Language：Japanese   Publisher：(株)Gakken  

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Language：Japanese   Publisher：(株)Gakken  

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Language：Japanese   Publisher：(一社)日本皮膚免疫アレルギー学会  

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Language：Japanese   Publisher：(一社)日本皮膚免疫アレルギー学会  

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Language：Japanese   Publisher：(一社)日本皮膚免疫アレルギー学会  

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Language：English  

DOI： 10.1016/j.jaad.2024.11.030

PubMed

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Language：English   Publishing type：Research paper (scientific journal)  

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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Language：Japanese   Publisher：(一社)日本組織適合性学会  

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Language：English   Publishing type：Research paper (scientific journal)  

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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Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

Abstract

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) represent a severe spectrum of rare mucocutaneous reactions, primarily drug-induced and characterized by significant morbidity and mortality. These conditions manifest through extensive skin detachment, distinguishing them from other generalized skin eruptions. The rarity and severity of SJS/TEN underscore the importance of accurate diagnostic criteria and effective treatments, which are currently lacking consensus. This review proposes new diagnostic criteria to improve specificity and global applicability. Recent advancements in understanding the immunopathogenesis of SJS/TEN are explored, emphasizing the role of drug-specific T cell responses and HLA polymorphisms in disease onset. The review also addresses current therapeutic approaches, including controversies surrounding the use of immunosuppressive agents and the emerging role of TNF-α inhibitors. Novel therapeutic strategies targeting specific pathogenic mechanisms, such as necroptosis and specific immune cell pathways, are discussed. Furthermore, the development of new drugs based on these insights, including targeted monoclonal antibodies and inhibitors, are examined. The review concludes by advocating for more robust and coordinated efforts across multidisciplinary medical fields to develop effective treatments and diagnostic tools for SJS/TEN, with the aim of improving patient outcomes and understanding of the disease and its mechanisms.

DOI： 10.1093/bjd/ljae321

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Language：Japanese   Publisher：(一社)日本臨床免疫学会  

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Language：Japanese   Publisher：(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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Other Link： 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

Language：Japanese   Publisher：日本皮膚科学会-西部支部  

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Language：English   Publishing type：Research paper (scientific journal)  

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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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：日本臨床皮膚科医会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(株)協和企画  

＜文献概要＞症例のポイント ・左腎細胞癌術後の局所再発,リンパ節転移に対するニボルマブ/イピリムマブ(NIVO/IPI)初回投与後に水疱を伴う難治性扁平苔癬型薬疹(lichenoid drug eruption:LDE)を生じた.・全身性ステロイド投与にて皮疹は改善したが,ステロイド中止から2ヵ月後に誘因なく同症状が再燃し,最終的に長期のステロイド投与を要した.・再燃時の皮膚障害はGrade 3と重症であり,永続的にNIVO/IPIは中止となった.・NIVO/IPIは初回投与以降中止されたが,原疾患に対する追加治療なしにすべての癌病巣は消失し,2年間完全奏効を維持している.

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Language：Japanese   Publisher：(一社)日本皮膚免疫アレルギー学会  

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Language：Japanese   Publisher：(一社)日本皮膚免疫アレルギー学会  

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Language：Japanese   Publisher：(株)医学書院  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J01440&link_issn=&doc_id=20231026170011&doc_link_id=10.11477%2Fmf.1402229265&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1402229265&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

Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.jid.2023.09.282

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Language：Japanese   Publisher：(株)協和企画  

＜文献概要＞症例のポイント ・生物学的製剤投与中の乾癬患者に生じたIgA腎症を経験した.・乾癬患者が腎障害を合併する頻度は高いが,さらに生物学的製剤投与によりIgA腎症が誘発されることがある.・生物学的製剤投与中に尿所見に変化がみられた場合にはIgA腎症も念頭に精査を行う必要がある.

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jaad.2023.09.061

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Language：Japanese   Publisher：(株)南江堂  

＜文献概要＞はじめに 乾癬および掌蹠膿疱症(palmoplantar pustulosis:PPP)は,ともに皮疹と骨関節症状を合併しうる炎症性皮膚疾患である.乾癬に末梢関節炎,体軸関節炎および付着部炎を伴う場合は乾癬性関節炎(psoriatic arthritis:PsA)に,PPPの皮疹に骨関節炎を伴う場合は掌蹠膿疱症性骨関節炎(pustulotic arthro-osteitis:PAO)に診断される.PsA,PAO患者の中には,複数の科を受診しているにもかかわらず,皮疹と骨関節症状が同一疾患による症状と認識されずに骨関節症状が進行してしまうケースが散見される.本稿ではPsAとPAOの早期発見・早期診断に有用な臨床的特徴を整理し,皮膚科へ連携すべきポイントについて考えていきたい.また,皮膚科での診療の実際について併せて概説する.

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J00764&link_issn=&doc_id=20230829290019&doc_link_id=issn%3D0030-5901%26volume%3D74%26issue%3D9%26spage%3D991&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0030-5901%26volume%3D74%26issue%3D9%26spage%3D991&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening, severe mucocutaneous adverse reactions. Severity prediction at early onset is urgently required for treatment. However previous prediction scores have been based on data of blood tests. OBJECTIVE: This study aimed to present a novel score that predicts mortality in patients with SJS/TEN in the early stages, based on only clinical information. METHODS: We retrospectively evaluated 382 patients with SJS/TEN in development study. A clinical risk score for TEN (CRISTEN) was created according to the association of potential risk factors with death. We calculated the sum of these risk factors using CRISTEN, and this was validated in a multinational survey of 416 patients and was compared to previous scoring systems. RESULTS: The significant risk factors for death in SJS/TEN comprised of 10 items, including patients' age of ≥65 years, ≥10% BSA involvement, the use of antibiotics as culprit drugs, the use of systemic corticosteroid therapy prior to the onset, and mucosal damage affecting ocular, buccal, and genital mucosa. Renal impairment, diabetes, cardiovascular disease, malignant neoplasm, and bacterial infection were included as underlying diseases. The CRISTEN model showed good discrimination (AUC=0.884) and calibration. In the validation study, the AUC was 0.827, which was statistically comparable to those of previous systems. CONCLUSION: A scoring system based on only clinical information was developed to predict mortality in SJS/TEN and was validated in an independent multinational study. CRISTEN may predict individual survival probabilities and direct the management and therapy of patients with SJS/TEN.

DOI： 10.1016/j.jaip.2023.07.001

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Language：English   Publishing type：Research paper (scientific journal)  

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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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：English  

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are mucocutaneous diseases featured by severe sequelae and high mortality rates. In addition to ocular involvement, gynecological involvement is often observed in patients with TEN with possible occurrence of partial or complete adhesions of the labia majora, labia minora, and vaginal walls as severe sequelae. Although the gynecological sequelae of TEN severely affect patients' quality of life, there is a lack of awareness among medical professionals. Moreover, preventive measures and the effectiveness of treatment have not yet been fully verified. Herein, we describe a case of TEN with severe sequelae of eyelid and vaginal adhesions.

DOI： 10.7759/cureus.41496

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：English   Publishing type：Research paper (scientific journal)  

Osteopontin (OPN) was initially described as a protein involved in bone metabolism, but the roles played by OPN in the immune system and allergic reactions have attracted increasing attention. Here, we clarify the OPN-related dynamics of severe cutaneous adverse drug reactions, and assess whether the OPN level has utility for classifying such reactions and serving as a biomarker of severity. Serum OPN levels in patients with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS), Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and erythema multiforme-type drug reaction (EM-DR) were quantified by ELISA. The OPN sources were analyzed by dual immunofluorescence assay of DIHS, SJS/TEN and EM-DR biopsy specimens. The serum OPN levels of DIHS/DRESS patients (489.1 ± 37.0 ng/mL) and SJS/TEN patients (508.5 ± 47.8 ng/mL) were significantly higher compared with controls (314.4 ± 14.3 ng/mL; p < 0.001). After treatment, the serum OPN level of DIHS/DRESS patients decreased to that of controls. In addition, OPN levels in DIHS/DRESS patients and SJS/TEN patients were higher than in patients with EM-DR (Mann-Whitney U test, p < 0.05). However, when the Kruskal-Wallis test was used to compare the OPN levels among the three groups of patients, the difference was not significant (p = 0.055). Dual immunofluorescence assay revealed that T lymphocytes and macrophages were the main OPN sources in DIHS, SJS/TEN and EM-DR patients. These data suggest that the OPN level can be used to evaluate the severity of inflammation in patients experiencing drug reactions.

DOI： 10.1111/1346-8138.16670

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：English   Publishing type：Research paper (scientific journal)  

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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Language：English   Publishing type：Research paper (scientific journal)  

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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Language：English   Publishing type：Research paper (scientific journal)  

Systemic sclerosis (SSc) is a chronic, heterogenous disease of connective tissue characterized by organ fibrosis together with vascular injury and autoimmunity. Transforming growth factor (TGF)-β plays a central role in generating fibrosis, including SSc. Periostin is a matricellular protein playing a key role in the generation of fibrosis by amplifying the TGF-β signals. SOX (SRY-related HMG box) 11 is a transcription factor playing several important roles in organ development in embryos. We have previously shown that SOX11 induces periostin expression. However, the roles of the interactions among the TGF-β signals, periostin, and SOX11 remain unknown in the pathogenesis of SSc. In this study, we found that most clones of dermal fibroblasts derived from SSc patients showed constitutive, high expression of SOX11, which is significantly induced by TGF-β1. SOX11 forms a positive loop with periostin to activate the TGF-β signals in SSc dermal fibroblasts. Genetic deletion of Sox11 in Postn-expressing fibroblasts impairs dermal fibrosis by bleomycin. Moreover, using the DNA microarray method, we identified several fibrotic factors dependent on the TGF-β/SOX11/periostin pathway in SSc dermal fibroblasts. Our findings, taken together, show that a positive loop formed by SOX11 and periostin in fibroblasts upregulates the TGF-β signals, leading to skin fibrosis.

DOI： 10.1016/j.jid.2022.12.008

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Language：English   Publisher：(一社)日本研究皮膚科学会  

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Phototherapy and apremilast (oral phosphodiesterase-4 inhibitor) are well-known in the treatment of moderate to severe psoriasis vulgaris. However, current evidence on the efficacy and safety of their combination is not sufficient. This multicenter, randomized controlled study compared the efficacy and safety between phototherapy as monotherapy and phototherapy and apremilast as combination therapy in patients with psoriasis vulgaris. Patients with moderate to severe psoriasis vulgaris were assigned to combination (n = 29) and monotherapy (n = 13) groups. All patients underwent an 8-week phototherapy regimen comprising irradiation with narrowband UV-B. The patients in the combination group were also administered 10 mg to 60 mg of oral apremilast. We evaluated the improvement percentage based on the Psoriasis Area and Severity Index (PASI) score from baseline to week 8. Additionally, we evaluated the percentage of patients who achieved ≥75% improvement; changes in body surface area (BSA) and scores of EuroQol 5-dimensions 5-level, Dermatology Life Quality Index, and visual analog scale for pruritis from baseline to 4 and 8 weeks; and adverse events. Compared with the monotherapy group, the combination group had significantly lower PASI scores at 4 and 8 weeks and more patients who achieved a PASI score improvement of ≥75% at 8 weeks. Both groups exhibited a significant decrease in BSA; at 8 weeks, no significant difference was observed between the two groups, although the combination group tended toward a greater reduction in BSA. The intergroup differences in the changes at the three time points were not significant. Adverse events were more frequent in the combination group than in the monotherapy group. Our findings suggest that an 8-week combined apremilast and phototherapy regimen may not be adequate in patients for improvements in their subjective assessment of psoriasis, and longer treatment periods may be necessary.

DOI： 10.1111/1346-8138.16566

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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BACKGROUND: Monocytes and macrophages are implicated in inflammation and atherosclerosis, whereas monocytes are involved in psoriasis lesion formation. We previously reported a psoriatic inflammation-associated significant decrease in the membrane protein caveolin-1 (CAV-1) in psoriasis patient monocytes. However, the phenotype of circulating monocytes and their macrophage differentiation in psoriasis patients remain unclear. OBJECTIVE: We sought to clarify circulating monocyte and monocyte-derived macrophage (MDM) phenotypes in psoriasis patients with and without comorbidities. METHODS: Thirty-one patients with psoriasis vulgaris and 28 control subjects were included. Surface macrophage markers and inflammatory status were examined in circulating monocytes and MDMs from both groups. Expression of CD36, which mediates macrophage uptake of oxidized low-density lipoprotein (oxLDL), was evaluated in these cells. CAV-1-silenced monocytes were differentiated into macrophages to investigate the effects of CAV-1 downregulation on psoriatic inflammation and atherosclerosis. RESULTS: Macrophage surface markers were detectable in circulating monocytes. A significant M1 shift was detected in monocytes and MDMs in psoriasis patients, including those without cardiovascular disease risk factors, as compared to controls. MDMs of psoriasis patients had more CD36-expressing cells, which are associated with atherosclerosis risk. Additionally, CAV-1-silencing in monocytes increased the likelihood of M1-biased macrophage differentiation and increased pro-inflammatory cytokine production. CONCLUSIONS: Monocytes from psoriasis patients were more likely to differentiate into M1-dominant macrophages, correlating with inflammatory status and CAV-1 expression. These aberrant inflammatory monocytes not only contribute to psoriatic inflammation by producing psoriatic cytokines, but also have a phenotype that could increase atherosclerosis risk by uptake of oxLDL and formation of foam cells.

