記述言語：英語   掲載種別：研究論文（学術雑誌）  

The plasma membrane protein caveolin-1 (CAV-1) regulates signaling by inhibiting a wide range of kinases and other enzymes. Our previous study demonstrated that the downregulation of CAV-1 in psoriatic epidermal cells contributes to inflammation by enhancing JAK/STAT signaling, cell proliferation, and chemokine production. Administration of the CAV-1 scaffolding domain (CSD) peptide suppressed imiquimod (IMQ)-induced psoriasis-like dermatitis. To identify an optimal therapeutic peptide derived from CAV-1, we have compared the efficacy of CSD and subregions of CSD that have been modified to make them water soluble. We refer to these modified peptides as sCSD, sA, sB, and sC. In IMQ-induced psoriasis-like dermatitis, while all four peptides showed major beneficial effects, sB caused the most significant improvements of skin phenotype and number of infiltrating cells, comparable or superior to the effects of sCSD. Phosphorylation of STAT3 was also inhibited by sB. Furthermore, sB suppressed angiogenesis both in vivo in the dermis of IMQ-induced psoriasis mice and in vitro by blocking the ability of conditioned media derived from CAV-1-silenced keratinocytes to inhibit tube formation by HUVEC. In conclusion, sB had similar or greater beneficial effects than sCSD not only by cytokine suppression but by angiogenesis inhibition adding to its ability to target psoriatic inflammation.

DOI： 10.1038/s41598-024-71350-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Palmoplantar pustulosis (PPP) is a chronic relapsing inflammatory skin disease characterized by multiple vesicles, pustules, and erythematous plaques on the palms and soles. The exacerbation of PPP is strongly associated with focal infections, such as tonsillitis, dental infections, and sinusitis, in Japan. Recently, the neutrophil-to-lymphocyte ratio (NLR) has been widely used as a convenient and useful marker for clinical conditions and various diseases; however, an association between PPP and NLR has not yet been established. We retrospectively analyzed 79 patients with PPP from our hospital to evaluate the clinical significance of the NLR. The average NLR value in patients with PPP was significantly higher than that in healthy controls (2.30 ± 1.02 vs 1.69 ± 0.45, P < 0.001). A comparative analysis of patients with PPP with and without infectious complications showed that there was a statistical difference in the NLR between patients with PPP with and without focal infections, whereas no significant difference was found for metal allergy, smoking, and pustulotic arthro-osteitis. Multivariate analysis indicated that the NLR was significantly associated with focal infections (odds ratio = 18.38, 95% confidence interval 3.86-87.35, P < 0.001). The NLR was also significantly correlated with C-reactive protein levels (P = 0.013, r = 0.2857). Interestingly, after symptom improvement, the NLR significantly decreased from the baseline levels. Furthermore, statistical analysis using the Youden's index revealed that an NLR of 2.28 or higher was associated with the risk of any focal infections in patients with PPP. These results suggest that the NLR has potential applications as a biomarker of the presence of focal infections in patients with PPP.

DOI： 10.1111/1346-8138.17272

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記述言語：日本語   出版者・発行元：(一社)日本臨床免疫学会  

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記述言語：日本語   出版者・発行元：(株)協和企画  

＜文献概要＞ポイント ●ヒドロキシクロロキン(HCQ)開始から3年後までの経過がフォローできた74例のエリテマトーデス患者において,HCQ投与を中止・減量した症例に注目して臨床的解析を行った.●74例中24例(32%)でHCQ投与が中止されており,投与開始から1ヵ月以内の中止理由は全例が副作用によるものであった.●HCQを1ヵ月以上投与後に中止もしくは減量された症例において,中止群では8例中5例で症状の増悪を認めたのに対して,減量群では3例全例で症状は増悪しなかった.●HCQの減量はクロロキン網膜症などの長期的な副作用のリスク軽減に有益である可能性がある一方で,HCQの中止は症状増悪リスクが高く慎重な判断が必要である.

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J01268&link_issn=&doc_id=20240529440017&doc_link_id=10.24733%2Fpd.0000003839&url=https%3A%2F%2Fdoi.org%2F10.24733%2Fpd.0000003839&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Anti-SS-A/Ro antibody (anti-SSA), the diagnostic marker of Sjögren's syndrome (SS), is often detected in systemic sclerosis (SSc). Some patients are diagnosed with SSc/SS overlap syndromes, while there are anti-SSA-positive SSc cases without SS. In this study, we investigated the clinical characteristics of SSc with anti-SSA and clarified the clinical impact of this antibody in SSc. METHODS: A retrospective chart review was conducted of 156 patients with SSc at Yokohama City University Hospital from 2018 to 2021. Clinical data, laboratory data, imaging, and autoantibody positivity status were collected and analysed to assess the association between these variables and anti-SSA using multivariable logistic regression analysis. RESULTS: This cohort included 18 men and 138 women with SSc (median age, 69.0 years). Thirty-nine patients had diffuse cutaneous SSc (dcSSc) (25%), and 117 patients had limited cutaneous SSc (75%). Forty-four patients were anti-SSA-positive. Among them, 24 fulfilled the SS criteria. Multivariable logistic regression revealed that anti-SSA was statistically associated with interstitial lung disease (ILD; odds ratio [OR] = 2.67; 95% confidence interval [CI], 1.14-6.3; P = 0.024). Meanwhile, anti-SSA positivity tended to increase the development of digital ulcer (OR = 2.18; 95% CI, 0.99-4.82, P = 0.054). In the comparative analysis of the autoantibody single-positive and anti-SSA/SSc-specific autoantibody double-positive groups, the anti-SSA single-positive group showed a significantly increased risk of ILD (OR = 12.1; 95% CI, 2.13-140.57; P = 0.003). Furthermore, patients with SSc and anti-SSA indicated that anti-SSA-positive SSc without SS was strongly associated with dcSSc when compared to that in patients with SS (OR = 6.45; 95% CI, 1.23-32.60; P = 0.024). CONCLUSIONS: Anti-SSA positivity increases the risk of organ involvement, such as ILD, in patients with SSc. Additionally, the anti-SSA-positive SSc without SS population may have more severe skin fibrosis than others. Anti-SSA may be a potential marker of ILD and skin severity in SSc.

