峠岡 理沙

Ikaros, which is encoded by the Ikaros family zinc finger 1 (IKZF1) gene, is a zinc finger transcription factor. We have previously generated K5-Ikzf1-EGFP transgenic mice (Ikzf1 Tg) by introducing the IKZF1 isoform into epithelial cells expressing keratin 5, which develop patchy alopecia. However, there has been no detailed in vivo investigation of the function of IKZF1 in alopecia or of Ikaros expression in hair follicles of alopecia patients. Our aim was to investigate whether IKZF1 overexpression is involved in the pathogenesis of alopecia areata (AA) using Ikzf1 Tg and to examine Ikaros expression in human scalp skin. We grossly and histologically examined the alopecic lesions of Ikzf1 Tg and the skin of wild-type (WT) mice and the associated mRNA expression of inflammatory mediators. We also examined Ikaros' expression in human scalp skin. Grossly and histologically, we found that the Ikzf1 Tg developed AA-like lesions. Immunohistochemically, the hair follicles of the Ikzf1 Tg expressed high levels of the NKG2D ligand H60 and contained infiltrating CD8+NKG2D+ T cells. Interleukin 15, tumour necrosis factor-α, CXC chemokine ligand (Cxcl)1, Cxcl10, Cxcl11, signal transducer and activator of transcription (STAT)1, STAT3, Janus kinase (JAK)1 and JAK3 mRNA expression were significantly higher in the alopecic lesions of the Ikzf1 Tg than in the WT mice. Ikzf1 Tg given corticosteroid injections exhibited hair regrowth. Immunohistochemical analysis of scalp hair follicles showed that Ikaros was more highly expressed in AA patients than in non-AA controls. Our study suggests that IKZF1 and Ikaros are involved in the pathogenesis of AA.

Atopic dermatitis (AD) is a common skin disease. Although AD pathogenesis has been widely researched, inhibitory mechanisms in AD are still unclear. Sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of receptors recognising sialic acids; most Siglecs work as inhibitory receptors. Among Siglecs, Siglec-E is expressed on dendritic cells (DCs) and eosinophils, important immune cells in AD. Although Siglec-E inhibits Type 1 inflammatory diseases, how it influences AD is unknown. Thus, we investigated the role of Siglec-E in AD mouse model by using Siglec-E knockout (KO) mice. We demonstrated that Siglec-E attenuated AD-like inflammation of mice caused by topical application of MC903 on ear skin (MC903-induced AD). To reveal the role of Siglec-E in MC903-induced AD, we focused on Siglec-E on DCs and eosinophils. We first showed that Sigle-E was expressed on cutaneous DCs and migratory DCs of draining lymph nodes. Moreover, OX40L expression on cutaneous DCs was reduced in the presence of Siglec-E. In vitro experiments using cultured spleen DCs (SpDCs), highly expressing Siglec-E, revealed that IL-33 was involved in the induction of Siglec-E and confirmed that Siglec-E inhibited OX40L expression on SpDCs induced by IL-33. Moreover, CD4+ T cell-SpDC coculture revealed that Siglec-E inhibited Th2 polarisation under IL-33 stimulation. We finally revealed that Siglec-E was expressed on eosinophils and reduced the eosinophils infiltration to the MC903-treated ear skin with the suppression of CD49d, a necessary integrin for eosinophil migration to skin tissue [1], expression on eosinophils. These findings elucidated the inhibitory role of Siglec-E in MC903-induced AD.

BACKGROUND: Atopic dermatitis (AD) is a common chronic eczematous skin disease with severe pruritus. Several new therapeutic agents for AD such as dupilumab, an anti-IL-4Rα antibody, have been developed in recent years. We need to predict which agent is the best choice for each patient, but this remains difficult. OBJECTIVE: Our aim was to examine clinical background factors and baseline biomarkers that could predict the achievement of improved clinical outcomes in patients with AD treated with dupilumab. METHODS: A multicenter, prospective observational study was conducted on 110 patients with AD. The Eczema Area and Severity Index was used as an objective assessment, and the Patient-Oriented Eczema Measure and Numerical Rating Scale for Pruritus were used as patient-reported outcomes. In addition, some clinical background factors were evaluated. RESULTS: The achievement of an absolute Eczema Area and Severity Index of 7 or less was negatively associated with current comorbidity of food allergy and baseline serum lactate dehydrogenase (LDH) levels. There were negative associations between achievement of a Patient-Oriented Eczema Measure score of 7 or less and duration of severe AD and between achievement of an itching Numerical Rating Scale for Pruritus score of 1 or less and current comorbidity of allergic conjunctivitis or baseline serum periostin level. Furthermore, signal detection analysis showed that a baseline serum LDH level less than 328 U/L could potentially be used as a cutoff value for predicting the efficacy of dupilumab. CONCLUSION: Baseline biomarkers such as LDH and periostin and clinical background factors such as current comorbidity of food allergy and a long period of severe disease may be useful indicators when choosing dupilumab for systemic treatment for AD, as they can predict the efficacy of dupilumab.