DOI： 10.1016/j.jdermsci.2022.07.003

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BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening severe cutaneous adverse reactions (SCARs). Sepsis has been shown to be the main cause of death in SJS/TEN. The European SCAR study reported that 14.8 % of SJS/TEN patients were receiving systemic steroid therapy for their underlying condition prior to onset. However, it remained unclear whether this factor affected the mortality rate. OBJECTIVE: This study was performed to identify risk factors for sepsis in SJS/TEN patients. In addition, we compared patients who had and had not received systemic steroid therapy for their underlying condition. METHODS: A primary survey regarding the numbers of SJS/TEN patients between 2016 and 2018 was sent to 1205 institutions in Japan. A secondary survey seeking more detailed information was sent to institutions reporting SJS/TEN patients. We analyzed 315 SJS patients and 174 TEN patients using a logistic regression model, Wilcoxon's rank-sum test, χ2 test, and Fisher's exact test. RESULTS: Significant risk factors for sepsis included TEN, diabetes, and intensive care unit (ICU) admission. The mortality rate was significantly higher among patients with sepsis. Patients who had received systemic steroid therapy had a lower incidence of fever, and showed a higher mortality rate. CONCLUSION: Based on a nationwide epidemiological survey of SJS/TEN in Japan, we identified risk factors for sepsis and found that patients who had received steroid therapy for their underlying condition had a lower incidence of fever and a higher mortality rate.

DOI： 10.1016/j.jdermsci.2022.07.004

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), is a member of the genus Betacoronavirus. This virus was first detected in December 2019, and the situation quickly escalated to cause a global pandemic within a few months. COVID-19 had caused more than 5.5 million deaths as of January 2022. Hence, the urgency of effective vaccination contributed to the fastest rate of vaccine development seen to date (i.e., within 1.5 years). Despite reports of good vaccine efficacy without severe systemic reactions at the clinical trial stage, hypersensitivity reactions have been reported following worldwide vaccination campaigns. We provide a brief review regarding the structure of SARS-CoV-2. We also review the most acceptable types of vaccines in terms of safety profiles, namely the BNT162b2, mRNA-1273, and AZD1222 vaccines. This review aims to facilitate an understanding of the possible immune mechanisms regarding COVID-19-vaccination-related hypersensitivity reactions, such as thrombosis and thrombocytopenia, cutaneous adverse reactions, myocarditis, and perimyocarditis.

DOI： 10.3390/biomedicines10071641

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

DOI： 10.1016/j.ejca.2022.01.020

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Systemic autoimmune diseases are reportedly associated with a high frequency of drug allergies. In particular, systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), and adult-onset Still's disease (AOSD) have recently drawn attention. Based on previous reports, drug allergies have been reported in 17.1-63%, 7-40.1%, and 17.6-54% of patients with SS, SLE, and AOSD patients, respectively. Antimicrobial agents, including sulfa drugs and nonsteroidal anti-inflammatory drugs, are the most common causative agents of drug allergies. However, few studies have examined in detail the relationship between drug eruptions, a major symptom of drug allergy, and systemic autoimmune diseases, and their actual status remains unclear. These autoimmune diseases commonly exhibit a diverse range of skin manifestations in the course of these diseases, rendering it may be difficult to determine whether it is a true drug eruption. Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), a fatal, severe drug eruption, has also been associated with autoimmune diseases. The development of SS-like symptoms after SJS/TEN onset and high prevalence of anti-SS-A antibodies in SJS/TEN are intriguing observations. Although the presence of SLE is known to be a risk factor for SJS/TEN, common pathological conditions, such as excessive immune status, abnormal function of regulatory T cells, and neutrophil extracellular traps in autoimmune diseases such as SS and SLE, are potentially involved in the development of drug eruptions.

DOI： 10.1016/j.alit.2022.02.001

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DOI： 10.1016/j.alit.2022.02.003

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：English   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(株)診断と治療社  

＜産婦人科医におさえてほしいポイント＞・抗悪性腫瘍薬による手足症候群について、原因薬剤毎にその病態や症状、経過が異なることを理解する。特にリポソーマルドキソルビシンやマルチキナーゼ阻害薬による手足症候群は重症化しやすいため、しばしば休薬や追加治療が必要となる。・手足症候群は、薬剤投与前からの予防・軽症時の対応が重症化の回避につながるため、患者への生活指導、適切なタイミングでの皮膚科コンサルトが重要である。・ICIによる皮膚障害の大部分は軽症例だが、多彩な皮疹や予期せぬ経過をたどるため早期に皮膚科にコンサルトしていただくことをお勧めする。(著者抄録)

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(有)科学評論社  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：日本脊椎関節炎学会  

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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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DOI： 10.1093/rheumatology/keac519.

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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DOI： 10.1016/j.jdermsci.2021.10.005

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This study aimed to clarify the etiologic factors predicting acute ocular progression in SJS/ TEN, and identify patients who require immediate and intensive ophthalmological treatment. We previously conducted two Japanese Surveys of SJS/TEN (i.e., cases arising between 2005–2007 and between 2008–2010), and obtained the medical records, including detailed dermatological and ophthalmological findings, of 230 patients. Acute ocular severity was evaluated as none, mild, severe, and very severe. A multi-state model assuming the Markov process based on the Cox proportional hazards model was used to elucidate the specific factors affecting the acute ocular progression. Our findings revealed that of the total 230 patients, 23 (24%) of 97 cases that were mild at initial presentation worsened to severe/very severe. Acute ocular progression developed within 3 weeks from disease onset. Exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) and younger patient age were found to be statistically significant for the progression of ocular severity from mild to severe/very severe [hazard ratio (HR) 3.83; 95% confidence interval (CI) 1.48 to 9.91] and none to severe/very severe [HR 0.98; 95% CI 0.97 to 0.99], respectively. The acute ocular severity score at worst-condition was found to be significantly correlated with ocular sequelae. Thus, our detailed findings on acute ocular progression revealed that in 24% of SJS/TEN cases with ocular involvement, ocular severity progresses even after initiating intensive treatment, and that in younger-age patients with a history of exposure to NSAIDs, very strict attention must be given to their ophthalmological appearances.

DOI： 10.1371/journal.pone.0260730

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Language：Japanese   Publisher：(一社)日本皮膚免疫アレルギー学会  

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DOI： 10.1111/1346-8138.16014

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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免疫チェックポイント阻害薬による皮膚障害の重症化因子および皮膚障害の臨床型分類を検討する目的で、免疫チェックポイント阻害薬の使用経過で皮膚障害を発症した163人に対してアンケート形式の調査を行った。本研究では、有意な重症化因子は同定されなかったが、対象疾患と臨床型の検討で悪性黒色腫と白斑、肺癌と扁平苔癬様皮疹に関連がみられ、対象疾患により特徴的な臨床型を呈する可能性が考えられた。皮膚障害の重症群は全体の約10%であったがTENが2症例あり、免疫チェックポイント阻害薬投与中の重症薬疹に注意すべきと考えられた。(著者抄録)

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J01174&link_issn=&doc_id=20210728470005&doc_link_id=10.14924%2Fdermatol.131.1841&url=https%3A%2F%2Fdoi.org%2F10.14924%2Fdermatol.131.1841&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

Language：Japanese   Publisher：(公社)日本皮膚科学会  

免疫チェックポイント阻害薬による皮膚障害の重症化因子および皮膚障害の臨床型分類を検討する目的で、免疫チェックポイント阻害薬の使用経過で皮膚障害を発症した163人に対してアンケート形式の調査を行った。本研究では、有意な重症化因子は同定されなかったが、対象疾患と臨床型の検討で悪性黒色腫と白斑、肺癌と扁平苔癬様皮疹に関連がみられ、対象疾患により特徴的な臨床型を呈する可能性が考えられた。皮膚障害の重症群は全体の約10%であったがTENが2症例あり、免疫チェックポイント阻害薬投与中の重症薬疹に注意すべきと考えられた。(著者抄録)

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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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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OBJECTIVES: To determine clinical and genetic features of individuals with relapsing polychondritis (RP) likely caused by pathogenic somatic variants in ubiquitin-like modifier activating enzyme 1 (UBA1). METHODS: Fourteen patients with RP who met the Damiani and Levine criteria were recruited (12 men, 2 women; median onset age (IQR) 72.1 years (67.1-78.0)). Sanger sequencing of UBA1 was performed using genomic DNA from peripheral blood leukocytes or bone marrow tissue. Droplet digital PCR (ddPCR) and peptide nucleic acid (PNA)-clamping PCR were used to detect low-prevalence somatic variants. Clinical features of the patients were investigated retrospectively. RESULTS: UBA1 was examined in 13 of the 14 patients; 73% (8/11) of the male patients had somatic UBA1 variants (c.121A>C, c.121A>G or c.122T>C resulting in p.Met41Leu, p.Met41Val or p.Met41Thr, respectively). All the variant-positive patients had systemic symptoms, including a significantly high prevalence of skin lesions. ddPCR detected low prevalence (0.14%) of somatic variant (c.121A>C) in one female patient, which was subsequently confirmed by PNA-clamping PCR. CONCLUSIONS: Genetic screening for pathogenic UBA1 variants should be considered in patients with RP, especially male patients with skin lesions. The somatic variant in UBA1 in the female patient is the first to be reported.

DOI： 10.1136/annrheumdis-2021-220089

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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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Language：English   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(一社)日本皮膚免疫アレルギー学会  

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A 42-year-old man with a history of surgery for tongue cancer was referred to our hospital due to an abnormal chest shadow. High-resolution computed tomography showed lower lobe reticulation. A physical examination revealed nail dystrophy, oral leukoplakia, and reticulated hypopigmentation. Lung biopsy revealed subpleural and perilobular fibrosis, suggestive of usual interstitial pneumonia. However, multiple pathological findings, including homogenous fibrosis and cell infiltration in the centrilobular region, which were compatible with nonspecific interstitial pneumonia, and bronchiolitis were also seen. Genetic testing showed a hemizygous missense mutation in the DKC1 gene, and the patient was diagnosed with dyskeratosis congenita. Although anti-fibrotic therapy was initiated, the patient's respiratory function has continued to decrease.

DOI： 10.2169/internalmedicine.5143-20

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Previous clinical studies have shown that efficacy and serum brodalumab levels are dose dependent in patients with psoriasis receiving the same dose of brodalumab during the study. This study aimed to investigate the association between dosage, serum levels, and efficacy of brodalumab in Japanese patients with plaque psoriasis with dosage variations during the study. This was a post hoc exploratory analysis of a 108-week, multicenter, open-label extension study, which changed into a post-marketing surveillance study following brodalumab approval in Japan. Eligible patients with plaque psoriasis (n = 129) received brodalumab 140 mg every 4 weeks on Day 1; dosage change at physician's discretion from 140 mg every 8 weeks to 210 mg every 2 weeks was permitted; patients switched to 210 mg every 2 weeks during the post-marketing surveillance study. Exploratory endpoints included serum brodalumab levels at Weeks 28 and 108, its association with Psoriasis Area and Severity Index score, and Psoriasis Area and Severity Index score in patients receiving brodalumab 210 mg every 2 weeks at end of study. Median brodalumab trough levels were significantly higher (P < 0.05) at higher vs. lower dosages at Weeks 28 (n = 126) and 108 (n = 111) except for 140 mg every 2 weeks vs. 210 mg every 2 weeks at Week 108 and higher in patients with lower Psoriasis Area and Severity Index scores-significantly different only for Psoriasis Area and Severity Index score 0 vs. >2 at Week 28 (P = 0.0153). Of 100 patients receiving 210 mg every 2 weeks at end of study, 89% had a Psoriasis Area and Severity Index score ≤2. In patients with plaque psoriasis, brodalumab efficacy may depend upon sustained serum trough levels and can be restored by using the approved dose.

DOI： 10.1111/1346-8138.15690

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DOI： 10.1093/rheumatology/keaa112

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BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening severe cutaneous adverse reactions (SCARs). The first national epidemiological survey of SJS/TEN was carried out in 2008. We conducted a new survey to identify changes from the previous survey. OBJECTIVE: The present survey aimed to estimate the number of SJS/TEN patients in Japan between 2016 and 2018 (primary survey) and to clarify clinical epidemiological profiles (secondary survey). METHODS: A primary survey asking for numbers of SJS/TEN patients during the study period was sent to 1205 institutions nationwide. A secondary survey was sent to institutions reporting SJS/TEN patients, seeking detailed information. RESULTS: Yearly prevalence per million was 2.5 for SJS and 1 for TEN. The secondary survey allowed analysis of 315 SJS cases and 174 TEN cases from 160 institutions. Mean age was 53.9 years in SJS, and 61.8 years in TEN. Mortality rate was 4.1 % for SJS and 29.9 % for TEN. In TEN, mean age and mortality rates had increased from the previous survey. The ratio of expected to observed mortality calculated by SCORTEN score was lowest with high-dose steroid therapy (0.40), followed by steroid pulse therapy (0.52). CONCLUSION: The present findings suggest that the mortality rate of TEN has increased because of increases in mean ages of patients and patients with malignant neoplasm as underlying disease. When comparing the ratio of expected mortality to actual mortality, high-dose steroid therapy achieved the greatest reduction in mortality.