DOI： 10.1186/s13075-024-03325-6

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jaad.2023.09.061

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Morphea is characterized by initial inflammation followed by fibrosis of the skin and soft tissue. Despite its substantial morbidity, the pathogenesis of morphea is poorly studied. Previous work showed that CXCR3 ligands CXCL9 and CXCL10 are highly upregulated in the sera and lesional skin of patients with morphea. We found that an early inflammatory subcutaneous bleomycin mouse model of dermal fibrosis mirrors the clinical, histological, and immune dysregulation observed in human morphea. We used this model to examine the role of the CXCR3 chemokine axis in the pathogenesis of cutaneous fibrosis. Using the REX3 (Reporting the Expression of CXCR3 ligands) mice, we characterized which cells produce CXCR3 ligands over time. We found that fibroblasts contribute the bulk of CXCL9-RFP and CXCL10-BFP by percentage, whereas macrophages produce high amounts on a per-cell basis. To determine whether these chemokines are mechanistically involved in pathogenesis, we treated Cxcl9-, Cxcl10-, or Cxcr3-deficient mice with bleomycin and found that fibrosis is dependent on CXCL9 and CXCR3. Addition of recombinant CXCL9 but not CXCL10 to cultured mouse fibroblasts induced Col1a1 mRNA expression, indicating that the chemokine itself contributes to fibrosis. Taken together, our studies provide evidence that CXCL9 and its receptor CXCR3 are functionally required for inflammatory fibrosis.

DOI： 10.1016/j.jid.2022.11.025

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Post-orgasmic illness syndrome (POIS) is a rare disease characterized by flu-like symptoms persisting for 2-7 days after ejaculation. POIS has been chiefly attributed to allergic reactions to autologous seminal plasma. However, the exact pathophysiology remains unclear, and there is no effective treatment. We present the case of a 38-year-old man with a 10-year history of recurrent episodes of flu-like symptoms of 1-week duration after ejaculation. The patient was diagnosed with irritating bowel syndrome because of fatigue, myalgia, and lateral abdominal pain. After starting infertility treatment and increasing the frequency of intercourse with his wife, the patient noticed these symptoms after ejaculation. Based on these episodes and symptoms, POIS was suspected. To diagnose POIS, a skin prick test and an intradermal test were performed using his seminal fluid, with the latter yielding a positive result. The patient was diagnosed with POIS, and treatment with antihistamines was continued. Due to its rarity, POIS is often underdiagnosed and underreported; however, the skin test can be a valid diagnostic tool. In this case, the intradermal test result was positive according to the broadly accepted criteria for POIS. Although quality of life is often severely affected in patients with POIS, a lack of a clear understanding of the pathogenesis of POIS prevents early diagnosis. To make diagnoses earlier, it is undoubtedly important to take a detailed medical history and perform skin allergy tests, although the latter requires further validation.

DOI： 10.1111/1346-8138.16762

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block key mediators of tumor-mediated immune evasion. The frequency of its use has increased rapidly and has extended to numerous cancers. ICIs target immune checkpoint molecules, such as programmed cell death protein 1 (PD-1), PD ligand 1 (PD-L1), and T cell activation, including cytotoxic T-lymphocyte-associated protein-4 (CTLA-4). However, ICI-driven alterations in the immune system can induce various immune-related adverse events (irAEs) that affect multiple organs. Among these, cutaneous irAEs are the most common and often the first to develop. Skin manifestations are characterized by a wide range of phenotypes, including maculopapular rash, psoriasiform eruption, lichen planus-like eruption, pruritus, vitiligo-like depigmentation, bullous diseases, alopecia, and Stevens-Johnson syndrome/toxic epidermal necrolysis. In terms of pathogenesis, the mechanism of cutaneous irAEs remains unclear. Still, several hypotheses have been proposed, including activation of T cells against common antigens in normal tissues and tumor cells, increased release of proinflammatory cytokines associated with immune-related effects in specific tissues/organs, association with specific human leukocyte antigen variants and organ-specific irAEs, and acceleration of concurrent medication-induced drug eruptions. Based on recent literature, this review provides an overview of each ICI-induced skin manifestation and epidemiology and focuses on the mechanisms underlying cutaneous irAEs.