Platelet-activating factor (PAF) is an important chemical mediator in the field of inflammation, but its function in the skin is unclear. To unravel the role of PAF, we focused on lysophosphatidylcholine acyltransferase 2 (LPCAT2 also called LPLAT9), a biosynthetic enzyme involved in PAF production, and investigated the role of PAF in allergic contact dermatitis (ACD) and irritant contact dermatitis (ICD). We measured the amount of PAF in the skin and investigated the ear swelling responses and leukocyte infiltration into the skin following the application of 2,4,6-trinitro-1-chlorobenzene (TNCB) or croton oil in wild-type (WT) and LPCAT2 knockout (LPCAT2-KO) mice. The amount of PAF was increased in the skin of WT mice after TNCB or croton oil application but not detected in LPCAT2-KO mice. The ear swelling response was decreased in LPCAT2-KO mice compared with that in WT mice. In the ACD model, the numbers of lymphocytes, eosinophils, macrophages, mast cells and neutrophils were smaller in LPCAT2-KO mice than in WT mice. In the ICD model, the ear swelling response was also decreased in LPCAT2-KO mice compared with that in WT mice. When double staining of each inflammatory cell type and LPCAT2 was performed in ACD tissue, marked co-staining of the eosinophil marker and LPCAT2 was observed. In addition, LPCAT2 expression was observed in the epidermis. These results indicate that PAF is involved in the infiltration of several cell types into the sites of allergic and non-allergic skin inflammation. Furthermore, eosinophils and keratinocytes are primarily responsible for PAF production in skin inflammation.

BACKGROUND: To develop precision medicine for atopic dermatitis (AD), it is critical to establish relevant biomarkers. However, the characteristics of various biomarkers have not been fully understood. We previously carried out the Biomarkers to Predict Clinical Improvement of AD in Patients Treated with Dupilumab (B-PAD) study, a comprehensive nationwide study in Japan, to explore biomarkers for AD. OBJECTIVE: The aim of this study is to find biomarkers associated with objective and subjective clinical findings in patients with moderate-to-severe AD based on the B-PAD study and to identify biomarkers sensitive enough to assess the severity of AD. METHODS: We performed the B-PAD study as a consortium composed of 19 medical facilities in Japan, enrolling 110 patients with moderate-to-severe AD. We evaluated the Eczema Area and Severity Index (EASI) for objective assessment as well as the Patient-Oriented Eczema Measure (POEM) and a numeric rating scale for pruritus (pruritis-NRS) for subjective assessment, measuring 19 biomarkers at baseline. RESULTS: We found that 12, 6, and 7 biomarkers showed significant and positive associations with the EASI, POEM, and pruritis-NRS, respectively. Most of the biomarkers associated with either the POEM or the pruritis-NRS were included among the biomarkers associated with EASI. Of the biomarkers examined, CCL26/eotaxin-3 and SCCA2 were the most capable of assessing severity for EASI, as shown by the 2 kinds of receiver operating characteristic analyses, respectively, whereas lactate dehydrogenase was the best for both the POEM and pruritis-NRS, again using the 2 analyses. CONCLUSION: We found biomarkers associated with the EASI, POEM, and pruritis-NRS, respectively, based on the B-PAD study. Moreover, we identified CCL26/eotaxin-3 and/or SCCA2 as the biomarkers having the greatest ability to assess severity in the EASI; lactate dehydrogenase did the same for the POEM and pruritis-NRS. These findings will be useful in treating patients with moderate-to-severe AD.