DOI： 10.1016/j.jdermsci.2020.09.009

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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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The medical comorbidities including skin diseases are associated with male infertility. The most common cause of male infertility is the inability of testes to produce sperm; however, the influence of persistent dermatitis on testicular function has not been elucidated so far. We investigated the relationship between skin inflammation and impaired sperm production using a spontaneous dermatitis mouse model. We examined the breeding records of dermatitis mice and their wild-type littermates. Sperm count, motility, and viability were analyzed by direct microscopic observation and flow cytometry. In addition, testis and epididymis were histologically examined. Finally, sperm viability was evaluated in another dermatitis mouse model and in wild-type mice in which inflammatory cytokines were intraperitoneally administered. Compared to wild-type littermate mice, the number of children born was lower in mice with dermatitis. The body weight and testis size were decreased age-dependently. In the skin disease group, the sperm count and movement ratio were clearly decreased, and reduced sperm viability was observed. Histological examination revealed the detachment of Sertoli cells and reduced spermatogenesis. The fibrosis of epididymal stroma was severe, and it might affect defective sperm maturation in the epididymis. In addition, this phenomena was reproduced by a hapten applied dermatitis mouse model and the intraperitoneal administration of inflammatory cytokines. Once the skin is inflamed, inflammatory cytokines are produced and released, which may affect testicular and sperm function. Additional studies are needed to determine the relationship between male infertility and severe dermatitis in human.

DOI： 10.3390/biomedicines8090293

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DOI： 10.1111/1346-8138.15535

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Language：Japanese   Publisher：(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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DOI： 10.1016/j.jid.2019.12.025

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Copyright: © 2020 Kaieda et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Objective Surfactant protein D (SP-D) is considered a serum biomarker of various forms of interstitial lung disease (ILD). In this study, we examined the utility of SP-D as a predictive biomarker for mortality in patients with ILD associated with polymyositis/dermatomyositis (PM/DM) using large-scale multicentre cohort data. Methods We enrolled 381 patients with incident PM/DM-associated ILD in a multicentre retrospective cohort based on the availability of serum SP-D at the baseline. Demographic and clinical characteristics as well as the presence of autoantibodies to melanoma differentiation-associated gene 5 (MDA5) and aminoacyl tRNA synthetase were measured at the time of diagnosis, and follow-up survival data were collected prospectively. Results Seventy-eight patients died during the median observation period of 18 months, and the majority of patients died of ILD. The SP-D levels at baseline were significantly lower (P = 0.02) in a non-survivor subset than in a survivor subset among the entire enrolled patients. However, the SP-D levels were higher in the non-survivor subset than in the survivor subset based on the stratification by anti-MDA5-positive, anti-ARS-positive and, double-negativity, although there was an only statistically significant difference (P = 0.01) in the double-negative group. Surprisingly, the SP-D levels were within the upper limit of normal, 110 ng/mL, in 54 (87%) of 62 anti-MDA5-positive patients who died. In the double-negative group, the mortality rates were significantly higher (P = 0.002) in a subset with SP-D ≥127.6 ng/mL, the cut-off value for mortality calculated by the receiver operating characteristic curve, than the other subset. All of patients with SP-D <127.6 ng/mL survived. Conclusion Serum SP-D levels behave differently among patients with stratified by anti-MDA5 antibody, anti-ARS antibody and both negativity in PM/DM-associated ILD. Its use in clinical practice should be applied with caution on the basis of the presence or absence of anti-MDA5 antibody or anti-ARS antibody.

DOI： 10.1371/journal.pone.0234523

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Brodalumab, an interleukin-17 receptor A inhibitor, demonstrated rapid and robust efficacy with a favorable safety profile in patients with moderate to severe plaque psoriasis. Here, we present data from a multicenter, open-label extension study in patients with plaque psoriasis with/without psoriatic arthritis who completed 64 weeks of treatment with brodalumab (140 or 210 mg, every 2 weeks [Q2W]). Patients were enrolled to evaluate the long-term safety and efficacy of a modified dose of brodalumab. Eligible patients were switched to a reduced dose of brodalumab (140 mg every 4 weeks on day 1) in the extension study; the dose and dosing interval were modified sequentially at the physician's discretion (minimum 140 mg every 8 weeks and maximum 210 mg Q2W) until drug approval, after which all patients were switched to 210 mg Q2W for postmarketing surveillance. Of the 129 patients enrolled, 107 (82.9%) completed the 108-week or more extension study. All patients had psoriasis that was well controlled with brodalumab treatment on day 1. Improvement in psoriasis-related symptoms, evaluated with the Psoriasis Area and Severity Index, Psoriasis Scalp Severity Index, Dermatology Life Quality Index, Nail Psoriasis Severity Index, and American College of Rheumatology 20, 50 and 70, was maintained during the 108-week extension study. Brodalumab treatment was well tolerated throughout, and no new safety signals were identified. The most commonly reported treatment-related adverse event was nasopharyngitis, followed by influenza and oral candidiasis. No cases of serious candida infection or Crohn's disease were observed in this study. Serious treatment-related adverse events, such as appendicitis, brain abscess, bacterial meningitis, colon cancer, immunoglobulin A nephropathy and tubulointerstitial nephritis, were reported in one patient each. No anti-brodalumab-binding antibodies or brodalumab-neutralizing antibodies were detected in any patient throughout the extension study. Overall, the long-term efficacy and safety of brodalumab were demonstrated over 108 weeks.

DOI： 10.1111/1346-8138.15343

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: Adipose tissue (AT) is the largest endocrine organ, producing bioactive products called adipocytokines, which regulate several metabolic pathways, especially in inflammatory conditions. On the other hand, there is evidence that chronic inflammatory skin disease is closely associated with vascular sclerotic changes, cardiomegaly, and severe systemic amyloidosis in multiple organs. In psoriasis, a common chronic intractable inflammatory skin disease, several studies have shown that adipokine levels are associated with disease severity. Chronic skin disease is also associated with metabolic syndrome, including abnormal tissue remodeling; however, the mechanism is still unclear. We addressed this problem using keratin 14-specific caspase-1 overexpressing transgenic (KCASP1Tg) mice with severe erosive dermatitis from 8 weeks of age, followed by re-epithelization. The whole body and gonadal white AT (GWAT) weights were decreased. Each adipocyte was large in number, small in size and irregularly shaped; abundant inflammatory cells, including activated CD4+ or CD8+ T cells and toll-like receptor 4/CD11b-positive activated monocytes, infiltrated into the GWAT. We assumed that inflammatory cytokine production in skin lesions was the key factor for this lymphocyte/monocyte activation and AT dysregulation. We tested our hypothesis that the AT in a mouse dermatitis model shows an impaired thermogenesis ability due to systemic inflammation. After exposure to 4 °C, the mRNA expression of the thermogenic gene uncoupling protein 1 in adipocytes was elevated; however, the body temperature of the KCASP1Tg mice decreased rapidly, revealing an impaired thermogenesis ability of the AT due to atrophy. Tumor necrosis factor (TNF)-α, IL-1β and interferon (INF)-γ levels were significantly increased in KCASP1Tg mouse ear skin lesions. To investigate the direct effects of these cytokines, BL/6 wild mice were administered intraperitoneal TNF-α, IL-1β and INF-γ injections, which resulted in small adipocytes with abundant stromal cell infiltration, suggesting those cytokines have a synergistic effect on adipocytes. The systemic dermatitis model mice showed atrophy of AT and increased stromal cells. These findings were reproducible by the intraperitoneal administration of inflammatory cytokines whose production was increased in inflamed skin lesions.

DOI： 10.3390/ijms21093367

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DOI： 10.1016/j.ejca.2020.02.044

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BACKGROUND: Myositis and interstitial lung disease (ILD) frequently occur in patients with anti-aminoacyl-tRNA synthetase (ARS) antibodies. Nearly half of ARS-ILD patients have the acute or subacute form of the disease, and one-third of these patients show a deterioration in pulmonary function over the long-term course because of frequent recurrences and refractoriness to therapy. Several reports recently described different characteristics depending on the individual anti-ARS antibodies, and the anti-asparaginyl tRNA synthetase (KS) antibody was strongly linked to ILD rather than to myositis. We therefore hypothesized that KS-ILD may have clinical characteristics that differ from those of other ARS-ILDs. The aim of this study was to clarify the clinical, radiological, and pathological features of KS antibody-positive ILD. METHODS: We retrospectively analyzed 19 consecutive patients with KS-ILD who underwent initial clinical measurements and high-resolution computed tomography and pathological assessments. We also analyzed disease behavior based on pulmonary function test results during the follow-up period. RESULTS: Our KS-ILD cohort included patients with dermatomyositis (10.5%), primary Sjögren syndrome (5.3%), and idiopathic ILD (84.2%). Most patients presented with chronic onset (89.5%) and a nonspecific pattern of interstitial pneumonia at each radiological and pathological assessment (89.4% and 85.7%, respectively). The pulmonary function test results showed that the mean changes from the initial %forced vital capacity and %diffusing capacity of the lung for carbon monoxide at 3 years were 3.7% ± 2.9% and 9.35% ± 3.0%, respectively. CONCLUSIONS: Most KS-ILD patients showed a tendency for chronic disease onset and long-term stabilization of pulmonary function.

DOI： 10.1016/j.resinv.2019.12.003

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We developed a questionnaire to examine the findings of cutaneous arteritis among dermatological specialists experienced in vasculitis as certified by the Committee for guidelines for the management of vasculitis and vascular disorders of the Japanese Dermatological Association. We sent a questionnaire to 12 dermatological facilities identified through the revised Committee for guidelines for the management of vasculitis and vascular disorders of the Japanese Dermatological Association. Retrospective data obtained from 84 patients at the 12 dermatological facilities between 2012 January 2016 December were evaluated. The 84 patients were categorized into two groups, a systemic steroid treatment group (group 1, n = 52) and a no systemic steroid treatment group (group 2, n = 32). C-reactive protein in group 1 patients was significantly higher than that in group 2 patients. Frequency of fever, arthritis, myalgia- and peripheral neuropathy in group 1 was significantly higher than that in group 2. We propose that these symptoms could serve as early markers for the transfer from cutaneous arteritis to systemic polyarteritis nodosa. We further suggest that patients who are subsequently associated with cerebral hemorrhage and infarction, who are originally diagnosed as having cutaneous arteritis, could progress to systemic polyarteritis nodosa. The study demonstrated that it is important for dermatologists to detect these findings early in order to establish an accurate diagnosis and a timely treatment.

DOI： 10.1111/1346-8138.15273

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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

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It has been reported that obesity may be an aggravating factor for psoriasis. However, its pathological mechanism remains elusive. The adipocyte-derived hormone leptin primarily controls energy homeostasis by regulating appetite and modulates immunity. Strikingly, serum leptin levels are elevated in obese patients and positively correlate with body mass index. Additionally, leptin levels also correlate with severity of psoriasis, and knocking out leptin suppresses imiquimod-induced psoriatic inflammation in mice.

DOI： 10.1111/bjd.19133

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DOI： 10.1111/1346-8138.15142

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BACKGROUND: The European League Against Rheumatism/American College of Rheumatology classification criteria for inflammatory myopathies are able to classify patients with skin-predominant dermatomyositis (DM). However, approximately 25% of patients with skin-predominant DM do not meet two of the three hallmark skin signs and fail to meet the criteria. OBJECTIVES: To develop a set of skin-focused classification criteria that will distinguish cutaneous DM from mimickers and allow a more inclusive definition of skin-predominant disease. METHODS: An extensive literature review was done to generate items for the Delphi process. Items were grouped into categories of distribution, morphology, symptoms, antibodies, histology and contextual factors. Using REDCap™, participants rated these items in terms of appropriateness and distinguishing ability from mimickers. The relevance score ranged from 1 to 100, and the median score determined a rank-ordered list. A prespecified median score cut-off was decided by the steering committee and the participants. There was a pre-Delphi and two rounds of actual Delphi. RESULTS: There were 50 participating dermatologists and rheumatologists from North America, South America, Europe and Asia. After a cut-off score of 70 during the first round, 37 of the initial 54 items were retained and carried over to the next round. The cut-off was raised to 80 during round two and a list of 25 items was generated. CONCLUSIONS: This project is a key step in the development of prospectively validated classification criteria that will create a more inclusive population of patients with DM for clinical research. What's already known about this topic? Proper classification of patients with skin-predominant dermatomyositis (DM) is indispensable in the appropriate conduct of clinical/translational research in the field. The only validated European League Against Rheumatism/American College of Rheumatology criteria for idiopathic inflammatory myopathies are able to classify skin-predominant DM. However, a quarter of amyopathic patients still fail the criteria and does not meet the disease classification. What does this study add? A list of 25 potential criteria divided into categories of distribution, morphology, symptomatology, pathology and contextual factors has been generated after several rounds of consensus exercise among experts in the field of DM. This Delphi project is a prerequisite to the development of a validated classification criteria set for skin-predominant DM.