DOI： 10.3389/fimmu.2023.1071983

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Enhanced circulating blood periostin levels positively correlate with disease severity in patients with systemic sclerosis (SSc). Monocytes/macrophages are predominantly associated with the pathogenesis of SSc, but the effect of periostin on immune cells, particularly monocytes and macrophages, still remains to be elucidated. We examined the effect of periostin on monocytes and monocyte-derived macrophages (MDM) in the pathogenesis of SSc. The modified Rodnan total skin thickness score in patients with dcSSc was positively correlated with the proportion of CD80-CD206+ M2 cells. The proportion of M2 macrophages was significantly reduced in rPn-stimulated MDMs of HCs compared to that of SSc patients. The mRNA expression of pro-fibrotic cytokines, chemokines, and ECM proteins was significantly upregulated in rPn-stimulated monocytes and MDMs as compared to that of control monocytes and MDMs. A similar trend was observed for protein expression in the respective MDMs. In addition, the ratio of migrated cells was significantly higher in rPn-stimulated as compared to control monocytes. These results suggest that periostin promotes inflammation and fibrosis in the pathogenesis of SSc by possible modulation of monocytes/macrophages.

DOI： 10.1371/journal.pone.0281881

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Toxic epidermal necrolysis (TEN) is a fatal cutaneous adverse reaction that occasionally affects multiple organs. Acute respiratory distress syndrome (ARDS) is a rare complication that can cause rapid and potentially fatal pulmonary dysfunction. However, the mechanisms underlying TEN-induced ARDS remain unknown. This retrospective single-center study aimed to identify potential biomarkers for predicting ARDS onset in TEN patients. Pre-treatment serum samples were collected from 16 TEN patients and 16 healthy controls (HCs). The serum levels of cytokines/chemokines were determined using the Luminex Assay Human Premixed Multi-analyte kit. The expression levels of cytokines and chemokines in the skin were examined via immunohistochemistry. The serum levels of C-C motif chemokine ligand 2 (CCL2), interleukin (IL)-6, and IL-8 were significantly higher in TEN patients with ARDS than in those without ARDS and in HCs, whereas those of CCL2 and IL-8 were not significantly different between TEN patients without ARDS and HCs. There was no significant difference in CCL2 and IL-8 expression in the skin between TEN patients with and without ARDS. Interestingly, there were no significant differences in the cytokine/chemokine levels between TEN and other organ damage, other than ARDS and TEN without any organ damage. We further analyzed the changes in cytokine/chemokine levels before and after treatment in two TEN patients with ARDS. CCL2, IL-6, and IL-8 levels decreased after systemic treatment compared to their baseline levels before treatment at an early stage. These results suggest that IL-8 and CCL2 may be involved in the pathogenesis of TEN-induced ARDS and have potential application as predictive markers for ARDS onset.

DOI： 10.1111/1346-8138.16647

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Psoriasis is a systemic, chronic, immunologically-mediated disease affecting approximately 2%-4% of the worldwide population. It is well known that psoriasis is associated with several comorbidities such as metabolic syndrome, cardiovascular disease, and malignancy. Although meta-analyses and large prospective cohort studies have shown an increased risk of malignancies in patients with psoriasis worldwide, an association between psoriasis and malignancy onset has not yet been established in Japan. We retrospectively analyzed 360 patients with psoriasis at our hospital to evaluate the incidence and types of malignancies in these patients. The incidence rate of malignancy was 14.4% (52/360). Colorectal cancer was the most commonly associated malignancy (20.9%), followed by skin cancer (16.4%), gastric cancer (10.4%), and lung cancer (10.4%). The calculated age- and sex-standardized incidence ratio of malignancies was 1.235 (95% CI 0.952-1.601) which indicated that the malignancy rate was higher in patients with psoriasis than in the general population, although the difference was not statistically significant. Furthermore, the multivariate analysis revealed increased risk of malignancy in males (HR = 3.15; 95% CI 1.381-7.187; p < 0.001), psoriasis onset at older age (HR = 1.08; 95% CI 1.058-1.111; p < 0.01), and psoriatic erythroderma (HR = 4.44; 95% CI 1.354-14.581; p < 0.05). We also observed that treatment with biological agents tends to reduce the risk of developing malignancy; however, no statistical significance was found. These results suggest that periodic screening for malignancy should be recommended in patients with psoriasis having these risk factors and in those with poorly controlled psoriatic inflammation.

DOI： 10.1111/1346-8138.16644

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Organ fibrosis, particularly of the lungs, causes significant morbidity and mortality. Effective treatments are needed to reduce the health burden. A fragment of the carboxyl-terminal end of collagen XVIII/endostatin reduces skin and lung fibrosis. This fragment was modified to facilitate its production in plants, which resulted in the recombinant fusion protein, END55. We found that expression of END55 had significant anti-fibrotic effects on the treatment and prevention of skin and lung fibrosis in a bleomycin mouse model. We validated these effects in a second mouse model of pulmonary fibrosis involving inducible, lung-targeted expression of transforming growth factor β1. END55 also exerted anti-fibrotic effects in human lung and skin tissues maintained in organ culture in which fibrosis was experimentally induced. The anti-fibrotic effect of END55 was mediated by a decrease in the expression of extracellular matrix genes and an increase in the levels of matrix-degrading enzymes. Finally, END55 reduced fibrosis in the lungs of patients with systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF) who underwent lung transplantation due to the severity of their lung disease, displaying efficacy in human tissues directly relevant to human disease. These findings demonstrate that END55 is an effective anti-fibrotic therapy in different organs.