PURPOSE: To clarify the importance of administering topical steroids for the treatment of Stevens-Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN) with ocular involvement in the acute phase. DESIGN: Retrospective case series. METHODS: Using the medical records of acute SJS/TEN patients treated at the Kyoto Prefectural University of Medicine Hospital, Kyoto, Japan, between July 2006 and July 2017, the ocular findings, topical steroid dosage, systemic steroid dosage, and ocular sequelae were retrospectively examined. The level of cytokines in tear fluid and serum samples was also analyzed. RESULTS: This study involved 13 cases. In 10 cases in whom the clinical courses were recorded before the start of steroid therapy, the mean acute ocular severity score (AOSS: 3 = very severe; 2 = severe; 1 = mild; 0 = none) was 2.8 ± 0.4 points in the severest phase. The mean systemic steroid dose after steroid pulse therapy was 694 ± 386 mg and the mean topical steroid (0.1% betamethasone eye drop and ointment) dose was 13.4 ± 3.3 times daily in the severest phase. Analysis of cytokine levels of 4 cases showed that a cytokine storm occurred in the tear fluid after the steroid pulse therapy. At final follow-up, 16 eyes of 8 patients had a logMAR visual acuity of ≤0, and no serious ocular sequelae were observed. CONCLUSIONS: In patients with SJS/TEN, ocular surface inflammation remains strong even after systemic inflammation has improved post steroid pulse therapy, thus suggesting that both systemic and topical steroid therapy should be administered appropriately.

BACKGROUND: Early-onset atopic dermatitis is a strong risk factor for food allergy, suggesting that early effective treatment may prevent transcutaneous sensitization. OBJECTIVES: This study tested whether enhanced treatment of atopic dermatitis to clinically affected and unaffected skin is more effective in preventing hen's egg allergy than reactive treatment to clinically affected skin only. METHODS: This was a multicenter, parallel-group, open-label, assessor-blind, randomized controlled trial (PACI [Prevention of Allergy via Cutaneous Intervention] study). This study enrolled infants 7-13 weeks old with atopic dermatitis and randomly assigned infants in a 1:1 ratio to enhanced early skin treatment or conventional reactive treatment using topical corticosteroids (TCSs). The primary outcome was the proportion of immediate hen's egg allergy confirmed by oral food challenge at 28 weeks of age. RESULTS: This study enrolled 650 infants and analyzed 640 infants (enhanced [n = 318] or conventional [n = 322] treatment). Enhanced treatment significantly reduced hen's egg allergy compared with the conventional treatment (31.4% vs 41.9%, P = .0028; risk difference: -10.5%, upper bound of a 1-sided CI: -3.0%), while it lowered body weight (mean difference: -422 g, 95% CI: -553 to -292 g) and height (mean difference: -0.8 cm, 95% CI: -1.22 to -0.33 cm) at 28 weeks of age. CONCLUSIONS: This study highlighted the potential of well-controlled atopic dermatitis management as a component of a hen's egg allergy prevention strategy. The enhanced treatment protocol of this trial should be modified before it can be considered as an approach to prevent hen's egg allergy in daily practice to avoid the adverse effects of TCSs. After remission induction by TCSs, maintenance therapy with lower potency TCSs or other topical therapies might be considered as alternative proactive treatments to overcome the safety concerns of TCSs.