DOI： 10.1111/bjd.18096

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Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized as progressive and irreversible fibrosis in the interstitium of lung tissues. There is still an unmet need to develop a novel therapeutic drug for IPF. We have previously demonstrated that periostin, a matricellular protein, plays an important role in the pathogenesis of pulmonary fibrosis. However, the underlying mechanism of how periostin causes pulmonary fibrosis remains unclear. In this study, we sought to learn whether the cross-talk between TGF-β (transforming growth factor-β), a central mediator in pulmonary fibrosis, and periostin in lung fibroblasts leads to generation of pulmonary fibrosis and whether inhibitors for integrin αVβ3, a periostin receptor, can block pulmonary fibrosis in model mice and the TGF-β signals in fibroblasts from patients with IPF. We found that cross-talk exists between TGF-β and periostin signals via αVβ3/β5 converging into Smad3. This cross-talk is necessary for the expression of TGF-β downstream effector molecules important for pulmonary fibrosis. Moreover, we identified several potent integrin low-molecular-weight inhibitors capable of blocking cross-talk with TGF-β signaling. One of the compounds, CP4715, attenuated bleomycin-induced pulmonary fibrosis in vivo in mice and the TGF-β signals in vitro in fibroblasts from patients with IPF. These results suggest that the cross-talk between TGF-β and periostin can be targeted for pulmonary fibrosis and that CP4715 can be a potential therapeutic agent to block this cross-talk.

DOI： 10.1165/rcmb.2019-0245OC

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BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a devastating disease with a median survival of only three to 5 years. Fibroblast proliferation is a hallmark of IPF as is secretion of extracellular matrix proteins from fibroblasts. However, it is still uncertain how IPF fibroblasts acquire the ability to progressively proliferate. Periostin is a matricellular protein highly expressed in the lung tissues of IPF patients, playing a critical role in the pathogenesis of pulmonary fibrosis. However, it remains undetermined whether periostin affects lung fibroblast proliferation. METHODS: In this study, we first aimed at identifying periostin-dependently expressed genes in lung fibroblasts using DNA microarrays. We then examined whether expression of cyclins and CDKs controlling cell cycle progression occur in a periostin-dependent manner. We next examined whether downregulation of cell proliferation-promoting genes by knockdown of periostin or integrin, a periostin receptor, using siRNA, is reflected in the cell proliferation of lung fibroblasts. We then looked at whether lung fibroblasts derived from IPF patients also require periostin for maximum proliferation. We finally investigated whether CP4715, a potent inhibitor against integrin αVβ3 (a periostin receptor), which we have recently found blocks TGF-β signaling, followed by reduced BLM-induced pulmonary fibrosis in mice, can block proliferation of lung fibroblasts derived from IPF patients. RESULTS: Many cell-cycle-related genes are involved in the upregulated or downregulated genes by periostin knockdown. We confirmed that in lung fibroblasts, periostin silencing downregulates expression of several cell-cycle-related molecules, including the cyclin, CDK, and, E2F families, as well as transcription factors such as B-MYB and FOXM1. Periostin or integrin silencing slowed proliferation of lung fibroblasts and periostin silencing increased the distribution of the G0/G1 phase, whereas the distribution of the G2/M phase was decreased. Lung fibroblasts derived from IPF patients also required periostin for maximum proliferation. Moreover, CP4715 downregulated proliferation along with expression of cell-cycle-related genes in IPF lung fibroblasts as well as in normal lung fibroblasts. CONCLUSIONS: Periostin plays a critical role in the proliferation of lung fibroblasts and the present results provide us a solid basis for considering inhibitors of the periostin/integrin αVβ3 interaction for the treatment of IPF patients.

DOI： 10.1186/s12931-020-1299-0

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OBJECTIVE: To clarify the incidence, risk factors, and impact of malignancy in patients with PM/DM-associated interstitial lung disease (ILD). METHODS: This study used data from 497 patients with PM/DM-associated ILD enrolled in a multicentre, retrospective and prospective cohort of incident cases. Cancer-associated myositis (CAM) was defined as malignancy diagnosed within 3 years before or after PM/DM diagnosis. Demographic and clinical information was recorded at the time of diagnosis, and data about the occurrence of mortality and malignancy was collected. RESULTS: CAM was identified in 32 patients with PM/DM-associated ILD (6.4%). Patients with CAM were older (64 vs 55 years, P < 0.001), presented with arthritis less frequently (24% vs 49%, P = 0.01), and showed a lower level of serum Krebs von den Lungen-6 (687 vs 820 IU/l, P = 0.03) than those without CAM. The distribution of myositis-specific autoantibodies, including anti-melanoma differentiation-associated gene 5, anti-aminoacyl tRNA synthetase, and anti-transcriptional intermediary factor 1-γ antibodies, did not differ between the groups. Survival analysis demonstrated that CAM patients had a poorer survival than non-CAM patients (P = 0.006), primarily due to excess deaths by concomitant malignancy, while mortality due to ILD-related respiratory failure was similar between the groups (P = 0.51). CONCLUSION: Concomitant malignancy can occur in patients with PM/DM-associated ILD, and has significant impact on mortality. Older age, lack of arthritis, and a lower level of serum Krebs von den Lungen-6 at diagnosis are predictors of concomitant malignancy.

DOI： 10.1093/rheumatology/kez238

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© 2019 The Author(s). Published by S. Karger AG, Basel. We present a case of psoriasiform dermatitis developing during the treatment of juvenile idiopathic arthritis with tocilizumab (TCZ). The keratotic erythema with central healing showed a periodicity of growing worse 1 week after TCZ infusion, and then disappeared within 3 weeks. Skin biopsy showed parakeratosis, microabscess, rete ridge elongation, and abundant lymphocytes as well as a few neutrophil infiltrate in the upper dermis. TCZ is a humanized monoclonal antibody against interleukin 6 (IL-6) receptor. IL-6 plays a critical role in the differentiation from naïve T cells into Th17 cells in cooperation with transforming growth factor-β. IL-6 may be important in psoriasis pathogenesis, and therefore this phenomenon may be the adverse effect. The mechanism of TCZ-associated psoriasiform dermatitis is unclear. The serum IL-6 level seems to be elevated transitorily after TCZ administration, probably due to the competitive inhibition of IL-6 receptor alpha to IL-6. Excess free IL-6 may effect on other IL-6 family receptors. Since TCZ does not alter serum IL-17F level, another cytokine may be involved in the psoriasis formation in our case. Psoriasiform dermatitis during the use of TCZ may be due to relative cytokine balance disturbance.

DOI： 10.1159/000504429

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DOI： 10.1001/jamadermatol.2019.1668

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Toxic epidermal necrolysis (TEN) is a rare condition, causing life-threatening adverse cutaneous reactions. TEN occurrence after bone marrow transplantation (BMT) is a well-known phenomenon; however, to date, only a few cases have been reported in the published work. Here, we describe the case of a 53-year-old woman who experienced TEN after undergoing allogenic BMT for malignant lymphoma. Skin erosion spread across a maximum of 70% of the body surface area and severe mucosal lesions developed. Steroid pulse therapy, plasma apheresis and immunoglobulin therapy were administrated, which resulted in the complete resolution of TEN. However, she developed hemophagocytic lymphohistiocytosis and died 38 days after BMT, owing to rupture of the lower digestive tract complicated by multi-organ failure. In our case, engraftment failure occurred, and the peripheral white blood cell count was less than 100/μL during the TEN course, suggesting that the presence of only a few immune cells could cause TEN. Our findings showed that high mortality rates and widespread skin erosion could be regarded as the most important characteristics of TEN occurring after BMT.

DOI： 10.1111/1346-8138.14913

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Hydroxychloroquine is recommended as the first-line systemic treatment for cutaneous lupus erythematosus (CLE) in Western countries, and it was approved in Japan in 2016. However, the efficacy of hydroxychloroquine in various cutaneous lupus erythematosus subtypes in Japanese patients has not been elucidated to date. Therefore, we investigated the efficacy of hydroxychloroquine for the treatment of cutaneous manifestations according to CLE subtypes in Japanese patients. We enrolled 35 patients (29 diagnosed with systemic lupus erythematosus and six with CLE) in this retrospective study. We analyzed the efficacy of hydroxychloroquine for the treatment of cutaneous manifestations according to cutaneous lupus erythematosus subtypes, time to the first skin improvement, as well as effects on laboratory data and reduction of concomitant immunosuppressive drug administration at 16 and 32 weeks of therapy. Complete improvement was observed at high rates for acute CLE (ACLE); however, partial or non-improvement rates were higher for chronic CLE (CCLE) at 16 weeks. Several patients with alopecia without scarring achieved complete improvement at 32 weeks. CCLE tended to take more time to improve than ACLE. Overall, hydroxychloroquine was highly effective for skin: 87% of patients had at least some beneficial response at 16 weeks. Nevertheless, there were wide variations in complete improvement rates and duration for improvement among CLE subtypes. Our findings suggest that a therapeutic approach considering the subtypes of CLE will improve its management.

DOI： 10.1111/1346-8138.14802

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DOI： 10.1016/j.jaci.2019.01.004

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Caveolin-1 (CAV-1) is the principal component of caveolae that regulates a variety of signaling molecules and receptors. Our previous study revealed CAV-1 reduction in the epidermis of patients with psoriasis, which leads to enhanced Janus kinase/signal transducer and activator of transcription activation and cytokine production, suggesting that aberrant CAV-1 expression may contribute to psoriatic inflammation. This study aimed to investigate whether abnormal modulation of CAV-1 on immune cells is involved in the pathogenesis of psoriasis. We observed that CAV-1 level in psoriasis patients was apparently reduced in peripheral blood mononuclear cells (PBMCs) and it was prominent in CD14+ monocytes. CAV-1 silencing in monocytes represented elevated levels of interleukin (IL)-1β and IL-6, and those had enhanced chemotaxis activity. In a murine model of psoriasis-like inflammation induced by imiquimod, we observed a significant CAV-1 reduction in PBMCs. Systemic administration of CAV-1 scaffolding domain peptide significantly improved the skin phenotype with less macrophage infiltration. Taken together, aberrant CAV-1 expression in monocytes may be involved in the pathogenesis of psoriasis.

DOI： 10.1038/s41598-018-36767-5

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DOI： 10.1111/1346-8138.14237

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BACKGROUND: Low C-C chemokine receptor 1 (CCR1) and interleukin (IL)-10 expression is associated with risk of Behçet's disease (BD). The objective of the present study was to clarify the pathological roles of CCR1 and IL10 loci identified by previous BD genome-wide association studies (GWASs). METHODS: M1 and M2 macrophages (Mφ) were differentiated with granulocyte-macrophage colony-stimulating factor or macrophage colony-stimulating factor (M-CSF) from peripheral monocytes of healthy control subjects (HC) and patients with BD. Expression of CD68 and CD163 was evaluated to test for Mφ polarization. CCR1 and IL-10 messenger RNA (mRNA) and protein expression was compared according to CCR1 and IL10 single-nucleotide polymorphism (SNP) genotypes. The migratory ability of M1 and M2 Mφ toward CCR1 ligand macrophage inflammatory protein (MIP)-1α was compared. The ratio of M1 and M2 Mφ in skin lesions of BD and systemic sclerosis (SSc), which was reported to be M2 Mφ-dominant, was compared. To examine the plasticity of polarized Mφ, the differentiated cells were cultured with either the same or the other culture condition. RESULTS: Preferential expression of CD163, CCR1, and IL-10 was found in M2 Mφ compared with M1 Mφ. M2 Mφ migrated more sensitively to low concentrations of MIP-1α than M1 Mφ did. BD-derived M1 Mφ showed higher CCR1 surface expression than HC-derived M1 Mφ did. IL10 and CCR1 mRNA expression differences were observed by GWAS-identified SNP genotypes in polarized Mφ. BD skin lesions showed M1 Mφ predominance compared with SSc skin lesions. A plasticity assay revealed that M-CSF restored IL-10 synthesis and reduced IL-6 production by M1 Mφ. CONCLUSIONS: The present study reveals that GWAS-identified SNPs contribute to M1 Mφ-predominant inflammation in BD. Our data also suggest that the skewed Mφ polarization is correctable by immunological intervention.