DOI： 10.3390/biomedicines10112861

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Fibroproliferative disorders such as systemic sclerosis (SSc) have no effective therapies and result in significant morbidity and mortality. We recently demonstrated that the C-terminal domain of endostatin, known as E4, prevented and reversed both dermal and pulmonary fibrosis. Our goal was to identify the mechanism by which E4 abrogates fibrosis and its cell surface binding partner(s). Our findings show that E4 activated the urokinase pathway and increased the urokinase plasminogen activator (uPA) to type 1 plasminogen activator inhibitor (PAI-1) ratio. In addition, E4 substantially increased MMP-1 and MMP-3 expression and activity. In vivo, E4 reversed bleomycin induction of PAI-1 and increased uPA activity. In patients with SSc, the uPA/PAI-1 ratio was decreased in both lung tissues and pulmonary fibroblasts compared with normal donors. Proteins bound to biotinylated-E4 were identified as enolase-1 (ENO) and uPA receptor (uPAR). The antifibrotic effects of E4 required uPAR. Further, ENO mediated the fibrotic effects of TGF-β1 and exerted TGF-β1-independent fibrotic effects. Our findings suggest that the antifibrotic effect of E4 is mediated, in part, by regulation of the urokinase pathway and induction of MMP-1 and MMP-3 levels and activity in a uPAR-dependent manner, thus promoting extracellular matrix degradation. Further, our findings identify a moonlighting function for the glycolytic enzyme ENO in fibrosis.

DOI： 10.1172/jci.insight.144935

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記述言語：英語  

DOI： 10.1016/j.jdermsci.2021.10.005

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are fatal adverse skin reactions characterized by high fever, epidermal detachment, and mucositis. It is well known that SJS/TEN occasionally affects various organs, leading to permanent damage and death in some patients. Although acute liver dysfunction is a relatively common complication of SJS/TEN, severe acute liver dysfunction requiring liver transplantation is rare. We present the case of a 14-year-old girl with SJS complicated by severe and rapidly progressive liver dysfunction, specifically, acute liver failure (ALF) requiring liver transplantation. A lymphocyte transformation test showed positive results for acetaminophen and cefdinir. Furthermore, human leukocyte antigen (HLA) genotyping revealed the presence of the HLA-A*02:06 genotype, which is reported to be strongly associated with acetaminophen-related SJS/TEN with severe ocular complications. These results suggested that our patient may have presented with acetaminophen-induced SJS complicated by ALF, but no ocular complications. This is the first report of a pediatric patient with SJS who required liver transplantation. In rare instances, severe liver dysfunction requiring liver transplantation should be considered as a possible complication of SJS/TEN.

DOI： 10.1111/1346-8138.15963

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記述言語：日本語   出版者・発行元：金原出版(株)  

＜文献概要＞69歳,男性。港湾職員で肉体労働に従事している。13年前より左大腿後面の腫瘤を自覚,その後増大傾向があった。初診時,境界明瞭な75×63mmの弾性軟でドーム状の可動性良好な皮下腫瘤を認めた。切除術を施行し,病理組織像では割面像で内部に白色調の結節を伴う嚢胞が皮下脂肪織に存在した。強拡大像では胞巣周囲に裂隙を伴う基底細胞様細胞の増生や角質嚢胞がみられ,毛芽を模倣する構造も散見されcystic giant solitary trichoepitheliomaと診断した。自験例は本邦報告例では過去2番目の大きさであった。過去の報告例のなかには再発例や基底細胞癌に悪性転化した報告もあり,術後も注意深く経過観察する必要があると考えられた。

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2021&ichushi_jid=J01266&link_issn=&doc_id=20210422110009&doc_link_id=10.18888%2Fhi.0000002479&url=https%3A%2F%2Fdoi.org%2F10.18888%2Fhi.0000002479&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Monocytes and macrophages may be involved in the pathogenesis of systemic sclerosis (SSc); however, its etiology and regulation of monocyte and macrophage function in SSc remain unknown. Interferon regulatory factor (IRF) 8 is a transcriptional regulator that is essential for the differentiation and function of monocytes and macrophages, and thus may be involved in the regulation of macrophage phenotypes in SSc fibrosis. In this study, we measured IRF8 levels in circulating monocytes of 26 SSc patients (diffuse cutaneous SSc (dcSSc), n = 11; limited cutaneous SSc (lcSSc), n = 15) and 14 healthy controls. IRF8 levels were significantly suppressed in monocytes of dcSSc patients and correlated negatively with the modified Rodnan total skin thickness score. Next, we assessed cell surface markers, cytokine profiles, and extracellular matrix (ECM) expression levels in IRF8-silenced monocyte-derived macrophages (siIRF8-MDMs). siIRF8-MDMs displayed an M2 phenotype and significantly upregulated mRNA and protein levels of pro-fibrotic factors and ECM components. Finally, we assessed skin fibrosis in myeloid cell-specific IRF8 conditional knockout (IRF8flox/flox; Lyz2Cre/+) mice and found upregulated ECM mRNA levels and increased bleomycin-induced skin fibrosis. In conclusion, altered IRF8 regulation in monocytes and macrophages may be involved in SSc pathogenesis.

DOI： 10.1016/j.jid.2021.02.015

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are serious conditions characterized by necrosis of the skin and mucus membranes, and are mainly caused by medication and infections. Although the exact pathomechanism of SJS/TEN remains unclear, keratinocyte death is thought to be triggered by immune reactions to these antigens. While there is no established therapy for SJS/TEN, corticosteroids and intravenous immunoglobulin (IVIG) have been utilized as immunomodulator. We previously conducted a study to evaluate the efficacy of IVIG therapy in Japanese patients with SJS/TEN. IVIG was administered at a dosage of 400 mg/kg/day for 5 consecutive days as an additional therapy with systemic steroids. Prompt amelioration was observed in seven of the eight patients. All patients survived without sequelae. Recently, we retrospectively analyzed 132 cases of SJS/TEN treated in our two hospitals. The mortality rates in the patients treated with methylprednisolone pulse were 0% (0/31) for SJS and 7.0% (3/43) for TEN, and 0% (0/10) in the TEN patients treated with methylprednisolone pulse in combination with IVIG. These results suggest that early treatment with high-dose steroids, including methylprednisolone pulse therapy, and IVIG together with corticosteroids are possible therapeutic options to improve the prognosis of SJS/TEN.