IMPORTANCE: Quality of life (QOL) of patients with atopic dermatitis (AD) is reported to be the lowest among skin diseases. To our knowledge, mindfulness and self-compassion training has not been evaluated for adults with AD. OBJECTIVE: To evaluate the efficacy of mindfulness and self-compassion training in improving the QOL for adults with AD. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial conducted from March 2019 through October 2022 included adults with AD whose Dermatology Life Quality Index (DLQI) score, a skin disease-specific QOL measure, was greater than 6 (corresponding to moderate or greater impairment). Participants were recruited from multiple outpatient institutes in Japan and through the study's social media outlets and website. INTERVENTIONS: Participants were randomized 1:1 to receive eight 90-minute weekly group sessions of online mindfulness and self-compassion training or to a waiting list. Both groups were allowed to receive any dermatologic treatment except dupilumab. MAIN OUTCOMES AND MEASURES: The primary outcome was the change in the DLQI score from baseline to week 13. Secondary outcomes included eczema severity, itch- and scratching-related visual analog scales, self-compassion and all of its subscales, mindfulness, psychological symptoms, and participants' adherence to dermatologist-advised treatments. RESULTS: The study randomized 107 adults to the intervention group (n = 56) or the waiting list (n = 51). The overall participant mean (SD) age was 36.3 (10.5) years, 85 (79.4%) were women, and the mean (SD) AD duration was 26.6 (11.7) years. Among participants from the intervention group, 55 (98.2%) attended 6 or more of the 8 sessions, and 105 of all participants (98.1%) completed the assessment at 13 weeks. The intervention group demonstrated greater improvement in the DLQI score at 13 weeks (between-group difference estimate, -6.34; 95% CI, -8.27 to -4.41; P < .001). The standardized effect size (Cohen d) at 13 weeks was -1.06 (95% CI, -1.39 to -0.74). All secondary outcomes showed greater improvements in the intervention group than in the waiting list group. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of adults with AD, integrated online mindfulness and self-compassion training in addition to usual care resulted in greater improvement in skin disease-specific QOL and other patient-reported outcomes, including eczema severity. These findings suggest that mindfulness and self-compassion training is an effective treatment option for adults with AD. TRIAL REGISTRATION: https://umin.ac.jp/ctr Identifier: UMIN000036277.

The skin functions as a physical barrier and represents the first line of the innate immune system. There is increasing evidence that toll-like receptors (TLRs) are involved in the pathomechanisms of not only infectious diseases, but also non-infectious inflammatory diseases. Interestingly, it has been demonstrated that TLRs recognize both exogenous threats, e.g. bacteria and viruses, and endogenous danger signals related to inflammation, cell necrosis, or tissue damage. Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease, which is associated with impaired skin barrier function, increased skin irritability to non-specific stimuli, and percutaneous sensitization. The impairment of skin barrier function in AD allows various stimuli, such as potential allergens and pathogens, to penetrate the skin and activate the innate immune system, including TLR signaling, which can lead to the development of adaptive immune reactions. In this review, I summarize the current understanding of the roles of TLR signaling in the pathogenesis of AD, with special emphasis on skin barrier function and inflammation.

BACKGROUND: The pathogenesis of atopic dermatitis (AD) involves various mediators, including cytokines and chemokines, which are produced by immune cells, such as dendritic cells and lymphocytes, and non-immune cells, such as epidermal cells. Several mediators, including thymus and activation-regulated chemokine (TARC), are used as biomarkers for AD severity and activity. However, additional local and systemic biomarkers of AD are required. METHODS: This study will include 10 male patients with AD and 5 healthy adult males (age range: 20-80 years). The Eczema Area and Severity Index will be used to objectively evaluate the clinical findings. In addition, the severity of eruptions will be assessed on a 5-point scale by scoring symptoms (erythema, edema/papules, oozing/crusting, excoriation, lichenification, and xerosis), and the total intensity will be calculated by adding the symptom scores together. Subjective symptoms will be assessed using a peak pruritus numerical rating scale. Laboratory tests, including measurements of peripheral eosinophil count and serum total immunoglobulin E, TARC, and lactate dehydrogenase levels, will be performed. Using blood samples and extracts of stratum corneum samples obtained by tape stripping, we will conduct an exploratory analysis of protein expression using an antibody array to identify mediators whose levels are significantly altered in patients with AD. After 4 to 8 weeks, blood samples and stratum corneum samples will be collected again from AD patients. Moreover, we will examine whether the candidate proteins can be quantified using enzyme-linked immunosorbent assays. DISCUSSION: This is an important study exploring potential local and systemic biomarkers of AD. The results of this study will be clinically meaningful for the discovery of new biomarkers for diagnosing and assessing the severity of AD.

BACKGROUND: Platelets are involved in the pathomechanisms of atopic dermatitis (AD). This study aimed to elucidate the levels of platelet-related miRNAs, (miR-24 and miR-191) in the plasma of AD patients and their relationships with the disease severity and laboratory data. METHODS: miRNAs were detected in the subjects plasma using specifically primed quantitative reverse transcription polymerase chain reaction. RESULTS: The patients with severe AD had significantly higher plasma miR-24 or miR-191 levels than the patients with mild AD, the urticaria patients, and the healthy volunteers. The plasma miR-24 and miR-191 levels of the AD patients were correlated with their serum thymus and activation-regulated chemokine levels. In addition, plasma miR-24 and miR-191 levels were correlated with their plasma levels of platelet factor 4 and β-thromboglobulin. CONCLUSION: Our findings imply that miR-24 and miR-191 may be involved in the pathomechanisms responsible for the worsening of AD, possibly through their effects on platelet activation.