DOI： 10.1186/s13075-018-1613-0

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BACKGROUND: Periostin is a matricellular protein that belongs to a class of extracellular matrix (ECM)-related molecules defined by their ability to modulate cell-matrix interactions. We previously reported an elevated level of circulating periostin in patients with systemic sclerosis (SSc) and its association with the severity of skin sclerosis. OBJECTIVE: To examine the role of periostin in transforming growth factor (TGF)-β signaling involved in fibrosis. METHODS: Levels of periostin were examined in skin and lung fibroblasts obtained from SSc patients. Levels of ECM proteins and pro-fibrotic factors were evaluated in periostin-expressing human skin fibroblasts in the presence or absence of TGF-β. Effects of periostin on the Smad proteins were also evaluated following stimulation with TGF-β by immunoblotting, immunofluorescence staining, and RNA interference. RESULTS: Periostin was strongly expressed in skin and lung fibroblasts from SSc patients. Although recombinant periostin alone did not affect ECM protein levels, TGF-β and recombinant periostin treatment or periostin overexpression in skin fibroblasts significantly enhanced the production of ECM proteins. Overexpression of periostin in the presence of TGF-β also augmented expressions of α-smooth muscle actin and early growth response-1 but decreased the level and activity of matrix metalloproteinase 1. Interestingly, the level of Smad 7, a TGF-β-inducible inhibitor of TGF-β signaling, was reduced in periostin-expressing fibroblasts but increased in periostin-silenced fibroblasts. In addition, Smad 7 reduction induced by periostin was partially inhibited in integrin αV-silenced fibroblasts. CONCLUSION: Periostin contributes to fibrosis by enhancing TGF-β signaling via Smad 7 inhibition, which may lead to ECM deposition and periostin generation.

DOI： 10.1016/j.jdermsci.2018.02.001

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Autosomal recessive cerebellar ataxias (ARCAs) are clinically and genetically heterogeneous neurological disorders. Through whole-exome sequencing of Japanese ARCA patients, we identified three index patients from unrelated families who had biallelic mutations in ERCC4. ERCC4 mutations have been known to cause xeroderma pigmentosum complementation group F (XP-F), Cockayne syndrome, and Fanconi anemia phenotypes. All of the patients described here showed very slowly progressive cerebellar ataxia and cognitive decline with choreiform involuntary movement, with young adolescent or midlife onset. Brain MRI demonstrated atrophy that included the cerebellum and brainstem. Of note, cutaneous symptoms were very mild: there was normal to very mild pigmentation of exposed skin areas and/or an equivocal history of pathological sunburn. However, an unscheduled DNA synthesis assay of fibroblasts from the patient revealed impairment of nucleotide excision repair. A similar phenotype was very recently recognized through genetic analysis of Caucasian cerebellar ataxia patients. Our results confirm that biallelic ERCC4 mutations cause a cerebellar ataxia-dominant phenotype with mild cutaneous symptoms, possibly accounting for a high proportion of the genetic causes of ARCA in Japan, where XP-F is prevalent.

DOI： 10.1038/s10038-017-0408-5

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DOI： 10.1684/ejd.2017.3174

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BACKGROUND: Recent studies have indicated that serum levels of squamous cell carcinoma antigen (SCCA) 1 and 2 induced by type 2 cytokines such as IL-4 and IL-13, are increased in patients with atopic dermatitis (AD). However, no clinical studies have analyzed serum levels of SCCA2 in larger series of AD patients or their association with various clinical characteristics. This study was performed to clarify whether serum levels of SCCA2 are associated with disease severity and clinical phenotypes of adult AD patients. METHODS: An enzyme-linked immunosorbent assay was performed to examine serum SCCA2 levels in 240 adult patients with AD and 25 healthy controls in this study. Serum SCCA2 levels were analyzed with clinical characteristics and laboratory parameters including thymus and activation-regulated chemokine (TARC), lactate dehydrogenase (LDH), blood eosinophils, total IgE, and specific IgE (Japanese cedar pollen, Dermatophagoides farina, Candida, malassezia, Staphylococcal enterotoxin B). Expression of SCCA2 in AD eruption was examined by immunohistochemistry. The effect of treatment on serum SCCA2 was also assessed. RESULTS: Serum SCCA2 level showed a positive correlation with disease severity, levels of TARC, LDH, eosinophil counts, and IgE levels. Robust expression of SCCA2 was detected in the supra basal keratinocytes in the epidermis of AD patients. Serial measurements of serum SCCA2 revealed decreased levels of SCCA2 after treatment for AD. CONCLUSIONS: Serum SCCA2 levels reflected disease severity and clinical type of AD. Serum SCCA2 may thus be a relevant biomarker for AD.

DOI： 10.1016/j.alit.2017.06.016

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© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. Objective. To identify initial predictors of poor survival in patients with PM/DM-associated interstitial lung disease (ILD). Methods. We established a multicentre retrospective cohort of incident cases of PM/DM-associated ILD from 44 institutions across Japan (Multicentre Retrospective Cohort of Japanese Patients with Myositisassociated ILD, JAMI). Inclusion criteria were an onset age ≥16 years; PM/DM or clinically amyopathic DM according to the published criteria; imaging evidence of ILD; and availability of serum samples for assays of autoantibodies such as anti-melanoma differentiation-associated gene 5 and anti-aminoacyl tRNA synthetase. We collected demographic data and clinical characteristics recorded at the time of diagnosis, as well as follow-up survival data. Predictors of ILD-related mortality were identified by univariate and multivariate analyses. Results. JAMI enrolled a cohort of 497 patients with PM (15%), classic DM (32%) and clinically amyopathic DM (53%). During the observation period (median 20 months), 76 died of respiratory insufficiency directly related to ILD. Univariate analysis revealed several initial parameters associated with ILD mortality, including demographic, clinical, laboratory, imaging and autoantibody variables. We used multivariate analysis with a stepwise selection of parameters to generate an appropriate predictive model, and identified the following independent risk factors for ILD mortality: age at onset ≥60 years [hazard ratio (HR) = 4.3, 95% CI: 2.4, 7.5], CRP ≥1 mg/dl (HR = 2.6, 95% CI: 1.5, 4.8), peripheral capillary oxygen saturation <95% (HR = 2.0, 95% CI: 1.2, 3.4) and anti-melanoma differentiation-associated gene 5 antibody (HR = 7.5, 95% CI: 2.8, 20.2). Conclusion. We established a large cohort of incident cases of PM/DM-associated ILD, and successfully identified independent predictors of short-term ILD mortality.

DOI： 10.1093/rheumatology/key060

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DOI： 10.1111/1346-8138.13711

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BACKGROUND: Atopic dermatitis (AD) is a chronic, pruritic inflammatory skin disease in which type 2 allergic inflammation plays an important role. Collagen tripeptide (CTP) is a functional collagen fraction with a high content of Gly-X-Y tripeptides. OBJECTIVE: To examine the effect of CTP on inflammation in AD. METHODS: Levels of inflammatory cytokines and chemokines, such as thymus- and activation-regulated chemokine (TARC), macrophage-derived chemokine, and thymic stromal lymphopoietin (TSLP), were examined in human keratinocytes supplemented with or without CTP under AD-like inflammation. To evaluate the functional effect of CTP, a migration assay was performed using the supernatants of cultured keratinocytes treated with CTP. The signaling pathway for CTP inhibitory activity was also determined. Additionally, we conducted a clinical trial with seventeen AD patients who were assigned randomly to receive daily for 12 weeks either 3.9g of a CTP product or normal collagen peptides (CP). The eruption area, severity scoring of atopic dermatitis (SCORAD), skin hydration, transepidermal water loss (TEWL), and itching score were evaluated. The levels of TARC, serum IgE, lactate dehydrogenase, and eosinophil counts at week 12 were also compared with those at the start of administration. RESULTS: In human keratinocytes, TARC and TSLP mRNA and protein levels were inhibited significantly by CTP treatment under AD-like inflammation. Supernatants obtained from CTP-treated keratinocytes inhibited cell migration. STAT1 phosphorylation was significantly decreased by CTP in a dose-dependent manner. In the clinical trial, 13 patients (7 for CTP, 6 for CP) completed the study. The eruption area, SCORAD, and TEWL at week 12 were reduced significantly compared with the initial values in the CTP but not CP group. A significant reduction in the serum TARC level was observed only in the CTP group at week 12. Other blood parameters were not improved in either group. CONCLUSION: CTP may have therapeutic benefit for AD by inhibiting type 2-skewed allergic inflammation.

DOI： 10.1016/j.jdermsci.2017.09.002

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Psoriatic arthritis (PsA), a chronic inflammatory arthropathy associated with psoriasis, is an intractable immune disorder and refractory to pharmacological intervention. We assessed efficacy of selective depletion of myeloid lineage leukocytes in patients with PsA in a multicenter setting. A total of 20 patients with moderate to severe PsA refractory to conventional and biological disease-modifying antirheumatic drugs were included. Eligible patients had 3 points or more in the classification criteria for PsA. Each patient received five sessions, once a week, of adsorptive granulocyte and monocyte apheresis (GMA) with the Adacolumn® . The primary efficacy outcome was 20% or more decrease in the American College of Rheumatology score 20 (ACR20). Partial responders could receive an additional five GMA sessions. Of 20 patients, two did not complete the study, nine responded to five GMA sessions and nine received 10 sessions. At the first evaluation 2 weeks after the last GMA session, 13 of the 20 (65.0%) patients achieved ACR20. ACR20 was maintained in seven of 10 (70%) and five of 10 (50%) patients at the follow-up evaluation points 8 and 20 weeks after the last GMA session, respectively. GMA was well tolerated without any safety concern. This study demonstrates that GMA with the Adacolumn was effective with good safety profile in patients with PsA refractory to pharmacologicals. The results indicate a major role for myeloid leukocytes in the immunopathogenesis of PsA. A large controlled study is warranted to fully evaluate the efficacy of Adacolumn GMA in patients with PsA.

DOI： 10.1111/1346-8138.13975

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Melanoma has an extremely poor prognosis due to its rapidly progressive and highly metastatic nature. Several therapeutic drugs have recently become available, but are effective only against melanoma with specific BRAF gene mutation. Thus, there is a need to identify other target molecules. We show here that Transient receptor potential, canonical 3 (TRPC3) is widely expressed in human melanoma. We found that pharmacological inhibition of TRPC3 with a pyrazole compound, Pyr3, decreased melanoma cell proliferation and migration. Similar inhibition was observed when the TRPC3 gene was silenced with short-hairpin RNA (shRNA). Pyr3 induced dephosphorylation of signal transducer and activator of transcription (STAT) 5 and Akt. Administration of Pyr3 (0.05 mg/kg) to mice implanted with human melanoma cells (C8161) significantly inhibited tumor growth. Our findings indicate that TRPC3 plays an important role in melanoma growth, and may be a novel target for treating melanoma in patients.

DOI： 10.1007/s12576-016-0480-1

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BACKGROUND: Patients with steroid-resistant bullous pemphigoid (BP) require an appropriate treatment option. OBJECTIVE: A multicenter, randomized, placebo-controlled, double-blind trial was conducted to investigate the therapeutic effect of high-dose intravenous immunoglobulin (IVIG; 400mg/kg/day for 5days) in BP patients who showed no symptomatic improvement with prednisolone (≥0.4mg/kg/day) administered. METHODS: We evaluated the efficacy using the disease activity score on day15 (DAS15) as a primary endpoint, and changes in the DAS over time, the anti-BP180 antibody titer, and safety for a period of 57days as secondary endpoints. RESULTS: We enrolled 56 patients in this study. The DAS15 was 12.5 points lower in the IVIG group than in the placebo group (p=0.089). The mean DAS of the IVIG group was constantly lower than that of the placebo group throughout the course of observation, and a post hoc analysis of covariance revealed a significant difference (p=0.041). Furthermore, when analyzed only in severe cases (DAS≥40), the DAS15 differed significantly (p=0.046). The anti-BP180 antibody titers showed no difference between the two groups. CONCLUSION: IVIG provides a beneficial therapeutic outcome for patients with BP who are resistant to steroid therapy.

DOI： 10.1016/j.jdermsci.2016.11.003

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DOI： 10.1111/1346-8138.13434

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The natural course of idiopathic pulmonary fibrosis (IPF) is variable. Predicting disease progression and survival in IPF is important for treatment. We previously demonstrated that serum periostin has the potential to be a prognostic biomarker for IPF. Our aim was to use monomeric periostin in a multicenter study to evaluate its efficacy in diagnosing IPF and predicting its progression. To do so, we developed a new periostin kit to detect only monomeric periostin. The subjects consisted of 60 IPF patients in a multicenter cohort study. We applied monomeric periostin, total periostin detected by a conventional kit, and the conventional biomarkers-KL-6, SP-D, and LDH-to diagnose IPF and to predict its short-term progression as estimated by short-term changes of %VC and % DL, CO. Moreover, we compared the fraction ratios of monomeric periostin to total periostin in IPF with those in other periostin-high diseases: atopic dermatitis, systemic scleroderma, and asthma. Monomeric periostin showed the greatest ability to identify IPF comparable with KL-6 and SP-D. Both monomeric and total periostin were well correlated with the decline of %VC and % DL, CO. Clustering of IPF patients into high and low periostin groups proved useful for predicting the short-term progression of IPF. Moreover, the relative ratio of monomeric periostin was higher in IPF than in other periostin-high diseases. Measuring monomeric periostin is useful for diagnosing IPF and predicting its short-term progression. Moreover, the ratio of monomeric periostin to total periostin is elevated in IPF compared to other periostin-high diseases.