DOI： 10.3389/fmed.2021.636924

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening disorders characterized by widespread epidermal necrosis of the skin and mucosa. The severity-of-illness scoring system for TEN (SCORTEN) was widely used since 2000 as a standard prognostic tool consisting of seven clinical values. METHODS: To evaluate the prognosis using current treatments and risk factors for mortality, we retrospectively analyzed 59 cases of TEN, including SJS/TEN overlap treated in two university hospitals from January 2000 to March 2020. RESULTS: The mortality rate of TEN was 13.6% (8/59). All patients treated with high-dose steroid administration in combination with plasma exchange and/or immunoglobulin therapy recovered. Logistic regression analysis showed nine clinical composite scores, namely: heart rate (≧120 bpm), malignancy present, percentage of body surface area with epidermal detachment (>10%), blood urea nitrogen (>28 mg/dL), serum bicarbonate level (<20 mEq/L), serum glucose level (>252 mg/dL), age (≧71 years), the interval between disease onset and treatment initiation at the specialty hospital (≧8 days), and respiratory disorder within 48 h after admission. The receiver operating characteristic curves confirmed a high potential for predicting the prognosis of TEN. CONCLUSIONS: Recent developments in treatment strategies have contributed to the improved prognosis of TEN patients. A modified severity scoring model composed of nine scores may be helpful in the prediction of TEN prognosis in recent patients. Further large-scale studies are needed to confirm mortality findings to improve prognostication in patients with TEN.

DOI： 10.1016/j.alit.2020.11.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

High-mobility group box 1 (HMGB-1) is a highly abundant pro-inflammatory protein associated with the pathogenesis of inflammatory and autoimmune diseases. HMGB-1 expression level increases in patients with psoriasis vulgaris (PV). However, HMGB-1 expression in patients with generalized pustular psoriasis (GPP) is unknown. In this study, we investigated HMGB-1 expression in GPP. HMGB-1 expression levels were examined in the skin and serum of patients with GPP, PV, atopic dermatitis (AD) and healthy controls (HC) using enzyme-linked immunosorbent assay and immunohistochemistry. The elevation in HMGB-1 expression was significantly higher in GPP patients than in PV, AD and HC patients. In addition, patients with GPP had elevated serum HMGB-1 levels compared with those with AD and HC. Furthermore, serum HMGB-1 levels were significantly decreased after systemic treatment. In the correlation analysis, a significant positive correlation was detected between serum HMGB-1 levels and the Japanese severity score for GPP. HMGB-1 may be involved in the pathogenesis of GPP and can be useful to evaluate disease severity and the effectiveness of GPP treatment.

DOI： 10.1111/1346-8138.15467

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記述言語：英語  

DOI： 10.1111/1346-8138.15535

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記述言語：英語  

DOI： 10.1111/1346-8138.15395

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/rheumatology/keaa112

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Dermatomyositis (DM) is an autoimmune inflammatory disease characterized by skin eruptions and myositis. Anti-transcriptional intermediary factor 1-γ antibody (anti-TIF1-γ Ab) is one of the most frequently detected myositis-specific autoantibodies and adults positive for anti-TIF1-γ have markedly higher rates of malignancy. Our aim was to determine the clinical associations of anti-TIF1-γ levels in 31 Japanese adult DM patients positive for anti-TIF1-γ. We determined associations between the anti-TIF1-γ index and patient characteristics and disease severities. Sixteen patients with anti-TIF1-γ Ab had concomitant malignancies. A mild positive correlation was found between the levels of serum creatine phosphokinase at the first visit and anti-TIF1-γ levels. In contrast, there was no significant difference in the anti-TIF1-γ Ab index between patients with and without malignancy. Dysphagia tended to be observed in patients with malignancy. On sequential analysis, anti-TIF1-γ levels in patients without malignancy were lower or turned negative after treatment for DM. Ab titers tended to be sustained in patients with stage IV malignancies. Interestingly, a re-increase in the Ab titer was observed on recurrence of malignancy or increase in DM activity. Four patients were completely cured of their malignancies, and anti-TIF1-γ levels in three patients turned negative with the loss of DM activity. These data suggest that higher anti-TIF1-γ titers may not directly indicate the presence of malignancy. Nevertheless, longitudinal changes in the anti-TIF1-γ index in individual patients may partially reflect activities of both DM and malignancy.