BACKGROUND: The Japanese baseline series (JBS), established in 1994, was updated in 2008 and 2015. The JBS 2015 is a modification of the thin-layer rapid-use epicutaneous (TRUE) test (SmartPractice Denmark, Hillerød, Denmark). No nationwide studies concerning the TRUE test have previously been reported. OBJECTIVES: To determine the prevalence of sensitizations to JBS 2015 allergens from 2015 to 2018. METHODS: We investigated JBS 2015 patch test results using the web-registered Skin Safety Care Information Network (SSCI-Net) from April 2015 to March 2019. RESULTS: Patch test results of 5865 patients were registered from 63 facilities. The five allergens with the highest positivity rates were gold sodium thiosulfate (GST; 25.7%), nickel sulfate (24.5%), urushiol (9.1%), p-phenylenediamine (PPD; 8.9%), and cobalt chloride (8.4%). The five allergens with the lowest positivity rates were mercaptobenzothiazole (0.8%), formaldehyde (0.9%), paraben mix (1.1%), mercapto mix (1.1%), and PPD black rubber mix (1.4%). CONCLUSIONS: Nickel sulfate and GST had the highest positivity rates. The JBS 2015, including a modified TRUE test, is suitable for baseline series patch testing.

Background: We have hypothesized that different factors are involved in the severity of ACD and AD because some but not all patients with atopic dermatitis (AD) present with allergic conjunctival disease (ACD) including severe types such as atopic keratoconjunctivitis (AKC) with/without giant papillae. We previously reported that plasma miR-628-3p was up-regulated in AD with severe ACD, but not in severe AD without severe ACD or in our healthy controls. In this study, to investigate the pathogenesis of AD with and without severe ACD, we performed comprehensive plasma miRNA analysis and studied the function of some miRNAs which were significantly up-regulated in ACD. Methods: Transcriptomics analysis of miRNA was performed using the microarray platform from the plasma of nine individuals (AD, severe ACD, controls: n = 3 each). To confirm up-regulation of the 12 miRNAs of the eight miRNA groups we focused on, we performed quantitative miRNA polymerase chain reaction (PCR) assays using 80 plasma samples (AD: 23, severe ACD: 17, controls: 40). To study the function of the eight miRNAs which were significantly up-regulated in ACD, we transfected their mimic to THP-1 cells, a monocyte cell line, and performed comprehensive gene expression analysis of them. The up-regulation of gene expression of interest in transfected THP-1 cells with the hsa-let-7a-5p miRNA mimic was confirmed by quantitative RT-qPCR assay. Results: Quantitative miRNA PCR assays showed that hsa-let-7a-5p, hsa-let-7days-3p, hsa-let-7e-5p, and hsa-miR-151a-5p were significantly up-regulated in both AD-ACD + and AD-ACD - as were hsa-miR-130a-3p, hsa-miR-151a-3p, has-miR-27b-3p, and hsa-miR-146a-5p in AD-ACD + but not in AD-ACD - . The functions of each miRNA were investigated by comprehensive gene expression analysis of THP-1 cells transfected with each miRNA mimic. Of the eight miRNAs, hsa-let-7a-5p, hsa-let-7e-5p, has-miR-27b-3p, and hsa-miR-146a-5p mimic-transfected THP-1 cells showed the up-regulation of CXCL10 (IP-10; interferon gamma-induced protein 10), which might be one of the innate immune-related genes. Quantitative RT-qPCR assays of transfected THP-1 cells with the hsa-let-7a-5p miRNA mimic showed that the 17 genes up-regulated more than 10-fold in the comprehensive gene expression analysis, and TLR3, RIG-I, and MDA5, important innate immune-related genes, were significantly up-regulated. TNFSF13B, AIM2, USP41, STAP1, GBP4, CCL8, and IFI27, reportedly down-regulated by the hsa-miR-628-3p mimic, were also significantly up-regulated in the transfected cells. Conclusion: Hsa-let-7a-5p, which was significantly up-regulated in AD-ACD + and AD-ACD - , could positively regulate the important innate immune-related genes such as TLR3, RIG-I, and MDA5. It is possible that in an allergic disease such as atopic keratoconjunctivitis and/or dermatitis, innate immune responses might be positively regulated by hsa-let-7a-5p in the plasma.