DOI： 10.1371/journal.pone.0174547

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DOI： 10.1111/1346-8138.13177

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BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe adverse drug reactions with high mortality. METHODS: To present the clinical characteristics of SJS and TEN in Japan and evaluate the efficacy of treatments, we retrospectively analyzed cases of SJS and TEN treated in 2 university hospitals during 2000-2013. RESULTS: Fifty-two cases of SJS (21 males and 31 females; average age, 55.1 years) and 35 cases of TEN (17 males and 18 females; average age, 56.6 years) were included in this study. Twenty-eight cases of SJS (53.8%) and all cases of TEN were caused by drugs. Hepatitis was the most common organ involvement in both SJS and TEN. Renal dysfunction, intestinal disorder, and respiratory disorder were also involved in some cases. The major complication was pneumonia and sepsis. All cases except for 3 cases were treated systemically with corticosteroids. Steroid pulse therapy was performed in 88.6% of TEN. Plasmapheresis and/or immunoglobulin therapy was combined with steroid therapy mainly in TEN after 2007. The mortality rate was 6.9% and the rates for SJS and TEN were 1.9% and 14.3%, respectively. These were much lower than predicted mortality according to a severity-of-illness scoring system for TEN prognosis (SCORTEN) score. When comparing the mortality rate between 2000-2006 and 2007-2013, it was decreased from 4.5% to 0.0% in SJS and from 22.2% to 5.3% in TEN. CONCLUSIONS: Treatment with steroid pulse therapy in combination with plasmapheresis and/or immunoglobulin therapy seems to have contributed to prognostic improvement in SJS/TEN.

DOI： 10.1016/j.alit.2015.09.001

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BACKGROUND: Squamous cell carcinoma antigen (SCCA) belongs to the ovalbumin-serpin family and is a known tumour marker. Expression of SCCA is upregulated in the serum and skin of patients with psoriasis. OBJECTIVES: The aim of this study was to determine SCCA2 levels in association with disease severity and treatment efficacy in patients with psoriasis. MATERIALS AND METHODS: Patients with psoriasis (n = 123) and healthy controls (n = 25) were enrolled in this prospective cross-sectional study. Enzyme-linked immunosorbent assay (ELISA) analysis was performed to determine serum SCCA2 levels. SCCA2 expression in skin was evaluated using immunohistochemical analysis. Serum SCCA2 levels were compared with Psoriasis Area Severity Index (PASI) scores. The effect of treatment on serum SCCA2 levels was assessed using serial examinations. Induction of SCCA2 by several psoriatic cytokines in human keratinocytes was evaluated. RESULTS: The serum levels of SCCA2 were significantly higher in patients with psoriasis than healthy controls and correlated well with disease severity. Increased SCCA2 staining was observed in lesional skin but not in nonlesional skin of patients with psoriasis. In addition, SCCA2 expression levels in skin correlated with serum concentrations of SCCA2. SCCA2 significantly decreased according to improvement of PASI scores. Interleukin (IL)-17 and IL-22 synergistically increased the production of SCCA2 at both mRNA and protein levels in human keratinocytes. CONCLUSIONS: Significant elevation of SCCA2 is associated with disease severity and reflects treatment efficacy. SCCA2 may be a useful biomarker in psoriasis, reflecting T-helper 17-type inflammation - the main determinant of the severity of psoriasis.

DOI： 10.1111/bjd.14426

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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. CAV1 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-α (TNF-α), 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-α, 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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BACKGROUND: Epidermal hyperplasia is a histological hallmark observed in both atopic dermatitis (AD) and psoriasis, although the clinical features and the underlying immunological disorders of these diseases are different. We previously showed that periostin, a matricellular protein, plays a critical role in epidermal hyperplasia in AD, using a mouse model and a 3-dimensional organotypic coculture system. In this study, we explore the hypothesis that periostin is involved in epidermal hyperplasia in psoriasis. METHODS: To examine expression of periostin in psoriasis patients, we performed immunohistochemical analysis on skin biopsies from six such patients. To investigate periostin's role in the pathogenesis of psoriasis, we evaluated periostin-deficient mice in a psoriasis mouse model induced by topical treatment with imiquimod (IMQ). RESULTS: Periostin was substantially expressed in the dermis of all investigated psoriasis patients. Epidermal hyperplasia induced by IMQ treatment was impaired in periostin-deficient mice, along with decreased skin swelling. However, upon treatment with IMQ, periostin deficiency did not alter infiltration of inflammatory cells such as neutrophils; production of IL-17, -22, or -23; or induction/expansion of IL-17- and IL-22-producing group 3 innate lymphoid cells. CONCLUSIONS: Periostin plays an important role during epidermal hyperplasia in IMQ-induced skin inflammation, independently of the IL-23-IL-17/IL-22 axis. Periostin appears to be a mediator for epidermal hyperplasia that is common to AD and psoriasis.

DOI： 10.1016/j.alit.2014.06.001

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DOI： 10.1684/ejd.2015.2622

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Background Recent findings indicate that periostin, an extracellular matrix protein induced by T helper 2 cytokines, plays a critical role in the pathogenesis of atopic dermatitis (AD).
Objectives To determine whether serum periostin level is associated with clinical phenotype in adult patients with AD.
Methods An enzyme-linked immunosorbent assay was performed to determine serum periostin levels in 257 adult patients with AD, 66 patients with psoriasis vulgaris (PV) as a disease control and 25 healthy controls. Serum periostin levels were analysed together with clinical characteristics and laboratory parameters, including thymus and activation-regulated chemokine (TARC), lactate dehydrogenase (LDH), blood eosinophil count and total IgE. Immunohistochemical analysis evaluated the expression of periostin in association with various clinical phenotypes of AD. The effect of treatment on serum periostin level was also assessed.
Results Serum periostin was significantly higher in patients with AD than in patients with PV and healthy controls. Periostin level was found to be positively correlated with disease severity, TARC level, LDH level and eosinophil count, but not with IgE level. Higher serum periostin level was observed in patients with extrinsic AD compared with patients with intrinsic AD; the positive correlation of disease severity disappeared in patients with intrinsic AD. Robust expression of periostin was detected in the dermis of patients with AD with erythroderma, lichenification and, to a lesser extent, scaly erythema. Serial measurement of serum periostin revealed decreased levels of periostin after treatment for AD.
Conclusions Periostin may play a critical role in disease severity and chronicity in the pathogenesis of AD.

DOI： 10.1111/bjd.12943

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Extracellular matrix (ECM) is not only involved in the maintenance of normal physiological tissue but also in interactions with other ECM components, tissue remodeling, and modulating immune responses. The skin provides a distinctive environment characterized by rich fibroblasts producing various ECM proteins, epithelial-mesenchymal interactions, and immune responses induced by external stimuli. Recently, periostin-a matricellular protein-has been highlighted for its pivotal functions in the skin. Analysis of periostin null mice has revealed that periostin contributes to collagen fibrillogenesis, collagen cross-linking, and the formation of ECM meshwork via interactions with other ECM components. Periostin expression is enhanced by mechanical stress or skin injury; this is indicative of the physiologically protective functions of periostin, which promotes wound repair by acting on keratinocytes and fibroblasts. Along with its physiological functions, periostin plays pathogenic roles in skin fibrosis and chronic allergic inflammation. In systemic sclerosis (SSc) patients, periostin levels reflect the severity of skin fibrosis. Periostin null mice have shown reduced skin fibrosis in a bleomycin-induced SSc mouse model, indicating a key role of periostin in fibrosis. Moreover, in atopic dermatitis (AD), attenuated AD phenotype has been observed in periostin null mice in a house dust mite extract-induced AD mouse model. Th2 cytokine-induced periostin acts on keratinocytes to produce inflammatory cytokines that further enhance the Th2 response, thereby sustaining and amplifying chronic allergic inflammation. Thus, periostin is deeply involved in the pathogenesis of AD and other inflammation-related disorders affecting the skin. Understanding the dynamic actions of periostin would be key to dissecting pathogenesis of skin-related diseases and to developing novel therapeutic strategies.

DOI： 10.2332/allergolint.13-RAI-0685

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DOI： 10.1684/ejd.2014.2442

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BACKGROUND: Recent findings indicate that periostin, an extracellular matrix protein induced by T helper 2 cytokines, plays a critical role in the pathogenesis of atopic dermatitis (AD). OBJECTIVES: To determine whether serum periostin level is associated with clinical phenotype in adult patients with AD. METHODS: An enzyme-linked immunosorbent assay was performed to determine serum periostin levels in 257 adult patients with AD, 66 patients with psoriasis vulgaris (PV) as a disease control and 25 healthy controls. Serum periostin levels were analysed together with clinical characteristics and laboratory parameters, including thymus and activation-regulated chemokine (TARC), lactate dehydrogenase (LDH), blood eosinophil count and total IgE. Immunohistochemical analysis evaluated the expression of periostin in association with various clinical phenotypes of AD. The effect of treatment on serum periostin level was also assessed. RESULTS: Serum periostin was significantly higher in patients with AD than in patients with PV and healthy controls. Periostin level was found to be positively correlated with disease severity, TARC level, LDH level and eosinophil count, but not with IgE level. Higher serum periostin level was observed in patients with extrinsic AD compared with patients with intrinsic AD; the positive correlation of disease severity disappeared in patients with intrinsic AD. Robust expression of periostin was detected in the dermis of patients with AD with erythroderma, lichenification and, to a lesser extent, scaly erythema. Serial measurement of serum periostin revealed decreased levels of periostin after treatment for AD. CONCLUSIONS: Periostin may play a critical role in disease severity and chronicity in the pathogenesis of AD.

DOI： 10.1111/bjd.12943

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Extracellular matrix (ECM) is not only involved in the maintenance of normal physiological tissue but also in interactions with other ECM components, tissue remodeling, and modulating immune responses. The skin provides a distinctive environment characterized by rich fibroblasts producing various ECM proteins, epithelial-mesenchymal interactions, and immune responses induced by external stimuli. Recently, periostin-a matricellular protein-has been highlighted for its pivotal functions in the skin. Analysis of periostin null mice has revealed that periostin contributes to collagen fibrillogenesis, collagen cross-linking, and the formation of ECM meshwork via interactions with other ECM components. Periostin expression is enhanced by mechanical stress or skin injury; this is indicative of the physiologically protective functions of periostin, which promotes wound repair by acting on keratinocytes and fibroblasts. Along with its physiological functions, periostin plays pathogenic roles in skin fibrosis and chronic allergic inflammation. In systemic sclerosis (SSc) patients, periostin levels reflect the severity of skin fibrosis. Periostin null mice have shown reduced skin fibrosis in a bleomycin-induced SSc mouse model, indicating a key role of periostin in fibrosis. Moreover, in atopic dermatitis (AD), attenuated AD phenotype has been observed in periostin null mice in a house dust mite extract-induced AD mouse model. Th2 cytokine-induced periostin acts on keratinocytes to produce inflammatory cytokines that further enhance the Th2 response, thereby sustaining and amplifying chronic allergic inflammation. Thus, periostin is deeply involved in the pathogenesis of AD and other inflammation-related disorders affecting the skin. Understanding the dynamic actions of periostin would be key to dissecting pathogenesis of skin-related diseases and to developing novel therapeutic strategies.

DOI： 10.2332/allergolint.13-RAI-0685

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Systemic sclerosis (SSc) is characterized by excessive fibrosis of the skin and internal organs due to fibroblast proliferation and excessive production of extracellular matrix (ECM). We have shown that insulin-like growth factor binding protein (IGFBP)-5 plays an important role in the development of fibrosis in vitro, ex vivo, and in vivo. We identified a membrane-associated adaptor protein, downstream of tyrosine kinase/docking protein (DOK)5, as an IGFBP-5-regulated target gene using gene expression profiling of primary fibroblasts expressing IGFBP-5. DOK5 is a tyrosine kinase substrate associated with intracellular signaling. Our objective was to determine the role of DOK5 in the pathogenesis of SSc and specifically in IGFBP-5-induced fibrosis. DOK5 mRNA and protein levels were increased in vitro by endogenous and exogenous IGFBP-5 in primary human fibroblasts. DOK5 upregulation required activation of the mitogen-activated protein kinase (MAPK) signaling cascade. Further, IGFBP-5 triggered nuclear translocation of DOK5. DOK5 protein levels were also increased in vivo in mouse skin and lung by IGFBP-5. To determine the effect of DOK5 on fibrosis, DOK5 was expressed ex vivo in human skin in organ culture. Expression of DOK5 in human skin resulted in a significant increase in dermal thickness. Lastly, levels of DOK5 were compared in primary fibroblasts and lung tissues of patients with SSc and healthy donors. Both DOK5 mRNA and protein levels were significantly increased in fibroblasts and skin tissues of patients with SSc compared with those of healthy controls, as well as in lung tissues of SSc patients. Our findings suggest that IGFBP-5 induces its pro-fibrotic effects, at least in part, via DOK5. Furthermore, IGFBP-5 and DOK5 are both increased in SSc fibroblasts and tissues and may thus be acting in concert to promote fibrosis.