DOI： 10.1111/1346-8138.15284

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

: Systemic sclerosis (SSc) is a complex multi-system autoimmune disease characterized by immune dysregulation, vasculopathy, and organ fibrosis. Skin fibrosis causes high morbidity and impaired quality of life in affected individuals. Animal models do not fully recapitulate the human disease. Thus, there is a critical need to identify ex vivo models for the dermal fibrosis characteristic of SSc. We identified genes regulated by the pro-fibrotic factor TGFβ in human skin maintained in organ culture. The molecular signature of human skin overlapped with that which was identified in SSc patient biopsies, suggesting that this model recapitulates the dermal fibrosis characteristic of the human disease. We further characterized the regulation and functional impact of a previously unreported gene in the setting of dermal fibrosis, COL22A1, and show that silencing COL22A1 significantly reduced TGFβ-induced ACTA2 expression. COL22A1 expression was significantly increased in dermal fibroblasts from patients with SSc. In summary, we identified the molecular fingerprint of TGFβ in human skin and demonstrated that COL22A1 is associated with the pathogenesis of fibrosis in SSc as an early response gene that may have important implications for fibroblast activation. Further, this model will provide a critical tool with direct relevance to human disease to facilitate the assessment of potential therapies for fibrosis.

DOI： 10.3390/genes10020075

PubMed

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記述言語：英語   出版者・発行元：WILEY  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

The murine bleomycin (BLM)-induced fibrosis model is the most widely used in systemic sclerosis (SSc) studies. It has been reported that systemic delivery of BLM via continuous diffusion from subcutaneously implanted osmotic minipumps can cause fibrosis of the skin, lungs, and other internal organs. However, the mouse strain, dosage of BLM, administration period, and additional important features differ from one report to the next. In this study, by employing the pump model in C57BL/6J mice, we show a dose-dependent increase in lung fibrosis by day 28 and a transient increase in dermal thickness. Dermal thickness and the level of collagen in skin treated with high-dose BLM was significantly higher than in skin treated with low dose BLM or vehicle. A reduction in the thickness of the adipose layer was noted in both high and low dose groups at earlier time points suggesting that the loss of the fat layer precedes the onset of fibrosis. High-dose BLM also induced dermal fibrosis and increased expression of fibrosis-associated genes ex vivo in human skin, thus confirming and extending the in vivo findings, and demonstrating that a human organ culture model can be used to assess the effect of BLM on skin. In summary, our findings suggest that the BLM pump model is an attractive model to analyze the underlying mechanisms of fibrosis and test the efficacy of potential therapies. However, the choice of mouse strain, duration of BLM administration and dose must be carefully considered when using this model.

DOI： 10.1371/journal.pone.0179917

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

DOI： 10.1111/1346-8138.13190

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PubMed

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記述言語：日本語   出版者・発行元：公益社団法人 日本皮膚科学会  

当科における2000年1月～2012年5月までの12年間における薬剤性乾癬と診断された患者を集計し，臨床的・病理学的な特徴について検討した．男性19例，女性15例，原因薬剤は63.6%を高血圧治療薬が占め，なかでもカルシウム拮抗薬が最も多かった．臨床型は様々であるが局面型が最も多かった．病理組織学的には乾癬の組織像に加えて液状変性やリンパ球が真皮上層から真皮表皮境界部に浸潤する苔癬様の所見がみられた．投薬中の患者に乾癬の発症や悪化をみた場合には，薬剤性乾癬を念頭に置き診療することが重要である．

DOI： 10.14924/dermatol.126.295

CiNii Books

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その他リンク： https://jlc.jst.go.jp/DN/JLC/20021778931?from=CiNii

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Psoriasis is a chronic inflammatory skin disease characterized by excessive proliferation and abnormal keratinocyte development, in which T helper type 17 cells and signal transducer and activator of transcription 3 (STAT3) activation have pivotal roles. Moreover, caveolin-1 (CAV-1) has been implicated in the regulation of signal transduction, and aberrant CAV-1 expression is involved in a variety of diseases. However, whether CAV-1 is involved in psoriasis is unknown. Here we examined CAV-1 expression in the psoriatic epidermis and investigated its role in the pathogenesis of psoriasis. CAV-1 was markedly reduced in lesional epidermis of psoriasis patients. CAV/ silencing in keratinocytes in vitro revealed significant activation of STAT3, leading to increased expression of keratin 16 and several cytokine/chemokines, such as IL-6, C-X-C chemokine ligand 8 (CXCL8), CXCL9, and C-C chemokine ligand 20. In addition, psoriasis-related cytokines, including tumor necrosis factor-a (TNF-a), decreased CAV-1 expression in keratinocytes. Finally, administration of CAV-1 scaffolding domain peptide in a murine model of psoriasis-like skin inflammation induced by imiquimod improved the skin phenotype and reduced epidermal thickness and infiltrating cell counts. Furthermore, expression of TNF-a, IL-17A, and IL-23 was significantly suppressed by this treatment. Collectively, our study indicated that CAV-1 participates in the pathogenesis of psoriasis by regulating the STAT3 pathway and cytokine networks.

DOI： 10.1038/jid.2015.249

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Several interleukin (IL)-10 producing B-cell subsets have been identified recently. However, few studies have examined the role of them in toxic epidermal necrolysis (TEN). We describe a 41-year-old woman with TEN who had B-cell lymphoma and a history of treatments including B-cell depletion therapy. Her re-epithelization was still ongoing after 7months, despite treatments. To investigate her immune system, we compared cytokine and chemokine production from B cells and non-B cells isolated from the patient and another non-lymphoma TEN patient. IL-10 production from B cells decreased in the patient compared with the control TEN-only patient. Cytokine and chemokine levels from non-B cells involved in inflammation were elevated in the patient compared with the control patient. In conclusion, this study demonstrates that IL-10 from B cells as well as regulatory T cells is critical in the pathogenesis of TEN, and that B-cell dysfunction based on B-cell lymphoma and B-cell depletion therapy may be involved in the intractability of TEN.