Environmental light levels can affect physiological functions, such as general activity, body temperature and metabolism. Irregular lifestyles, such as those involving exposure to light during the night, can exacerbate the clinical symptoms of several inflammatory skin diseases. However, the effects of constant light exposure on immune responses are not fully understood. This study aimed to elucidate the effects of constant light exposure on two major types of skin reactions, allergic contact dermatitis (ACD) and irritant contact dermatitis (ICD). BALB/c mice were kept under constant light conditions or a normal light and dark cycle, and their ACD and ICD responses were assessed after the topical application of 2,4,6-trinitro-1-chlorobenzene and croton oil, respectively, to the ear skin. Interestingly, in both ACD and ICD, the ear-swelling response and local leukocyte infiltration were aggravated by constant exposure to light, which has previously been shown to severely disturb the behavioural rhythms of mice. In ACD, these findings were accompanied by increases in the numbers of degranulated mast cells and eosinophils. These results suggest that constant light exposure intensifies allergic and non-allergic skin inflammation.

BACKGROUND: A wide gender gap exists in many fields in Japan, including the academic society of dermatology. Women are substantially underrepresented in the highest academic ranks. OBJECTIVE: We aimed to clarify the possible factors contributing to the current gender gap in the field of academic dermatology and to recommend necessary measures to decrease the gender gap. METHODS: We performed a cross-sectional study of faculty members' academic productivity at the dermatology departments of all the educational institutions in Japan in 2019. RESULTS: Women had significantly lower academic productivity than men. A significant gender difference in academic productivity was found in lecturers and assistant professors but not in associate professor and professor positions. This gender difference was still significant after normalizing the productivity for career length. CONCLUSION: Our findings suggest the need to encourage women lecturers and assistant professors to improve their academic achievement to decrease the gender gap in academic dermatology.

The number of patients with metal allergies has increased recently, and patch testing is useful for investigating such patients. However, the efficacy of restoration removal in patients with oral metal allergies is disputed. This study aimed to investigate the relationships between oral symptoms and metal allergies. We conducted a retrospective analysis of 60 patients with oral symptoms. The most common oral symptom was an abnormal oral sensation. Thirty-eight percent of the patients exhibited positive allergic reactions to one or more metal. Nickel was the metal allergen that produced positive reactions most frequently. Of the seven patients whose restorations were removed, complete and partial remission were achieved in one and two patients, respectively. Interestingly, metal alloy removal was effective in 33% (n = 1) of the positive patch test group and 50% (n = 2) of the non-positive patch test group. Our results demonstrated the difficulty of predicting the efficacy of restoration removal at ameliorating oral metal allergies based on patch testing alone.

BACKGROUND: Atopic dermatitis (AD) is a common eczematous skin disorder that profoundly reduces the quality of life due to intractable pruritus. Excellent therapeutic success of the anti-interleukin 4 receptor-α antibody dupilumab in clinical trials and a real-world clinical context indicates the crucial roles of interleukin (IL)-4 and IL-13 in the pathogenesis of AD. Along with the clinical improvement in skin scores and pruritus, dupilumab significantly and progressively reduces and normalizes the upregulated expression of T helper type 2 signatures such as Chemokine (C-C motif) ligand (CCL)17, CCL18, CCL22, and CCL26 in the lesional skin of AD. However, no blood/serum biomarkers are known to predict good or poor outcome in patients with AD treated with dupilumab. METHODS: Patients are at least 18 years of age and have moderate-to-severe AD with Eczema Area and Severity Index (EASI) ≥16, Investigator's Global Assessment ≥3, and body surface area ≥10%. We are going to enroll more than 130 subjects from 18 medical facilities. Clinical objective findings will be evaluated by EASI. Subjective symptoms will be assessed by Patient-Oriented Eczema Measure, Numerical Rating Scale for Pruritus (Pruritus-NRS), Skin Comfort-NRS, and Treatment Satisfaction-NRS. We will measure 18 blood/serum biomarkers including % eosinophils in blood cell count, lactate dehydrogenase, total IgE, soluble interleukin 2 receptor, CCL17, CCL18, CCL22, CCL26, CCL27, IL-13, IL-22, IL-24, IL-25, IL-31, IL-33, thymic stromal lymphopoietin, periostin, and squamous cell carcinoma antigen-2. The clinical evaluation and biomarker sampling will be performed at 0, 2, 4, 8, and 16 weeks of dupilumab treatment. We will also perform proteomic analysis (of roughly 300 proteins) of the patients' sera obtained at 0 and 2 weeks of treatment. The primary endpoint is the association between "baseline levels of 18 biomarkers" and "% change from baseline of EASI at 16 weeks of dupilumab treatment." DISCUSSION: This is the first clinical trial to explore the biomarkers, including potential proteomic markers, most strongly associated with improvement in EASI in patients with moderate-to-severe AD treated with dupilumab for 16 weeks (B-PAD study). A limitation is that we will only enroll Japanese patients.

Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease, associated with impaired skin barrier function and an atopic background. Various complicating factors, such as irritants, aeroallergens, food, microbial organisms, contact allergens, sweat, and scratching can induce the development of AD symptoms. Irritants, including soap/shampoo and clothes, can cause itching and eczematous lesions. In addition, young children with AD tend to become sensitized to eggs, milk, or peanuts, while older children and adults more often become sensitized to environmental allergens, such as house dust mites (HDM), animal dander, or pollen. Serum-specific IgE levels and skin prick test reactions to food tend to show high negative predictive values and low specificity and positive predictive values for diagnosing food allergy. On the other hand, AD adult patients tend to have severe skin symptoms and exhibit high HDM-specific IgE levels. Microbial organisms, e.g., Staphylococcus aureus and Malassezia furfur, might contribute to the pathogenetic mechanisms of AD. While sweat plays a major role in maintaining skin homeostasis, it can become an aggravating factor in patients with AD. Furthermore, scratching often exacerbates eczematous lesions. Several patient-specific complicating factors are seen in most cases. The identification and management of complicating factors are important for controlling AD.

2019年10月5日，金沢市で開催された第70回日本皮膚科学会中部支部学術大会において，本学会キャリア支援委員会企画のワークショップが開催された．ワーキンググループ峠岡委員長のもとテーマを「未来設計図」として，講師を広島大学蓮沼ワーキンググループ委員が担当，ファリシリテータを各ワーキンググループ委員が担当し，従来のメンター＆メンティーの相談会とは趣を変え，皮膚科医がどのような目標をもってキャリアを積んでいくのがよいか漠然とした将来像を具体化し，明日からの行動につながるセミナーを企画したのでここに報告する．

Platelets have diverse roles in immune processes in addition to their key functions in haemostasis and thrombosis. Some studies imply that platelets may be possibly related to the immune tolerance induction. However, the role of platelets in the development of immune tolerance is not fully understood. The purpose of this study was to investigate the role of platelets in the development of regulatory mechanisms responsible for cutaneous inflammation using a mouse model of low zone tolerance (LZT). Mice were treated with 2,4,6-trinitro-1-chlorobenzene (TNCB) 8 times every other day for tolerance induction with administration of anti-platelet antibody or control antibody during the tolerance induction phase every 3 days. After the treatment for the tolerance induction, mice were sensitized and then challenged with TNCB. The contact hypersensitivity (CHS) was significantly decreased at 24 hours after challenge in the mice with LZT than in those without LZT. Platelet depletion via administration of anti-platelet antibody reversed the inhibition of CHS and reduced the frequency of Foxp3+ Tregs in the inflamed skin and draining lymph nodes in mice with LZT. In addition, repeated low-dose skin exposure resulted in elevated plasma levels of transforming growth factor (TGF)-β1. Interestingly, platelet depletion reduced plasma TGF-β1 levels of mice with LZT. Furthermore, the CHS response was reduced by administration of recombinant TGF-β1 during platelet depletion in mice with LZT. Administration of anti-TGF-β antibody reversed the inhibition of the CHS responses. These results suggest that platelets are involved in the induction of immune tolerance via the release of TGF-β1.