or imputed single nucleotide polymorphisms. Replication was assessed by genotyping single nucleotide polymorphisms in independent samples comprising 45 patients with HWP allergy and 326 control subjects.

Results: Through the genome-wide association study, we identified significant associations with the class II HLA region on 6p21 (P = 2.16 × 10 for rs9271588 and P = 2.96 × 10 for HLA-DQα1 amino acid position 34) and with the RBFOX1 locus at 16p13 (rs74575857, P = 8.4 × 10). The associations were also confirmed in the replication data set. Both amino acid polymorphisms (HLA-DQβ1 amino acid positions 13 and 26) located in the P4 binding pockets on the HLA-DQ molecule achieved the genome-wide significance level (P < 5.0 × 10).

Conclusions: Our data provide the first demonstration of genetic risk for HWP allergy and show that this genetic risk is mainly represented by multiple combinations of HLA variants.
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http://dx.doi.org/10.1016/j.jaci.2019.06.034DOI Listing
November 2019

IL28B gene polymorphism is correlated with changes in low-density lipoprotein cholesterol levels after clearance of hepatitis C virus using direct-acting antiviral treatment.

J Gastroenterol Hepatol 2019 Nov 21;34(11):2019-2027. Epub 2019 Jun 21.

Department of Gastroenterology, Fukuoka University Faculty of Medicine, Fukuoka, Japan.

Background: Direct-acting antivirals (DAAs) rapidly clear hepatitis C virus (HCV), but the lipid dynamics after DAA treatment remain unknown. Low-density lipoprotein (LDL) cholesterolemia is the predicting factor for the onset and death of atherosclerotic cardiovascular diseases. Thus, in this study, we examined the frequency and risk of hyper-LDL cholesterolemia in HCV patients who achieved sustained virologic response (SVR) with DAA treatment.

Methods: A total of 121 patients with HCV genotype 1b, who achieved SVR with DAA treatment, were examined for serum levels of total cholesterol, LDL-cholesterol (LDL-C), high-density lipoprotein, and triglycerides from the start of treatment until 2 years after SVR (SVR-2y). ΔLDL-C was defined as the change in LDL-C levels from treatment initiation to SVR-2y. Hyper-LDL cholesterolemia was defined as ≥ 140 mg/dL LDL-C at SVR-2y. Stepwise multiple regression analysis was performed to determine whether ΔLDL-C and hyper-LDL cholesterolemia are associated with other factors, including viral kinetics.

Results: A total of 63, 3, and 55 patients were administered daclatasvir + asunaprevir, ombitasvir + paritaprevir + ritonavir, and ledipasvir + sofosbuvir, respectively. ΔLDL-C in patients with the IL28B (rs8099917) TG/GG genotype was significantly higher than in those with IL28B TT (27.3 ± 27.0 and 9.6 ± 27.3 mg/dL; P < 0.001). In addition, IL28B TG/GG was an independent risk factor for hyper-LDL cholesterolemia (odds ratio: 8.47; P < 0.001).

Conclusions: An IL28B polymorphism is associated with ΔLDL-C and hyper-LDL cholesterolemia after achieving SVR. Thus, lipid markers should be carefully monitored in patients who achieve SVR with DAA.
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http://dx.doi.org/10.1111/jgh.14741DOI Listing
November 2019
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