DOI： 10.1111/1346-8138.12909

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記述言語：英語   出版者・発行元：JOHN LIBBEY EUROTEXT LTD  

DOI： 10.1684/ejd.2014.2442

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記述言語：英語   出版者・発行元：WILEY-BLACKWELL  

DOI： 10.1111/bjd.13162

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

BCR-ABL tyrosine kinase inhibitors (TKI) have dramatically improved therapy for chronic myelogenous leukemia (CML). However, several problems leading to TKI resistance still impede a complete cure of this disease. IFN regulatory factor-8 (IRF8) is a transcription factor essential for the development and functions of immune cells, including dendritic cells. Irf8(-/-) mice develop a CML-like disease and IRF8 expression is downregulated in patients with CML, suggesting that IRF8 is involved in the pathogenesis of CML. In this study, by using a murine CML model, we show that BCR-ABL strongly inhibits a generation of dendritic cells from an early stage of their differentiation in vivo, concomitant with suppression of Irf8 expression. Forced expression of IRF8 overrode BCR-ABL (both wild-type and T315I-mutated) to rescue dendritic cell development in vitro, indicating that the suppression of Irf8 causes dendritic cell deficiency. Gene expression profiling revealed that IRF8 restored the expression of a significant portion of BCR-ABL-dysregulated genes and predicted that BCR-ABL has immune-stimulatory potential. Indeed, IRF8-rescued BCR-ABL-expressing dendritic cells were capable of inducing CTLs more efficiently than control dendritic cells. Altogether, our findings suggest that IRF8 is an attractive target in next-generation therapies for CML. (C) 2013 AACR.

DOI： 10.1158/0008-5472.CAN-13-0802

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記述言語：英語   出版者・発行元：JOHN LIBBEY EUROTEXT LTD  

DOI： 10.1684/ejd.2013.1953

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記述言語：日本語   出版者・発行元：日本皮膚科学会大阪地方会・日本皮膚科学会京滋地方会  

A thirty-one-year-old man consulted our clinic with widespread erythema, blisters and erosions on his body surface. These skin lesions rapidly deteriorated until they extended over 70% of his skin surface area and the patient showed a high serum level of anti-desmoglein 1 antibody (880 index). Based on the diagnosis of severe pemphigus foliaceus, we started rapid treatment with combination therapy consisting of oral prednisolone (70 mg/day at first dosage), double-filtration plasmapheresis (DFPP) and high-dose intravenous immunoglobulin (IVIG), which successfully achieved remission. Therefore, this combination therapy is considered useful in the treatment of severe pemphigus foliaceus in order to reduce corticosteroid dosage smoothly without disease relapse and to shorten the duration of admission.

DOI： 10.11340/skinresearch.9.4_370

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記述言語：日本語   出版者・発行元：日本小児臨床薬理学会  

造血幹細胞移植の前治療薬として再承認されたthiotepaは、一部が汗から排泄されるため、皮膚障害を発症することが知られている。認知機能低下があり、おむつの着用が必要であった髄芽腫の8歳男児に、thiotepaを含む大量化学療法を施行した。1日1回のシャワー浴を行い、おむつを頻回に交換し、保清に努めたが、患児はthiotepa投与後に、体表面積の10%以上を占める色素沈着(CTCAE version 5.0 grade 2)、陰嚢、肛門部に角層剥離(grade 2)、そして、日常生活が制限される皮膚疼痛(grade 3)を認めた。おむつ着用部のみに角層剥離が点在していたことから、thiotepaによる皮膚障害と診断した。おむつを着用している患者では、過剰な湿潤環境から汗が蓄積しやすく、thiotepaによる皮膚障害のリスクが増加すると考えられた。thiotepa投与期間中は頻回のシャワー浴を行い、汗の蓄積を減らす対策が必要と考えられた。(著者抄録)

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J-GLOBAL

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記述言語：英語   掲載種別：速報，短報，研究ノート等（学術雑誌）   出版者・発行元：JOHN WILEY & SONS LTD  

DOI： 10.1002/cia2.12138

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

2000年1月から2019年3月までに当大学2施設で経験したStevens-Johnson症候群(SJS)と中毒性表皮壊死症(TEN)132例を解析した。死亡率はSJSで1.3%、TENで12.5%であった。ステロイド投与に加え、免疫グロブリン大量静注療法や血漿交換療法との集学的治療が確立された直近7年間では、TENの死亡率は3.8%と予後の改善が認められた。また、TENの発症から2病院受診までの期間が死亡群に比べ、生存群で有意に短く、早期診断・早期治療の重要性が再確認された。(著者抄録)

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記述言語：日本語   出版者・発行元：金原出版(株)  

＜文献概要＞26歳,女性。頭痛,咽頭痛,便秘に対してカルバマゼピンを含む5剤開始後に発熱と皮疹が出現した。薬剤中止後も症状の増悪があり当科を初診した。体幹の多形紅斑,口唇と口腔内のびらん,眼球結膜充血を認め,Stevens-Johnson症候群と診断した。強い咽頭痛を伴い,ファイバースコープにて咽頭粘膜炎を認めた。ステロイドパルス療法を施行し,皮疹と咽頭痛は改善した。リンパ球刺激試験とパッチテストでカルバマゼピン陽性であった。過去の報告例と,当科で経験した咽頭病変を認めた症例を検討したところ,感染症によるStevens-Johnson症候群のほうが咽頭病変を誘発しやすい可能性が示唆された一方で,特定の薬剤が咽頭病変を誘発しやすいという傾向は認められなかった。