DOI： 10.1371/journal.pone.0087754

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INTRODUCTION: Altered phenotypes of circulating monocytes of patients with systemic sclerosis (SSc) have been reported, but the role of these alterations in the pathogenesis of SSc remains unclear. This study was undertaken to identify molecules that are preferentially expressed by SSc monocytes, and to investigate the roles of these molecules in the pathogenic process of SSc. METHODS: We analyzed circulating CD14⁺ monocytes isolated from 36 patients with SSc and 32 healthy control subjects. The monocytes' gene expression profiles were assessed by Oligo GEArray (SABiosciences, Frederic, MA, USA) and semiquantitative or quantitative PCR; their protein expression was evaluated in culture supernatants of unstimulated monocytes by immunoblotting or ELISA, and by immunocytostaining. Monocyte chemoattractant activity of CCL2 was assessed in a TransWell system (Corning Incorporated, Corning, NY, USA) in the presence or absence of chondroitin sulfate (CS). RESULTS: A step-wise approach to profiling gene expression identified that versican and CCL2 were upregulated in SSc monocytes. Subsequent analysis of proteins expressed in monocyte culture supernatants confirmed enhanced production of versican and CCL2 in SSc monocytes compared with control monocytes. CCL2 bound to CS chains of versican and colocalized with versican in the monocytes' Golgi apparatus. Finally, CCL2 had a greater ability to mediate monocyte migration when bound to CS chains, because this binding provided efficient formation of CCL2 gradients and protection from protease attack. CONCLUSION: Circulating monocytes with elevated versican and CCL2 levels may contribute to the fibrotic process in a subset of SSc patients by amplifying a positive feedback loop consisting of versican, CCL2, and the influx of monocytes.

DOI： 10.1186/ar4251

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New blood vessel formation is critical, not only for organ development and tissue regeneration, but also for various pathologic processes, such as tumor development and vasculopathy. The maintenance of the postnatal vascular system requires constant remodeling, which occurs through angiogenesis, vasculogenesis, and arteriogenesis. Vasculogenesis is mediated by the de novo differentiation of mature endothelial cells from endothelial progenitor cells (EPCs). Early studies provided evidence that bone marrow-derived CD14⁺ monocytes can serve as a subset of EPCs because of their expression of endothelial markers and ability to promote neovascularization in vitro and in vivo. However, the current consensus is that monocytic cells do not give rise to endothelial cells in vivo, but function as support cells, by promoting vascular formation and repair through their immediate recruitment to the site of vascular injury, secretion of proangiogenic factors, and differentiation into mural cells. These monocytes that function in a supporting role in vascular repair are now termed monocytic pro-angiogenic hematopoietic cells (PHCs). Systemic sclerosis (SSc) is a multisystem connective tissue disease characterized by excessive fibrosis and microvasculopathy, along with poor vascular formation and repair. We recently showed that in patients with SSc, circulating monocytic PHCs increase dramatically and have enhanced angiogenic potency. These effects may be induced in response to defective vascular repair machinery. Since CD14⁺ monocytes can also differentiate into fibroblast-like cells that produce extracellular matrix proteins, here we propose a new hypothesis that aberrant monocytic PHCs, once mobilized into circulation, may also contribute to the fibrotic process of SSc.

DOI： 10.14670/HH-28.175

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DOI： 10.1111/bjd.12117

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There are no effective treatments for fibrosis, an out-of-control wound-healing process in which excessive deposition of extracellular matrix (ECM) such as collagen, resulting in significant morbidity and mortality. Endostatin is a natural proteolytic fragment of collagen XVIII, which is known to possess potent antiangiogenic activity. Many clinical trials of endostatin have been conducted for anti-cancer therapy. In addition to antiangiogenic effects, recent studies have revealed that endostatin may suppress aberrant tissue remodeling and scarring. Neutralization of endogenous endostatin in rat myocardial infarction (MI) model worsened the outcomes of MI, indicating that endostatin may have protective role against left ventricular remodeling and heart failure after MI. Recently, we also reported inhibitory effects of peptides derived from endostatin on fibrosis. A peptide derived from the C-terminus of endostatin suppressed ECM production in fibroblasts in the presence of transforming growth factor-β (TGF-β), prevented TGF-β-induced dermal fibrosis ex vivo in human skin, and ameliorated skin and pulmonary fibrosis induced by bleomycin in vivo. The antifibrotic capacity was accompanied by reduced cell apoptosis and lower levels of lysyl oxidase and early growth response gene-1. Endostation may have the therapeutic potential for inhibiting fibrosis.

DOI： 10.2177/jsci.36.452

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Fibroproliferative disorders such as idiopathic pulmonary fibrosis and systemic sclerosis have no effective therapies and result in significant morbidity and mortality due to progressive organ fibrosis. We examined the effect of peptides derived from endostatin on existing fibrosis and fibrosis triggered by two potent mediators, transforming growth factor-β (TGF-β) and bleomycin, in human and mouse tissues in vitro, ex vivo, and in vivo. We identified one peptide, E4, with potent antifibrotic activity. E4 prevented TGF-β-induced dermal fibrosis in vivo in a mouse model, ex vivo in human skin, and in bleomycin-induced dermal and pulmonary fibrosis in vivo, demonstrating that E4 exerts potent antifibrotic effects. In addition, E4 significantly reduced existing fibrosis in these preclinical models. E4 amelioration of fibrosis was accompanied by reduced cell apoptosis and lower levels of lysyl oxidase, an enzyme that cross-links collagen, and Egr-1 (early growth response gene-1), a transcription factor that mediates the effects of several fibrotic triggers. Our findings identify E4 as a peptide with potent antifibrotic activity and a possible therapeutic agent for organ fibrosis.

DOI： 10.1126/scitranslmed.3003421

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Atopic dermatitis (AD) is a chronic inflammatory disease of the skin for which there are no reliable biomarkers to assess clinical severity. Serum interleukin-18 (IL-18) levels may be associated with AD severity. To identify putative biomarkers associated with clinical severity in adult AD patients, we enrolled 121 adult AD patients (mean age 35.7 years) and 50 healthy controls (mean age 31.7 years). We compared these groups for blood eosinophils and serum levels of IL-18, thymus and activation-regulated chemokine (TARC), total IgE, and lactate dehydrogenase (LDH). We also determined S. aureus enterotoxin B (SEB) specific IgE levels and the SCORingAD (SCORAD) scores for AD patients. For AD patients, stepwise logistic regression was used to estimate odds ratios (OR) for each biomarker for the likelihood of having AD, and multiple linear regression was used to identify biomarkers associated with SCORAD scores. Compared with healthy controls, adult AD patients had higher levels of IL-18, TARC, total IgE, eosinophils, and LDH. TARC levels had the highest OR for AD occurrence, while the OR for IL-18 was insignificant. Also, IL-18 was not related to the presence of SEB-IgE. Notably, IL-18 levels were significantly associated with SCORAD scores, as were TARC, total IgE, and LDH levels. A panel of biomarkers (IL-18, TARC, total IgE, and LDH) may be more useful to accurately assess clinical severity in adult AD patients.

DOI： 10.1007/s00403-011-1198-9

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BACKGROUND: Dry skin causes pruritus and discomfort in patients with xerosis and atopic dermatitis. General treatment for skin dryness involves the topical application of an emollient. However, more effective, simpler therapies are desired. Collagen tripeptide (CTP) is a highly purified, non-antigenic, low-allergenic collagen fraction that is known to have various biological effects. OBJECTIVE: To clarify the therapeutic effects of CTP for dry skin using acetone-induced dry skin model mice. METHODS: ICR mice were treated with acetone followed by oral administration of CTP (80 or 500mg/kg/day) for 3 days. Hyaluronic acid production induced by CTP was assessed using human dermal fibroblasts in vitro and in an acetone-induced dry skin model mice in vivo. Transepidermal water loss (TEWL) and scratching behavior were evaluated. Furthermore, the effects of CTP on intraepidermal nerve fibers and expression of semaphorin 3A (Sema3A) and nerve growth factor (NGF) were examined by immunohistochemistry and quantitative RT-PCR. RESULTS: CTP enhanced hyaluronic acid production in human dermal fibroblasts in vitro and in murine skin in vivo. Oral administration of CTP in acetone-induced dry skin model mice significantly decreased TEWL and suppressed scratching behavior. Intraepidermal nerve growth was dramatically inhibited in CTP-treated mice. Quantitative PCR analysis and immunohistochemical study revealed that CTP abolished the increased NGF and decreased Sema3A levels induced by acetone treatment. CONCLUSION: Oral administration of CTP improves dry skin and normalizes axon-guidance factors in the epidermis in addition to reducing pruritus. CTP may be used in a new therapeutic strategy against dry skin and pruritus.

DOI： 10.1016/j.jdermsci.2012.02.004

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Extracellular matrix deposition and tissue scarring characterize the process of fibrosis. Transforming growth factor beta (TGFβ) and Insulin-like growth factor binding protein-3 (IGFBP-3) have been implicated in the pathogenesis of fibrosis in various tissues by inducing mesenchymal cell proliferation and extracellular matrix deposition. We identified Syndecan-2 (SDC2) as a gene induced by TGFβ in an IGFBP-3-dependent manner. TGFβ induction of SDC2 mRNA and protein required IGFBP-3. IGFBP-3 independently induced production of SDC2 in primary fibroblasts. Using an ex-vivo model of human skin in organ culture expressing IGFBP-3, we demonstrate that IGFBP-3 induces SDC2 ex vivo in human tissue. We also identified Mitogen-activated protein kinase-interacting kinase (Mknk2) as a gene induced by IGFBP-3. IGFBP-3 triggered Mknk2 phosphorylation resulting in its activation. Mknk2 independently induced SDC2 in human skin. Since IGFBP-3 is over-expressed in fibrotic tissues, we examined SDC2 levels in skin and lung tissues of patients with systemic sclerosis (SSc) and lung tissues of patients with idiopathic pulmonary fibrosis (IPF). SDC2 levels were increased in fibrotic dermal and lung tissues of patients with SSc and in lung tissues of patients with IPF. This is the first report describing elevated levels of SDC2 in fibrosis. Increased SDC2 expression is due, at least in part, to the activity of two pro-fibrotic factors, TGFβ and IGFBP-3.

DOI： 10.1371/journal.pone.0043049

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Dermatomyositis (DM) is an idiopathic systemic inflammatory disease that is often accompanied by interstitial lung disease (ILD) or internal malignancy. New autoantibodies, anti-clinically amyopathic dermatomyositis 140 (anti-CADM-140) antibody (Ab) and anti-155/140 Ab, as well as anti-aminoacyl-tRNA synthetase (anti-ARS) Ab and anti-Mi-2 Ab, have been discovered and their utility indicated. However, the association between these autoantibodies and the clinical characteristics of DM is not fully understood, and it is unclear whether anti-155/140 Ab is "specific" to DM patients with internal malignancy. Therefore, we analyzed 55 DM patients and 18 non-DM patients with malignancy to evaluate the clinical characteristics, especially skin manifestations, in association with DM-specific autoantibodies detected by immunoprecipitation. Six patients (11%) had anti-CADM-140 Ab, nine (16%) had anti-155/140 Ab, eight (15%) had anti-ARS Ab and six (11%) had anti-Mi-2 Ab. The frequency of DM patients positive for any type of autoantibody was 53%. Among the 20 DM patients with ILD, three (15%) had both anti-CADM-140 Ab and rapidly progressive ILD, and required intensive therapy (P < 0.05). ILD found in anti-ARS Ab-positive patients did not progress rapidly. The prevalence of muscle involvement in patients with anti-CADM-140 Ab was 83%. Among the 18 DM patients with internal malignancy, four (22%) had anti-155/140 Ab, and internal malignancy was found in four cases (44%) of nine anti-155/140 Ab-positive patients. None of the non-DM patients with malignancy were positive for anti-155/140 Ab. In conclusion, the results of the present study indicate that anti-155/140 Ab is specific to DM patients with internal malignancy and that we may be able to predict prognosis of ILD and the presence of malignancy to some extent, suggesting that examination of autoantibodies in DM patients is clinically very useful. However, further investigation is needed because several findings differ from those of previous reports.