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J01266&link_issn=&doc_id=20200827140022&doc_link_id=10.18888%2Fhi.0000002132&url=https%3A%2F%2Fdoi.org%2F10.18888%2Fhi.0000002132&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

記述言語：日本語   出版者・発行元：(株)診断と治療社  

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記述言語：英語   掲載種別：速報，短報，研究ノート等（学術雑誌）   出版者・発行元：JOHN WILEY & SONS LTD  

Toxic epidermal necrolysis (TEN) is a life-threatening cutaneous reaction with several complications. Although acute respiratory distress syndrome (ARDS) is rare, it can cause rapid and potentially fatal pulmonary dysfunction. Here, we present a case of TEN with ARDS attributed to acetaminophen.

DOI： 10.1002/cia2.12101

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：金原出版  

＜文献概要＞69歳,男性。52歳時に尋常性乾癬を発症し,66歳時に当科を初診した。各種生物学的製剤で効果を維持できず,69歳時にブロダルマブへ変更し,皮疹は改善した。変更6ヵ月後に左上眼瞼の浮腫,疼痛が出現した。頭部CTで左篩骨洞から左眼窩内に突出する膿瘍を認め,眼窩蜂窩織炎と診断した。耳鼻科にて切開排膿,抗菌薬投与,プレドニゾロン40mg/日を投与し改善した。一時ブロダルマブを中止していたが,中止1ヵ月後より乾癬が再燃したため投与を再開した。眼窩蜂窩織炎は,慢性副鼻腔炎から進展する,高リスクの疾患である。生物学的製剤投与中,副鼻腔炎の発症リスクが増加する可能性も報告されており,生物学的製剤投与中の患者において副鼻腔炎のコントロールも重要である。

CiNii Books

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(一社)日本皮膚免疫アレルギー学会  

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記述言語：日本語   出版者・発行元：(一社)日本皮膚免疫アレルギー学会  

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記述言語：日本語   出版者・発行元：(一社)日本皮膚免疫アレルギー学会  

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記述言語：日本語   出版者・発行元：新興医学出版社  

＜ポイント＞●薬疹はアレルギー性と非アレルギー性に大別され抗リウマチ薬であるサラゾスルファピリジンは他の薬剤より重症薬疹をおこしやすく注意が必要である。●生物学的製剤の技手により逆説的反応や薬剤誘発性ループスなどの非アレルギー性薬疹が誘発される。●リウマチ性疾患における薬疹の頻度を調べた包括的な研究はないが、SLEやシェーグレン症候群では薬剤によって健常人よりも薬疹を発症しやすいことが知られている。(著者抄録)

CiNii Books

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(一社)日本皮膚免疫アレルギー学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

<p>2014年10月から2016年3月までの期間に抗PD-1抗体による皮膚障害を認めた7症例をまとめた．そのうち2例では複数の皮膚障害を併発した．皮膚障害の内訳は白斑，皮膚そう痒症，水疱形成，苔癬型薬疹，乾癬型薬疹であった．皮膚障害を認めた7例全ての症例で治療継続可能であった．肺癌をはじめ，今後更にPD-1抗体の適応が拡大されることが予想されるため，免疫チェックポイント阻害薬による新たな障害の出現に十分な注意が必要である．</p>

DOI： 10.14924/dermatol.126.2419

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記述言語：日本語   出版者・発行元：科学評論社  

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/2016374377

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：日本語   出版者・発行元：(一社)日本皮膚アレルギー・接触皮膚炎学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：NATURE PUBLISHING GROUP  

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記述言語：日本語  

J-GLOBAL

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J-GLOBAL

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記述言語：日本語   出版者・発行元：金原出版(株)  

57歳女。約5年前に掌蹠膿疱症と診断され、ステロイド・ビタミンD3製剤外用とビオチン内服療法で加療されたが、皮疹は寛解・増悪を繰り返していた。今回、皮疹の急激な増悪と左肩関節および胸鎖関節痛を認め当科受診となった。初診時、両手掌と両足底の踵部に落屑と小膿胞形成を伴う紅斑を認めた。なお、口腔内に多数の歯科金属を認め、金属パッチテストではクロム、コバルト、ニッケルが陽性であった。金属アレルギーを合併する掌蹠膿疱症と診断し、ロイコトリエン拮抗薬であるモンテルカストナトリウム内服を開始したところ、皮疹は徐々に改善し、4ヵ月後には略治した。

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：NATURE PUBLISHING GROUP  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：NATURE PUBLISHING GROUP  

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記述言語：日本語   出版者・発行元：(株)協和企画  

＜症例のポイント＞ウステキヌマブが著効した非結核性抗酸菌症を合併した尋常性乾癬を経験した。ウステキヌマブはIL-12とIL-23の共通サブユニットであるp40を標的としていることから、抗TNF-α製剤に比べ、非結核性抗酸菌症をはじめとする重篤な副作用が出現しにくいと推察された。実際にウステキヌマブ投与例での非結核性抗酸菌症の発症報告は現在のところ認められていない。ウステキヌマブは従来の抗TNF-α製剤では使用しにくい症例でも、安全かつ有効に使用できる可能性があると考えた。(著者抄録)

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD  

DOI： 10.1016/j.cyto.2013.06.278

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記述言語：日本語   出版者・発行元：金原出版  

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/2013129425

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-BLACKWELL  

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

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