DOI： 10.1111/j.1346-8138.2011.01262.x

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Our previous studies have demonstrated increased expression of insulin-like growth factor binding protein-5 (IGFBP-5) in fibrotic tissues and IGFBP-5 induction of extracellular matrix (ECM) components. The mechanism resulting in increased IGFBP-5 in the extracellular milieu of fibrotic fibroblasts is unknown. Since Caveolin-1 (Cav-1) has been implicated to play a role in membrane trafficking and signal transduction in tissue fibrosis, we examined the effect of Cav-1 on IGFBP-5 internalization, trafficking and secretion. We demonstrated that IGFBP-5 localized to lipid rafts in human lung fibroblasts and bound Cav-1. Cav-1 was detected in the nucleus in IGFBP-5-expressing fibroblasts, within aggregates enriched with IGFBP-5, suggesting a coordinate trafficking of IGFBP-5 and Cav-1 from the plasma membrane to the nucleus. This trafficking was dependent on Cav-1 as fibroblasts from Cav-1 null mice had increased extracellular IGFBP-5, and as fibroblasts in which Cav-1 was silenced or lipid raft structure was disrupted through cholesterol depletion also had defective IGFBP-5 internalization. Restoration of Cav-1 function through administration of Cav-1 scaffolding peptide dramatically increased IGFBP-5 uptake. Finally, we demonstrated that IGFBP-5 in the ECM protects fibronectin from proteolytic degradation. Taken together, our findings identify a novel role for Cav-1 in the internalization and nuclear trafficking of IGFBP-5. Decreased Cav-1 expression in fibrotic diseases likely leads to increased deposition of IGFBP-5 in the ECM with subsequent reduction in ECM degradation, thus identifying a mechanism by which reduced Cav-1 and increased IGFBP-5 concomitantly contribute to the perpetuation of fibrosis.

DOI： 10.1111/j.1582-4934.2010.01063.x

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BACKGROUND: An increase in interleukin (IL)-18 production from epidermal cells has been reported in an atopic dermatitis (AD) mouse model, and subsequent topical application of Staphylococcus aureus results in severe dermatitis. OBJECTIVES: To reveal the relationship between S. aureus colonization of skin lesions and keratinocyte IL-18 production, particularly in AD with relatively low serum IgE levels. We also aimed to establish a simple and noninvasive method of assaying IL-18 produced by epidermal keratinocytes to evaluate local skin inflammation and therapeutic effects in patients with AD. METHODS: IL-18 in the horny layer of the skin was collected via a tape-stripping method and measured in 95 patients with AD and 40 healthy controls by enzyme-linked immunosorbent assay (ELISA). Clinical severity, blood data and S. aureus skin colonization were evaluated before and after treatment. RESULTS: IL-18 levels in the horny layer were significantly higher in the skin lesions of patients with AD than in healthy controls and correlated with SCORAD, levels of serum IL-18, IgE, lactate dehydrogenase, thymus and activation-regulated chemokine, blood eosinophils and transepidermal water loss. In the AD group with serum IgE < 1500 IU mL(-1) , significantly higher IL-18 levels were observed in the horny layer of patients colonized with S. aureus compared with those who were not. CONCLUSIONS: Epidermal IL-18 production was associated with the severity of AD. Staphylococcus aureus colonization seems to contribute to this IL-18 production, especially in the AD group with relatively low IgE production. Tape stripping provides an easy and noninvasive method to assess epidermal IL-18 production by ELISA.

DOI： 10.1111/j.1365-2133.2010.10145.x

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INTRODUCTION: Microvasculopathy is one of the characteristic features in patients with systemic sclerosis (SSc), but underlying mechanisms still remain uncertain. In this study, we evaluated the potential involvement of monocytic endothelial progenitor cells (EPCs) in pathogenic processes of SSc vasculopathy, by determining their number and contribution to blood vessel formation through angiogenesis and vasculogenesis. METHODS: Monocytic EPCs were enriched and enumerated using a culture of peripheral blood mononuclear cells and platelets on fibronectin in 23 patients with SSc, 22 patients with rheumatoid arthritis (RA), and 21 healthy controls. To assess the capacity of monocytic EPCs to promote vascular formation and the contribution of vasculogenesis to this process, we used an in vitro co-culture system with human umbilical vein endothelial cells (HUVECs) on Matrigel® and an in vivo murine tumor neovascularization model. RESULTS: Monocytic EPCs were significantly increased in SSc patients than in RA patients or healthy controls (P = 0.01 for both comparisons). Monocytic EPCs derived from SSc patients promoted tubular formation in Matrigel® cultures more than those from healthy controls (P = 0.007). Transplantation of monocytic EPCs into immunodeficient mice resulted in promotion of tumor growth and blood vessel formation, and these properties were more prominent in SSc than healthy monocytic EPCs (P = 0.03 for both comparisons). In contrast, incorporation of SSc monocytic EPCs into the tubular structure was less efficient in vitro and in vivo, compared with healthy monocytic EPCs. CONCLUSIONS: SSc patients have high numbers of aberrant circulating monocytic EPCs that exert enhanced angiogenesis but are impaired in vasculogenesis. However, these cells apparently cannot overcome the anti-angiogenic environment that characterizes SSc-affected tissues.

DOI： 10.1186/ar3180

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INTRODUCTION: Behçet's disease (BD) is a multisystem inflammatory disorder, in which a T-helper 1 (Th1)-polarized immune response plays a major role in the pathogenic process. We evaluated the regulatory role of natural killer (NK) cells in Th1-biased immune responses in patients with BD. METHODS: We studied 47 patients with BD, including 10 with active disease (aBD) and 37 with inactive disease (iBD), and 29 healthy controls. The activation status and cytotoxic activity of NK cells were examined by flow cytometry. The levels of mRNAs for immune modulatory and cytotoxic molecules in NK cells were determined by quantitative PCR. The IL-12 signal strength in NK cells was determined by assessing the phosphorylation state of its downstream component, signal transducer and activator of transduction 4, by immunoblotting. Finally, NK cells' ability to modulate the Th1 response was evaluated by co-culturing NK cells and T cells without cell contact. RESULTS: CD69+-activated NK cells were significantly increased in aBD compared with iBD or control samples, although their cytotoxic activities were similar. The iBD NK cells showed downregulated IL-12 receptor beta2 mRNA levels compared with aBD or control NK cells. The increased IL-13 expression was detected in a subset of BD patients: most of them had iBD. The IL-13 expression level in iBD patients was significantly higher than the level in controls, but was not statistically different compared with the level in aBD patients. The gene expression profile in iBD patients was consistent with the NK type 2 phenotype, and the shift to NK type 2 was associated with disease remission. NK cells from iBD patients showed impaired IL-12-induced signal transducer and activator of transduction 4 phosphorylation. Finally, iBD, but not control, NK cells suppressed IFNgamma expression by aBD-derived CD4+ T cells in vitro. CONCLUSIONS: NK cells may control disease flare/remission in BD patients via NK type 2-mediated modulation of the Th1 response.

DOI： 10.1186/ar3005

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We have previously shown that insulin-like growth factor-binding protein-5 (IGFBP-5) is overexpressed in fibrotic lung tissues and that it induces production of extracellular matrix components such as collagen and fibronectin both in vitro and in vivo. We recently observed mononuclear cell infiltration in lung tissues of mice expressing IGFBP-5. We therefore examined the role of IGFBP-5 on the migration of immune cells. Migration assays demonstrated that IGFBP-5 induced migration of peripheral blood mononuclear cells (PBMCs) in a dose-dependent manner. Preferential migration of monocytes/macrophages, natural killer cells, and T cells was observed. Moreover, the CD4/CD8 ratio of migrating cells was significantly higher in vitro and in vivo in response to IGFBP-5. IGFBP-5 resulted in preferential migration of activated CD4(+) T cells and monocytes. Interestingly, IGFBP-5 also induced migration of primary human lung fibroblasts. Exogenous administration of IGFBP-5 induced activation of mitogen-activated protein kinase (MAPK) signaling cascade but not PI3K in PBMCs. IGFBP-5-induced migration was blocked by the MEK1/2 inhibitor U0126, suggesting that IGFBP-5-induced migration occurs via MAPK activation. Furthermore, monocytes treated with recombinant IGFBP-5 expressed the mesenchymal markers alpha-smooth muscle actin and fibronectin in vitro and in vivo, suggesting that IGFBP-5 can induce the transformation of monocytes into mesenchymal cells. Collectively, our results suggest that IGFBP-5 induces cell migration via MAPK-dependent and IGF-I-independent mechanisms.

DOI： 10.1165/rcmb.2008-0211OC

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Systemic sclerosis (SSc) is a connective tissue disease of unknown etiology. A hallmark of SSc is fibrosis of the skin and internal organs. We recently demonstrated increased expression of IGFBP-3 and IGFBP-5 in primary cultures of fibroblasts from the skin of patients with SSc. In vitro, IGFBP-3 and IGFBP-5 induced a fibrotic phenotype and IGFBP-5 triggered dermal fibrosis in mice. To assess the ability of IGFBPs to trigger fibrosis, we used an ex vivo human skin organ culture model. Our findings demonstrate that IGFBP-3 and IGFBP-5, but not IGFBP-4, increase dermal and collagen bundle thickness in human skin explants, resulting in substantial dermal fibrosis and thickening. These fibrotic effects were sustained for at least two weeks. Our findings demonstrate that human skin ex vivo is an appropriate model to assess the effects of fibrosis-inducing factors such as IGFBPs, and for evaluating the efficacy of inhibitors/therapies to halt the progression of fibrosis and potentially reverse it.

DOI： 10.2174/1874312900802010017

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Publishing type：Research paper (scientific journal)   Publisher：4 Suppl 50  

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Antiphospholipid syndrome (APS) is an autoimmune prothrombotic disorder associated with autoantibodies to phospholipid (PL)-binding proteins, such as beta(2)-glycoprotein I (beta(2)GPI). We have recently reported that binding of beta(2)GPI to anionic PL facilitates processing and presentation of the cryptic beta(2)GPI epitope that activates pathogenic autoreactive T cells. To clarify mechanisms that induce sustained presentation of the dominant antigenic beta(2)GPI determinant in patients with APS, T-cell proliferation induced by beta(2)GPI-treated phosphatidylserine liposome (beta(2)GPI/PS) was evaluated in bulk peripheral blood mononuclear cell cultures. T cells from patients with APS responded to beta(2)GPI/PS in the presence of immunoglobulin G (IgG) anti-beta(2)GPI antibodies derived from APS plasma, and this response was completely inhibited either by the depletion of monocytes or by the addition of anti-FcgammaRI antibody. These findings indicate that efficient presentation of the cryptic determinants can be achieved by monocytes undergoing FcgammaRI-mediated uptake of beta(2)GPI-bound anionic surfaces in the presence of IgG anti-beta(2)GPI antibodies. Finally, beta(2)GPI-bound oxidized LDL or activated platelets also induced the specific T-cell response. Continuous exposure to these anionic surfaces may play a critical role in maintaining the pathogenic anti-beta(2)GPI antibody response in patients with APS.

DOI： 10.1182/blood-2007-07-100008

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Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)   Publisher：Blackwell Publishing Ltd  

DOI： 10.1111/jdv.16851

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Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)   Publisher：JOHN WILEY & SONS LTD  

DOI： 10.1002/cia2.12138

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

悪性腫瘍治療薬である免疫チェックポイント阻害薬は、免疫のブレーキを解除し自己の抗腫瘍免疫を増強する作用機序であるため、その適応は腫瘍の種類の制限を受けにくい。そのため、保険適応取得の拡大が続いている。さらに、単剤療法ではなく、2剤の免疫チェックポイント阻害薬、もしくは他の悪性腫瘍治療薬との併用療法による抗腫瘍効果の増強が注目を浴び、臨床の現場で徐々に主流となりつつある。一方、その免疫学的作用機序から、免疫関連副作用(immune-related Adverse Event:irAE)が知られており、多診療科連携のもとに対処していく必要がある。その発症や重症化に関連するリスク因子の同定を目指した研究が全世界で行われており、将来的には有力なバイオマーカーが発見されることが期待されている。irAEとしての皮膚障害は、頻度は高く重症度は低いものが多い一方、時に重症化する。皮膚科医は、これら薬剤を使用するだけではなく、他診療科からのコンサルトを受ける機会も多いため、常にirAEの現状を把握しておく必要がある。本セミナリウムでは、皮膚科医が知っておくべき免疫チェックポイント阻害薬の基礎から、その皮膚障害に関する最近の話題を含めて概説する。(著者抄録)

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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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Language：Japanese   Publisher：日本臨床皮膚科医会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J01266&link_issn=&doc_id=20200123100010&doc_link_id=10.18888%2Fhi.0000001750&url=https%3A%2F%2Fdoi.org%2F10.18888%2Fhi.0000001750&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

Language：Japanese   Publisher：(一社)日本皮膚免疫アレルギー学会  

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Language：Japanese   Publisher：(株)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)

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Language：Japanese   Publisher：(株)全日本病院出版会  

巨細胞性動脈炎は、高安動脈炎とともに大型血管炎に含まれる肉芽腫性血管炎である。側頭動脈炎として長らく認識されてきたが、側頭動脈だけではなく頭蓋外領域の中型〜大型血管も傷害し多彩な症状を呈するため、巨細胞性動脈炎の名称使用が推奨された。皮膚科医が遭遇することは比較的少ないと考えられるが、側頭動脈の腫脹や圧痛、潰瘍形成、頭痛などを主訴に受診する可能性がある。早急な治療を必要とする眼病変や、脳神経病変、大動脈炎など、疾患の全体像の把握と迅速かつ長期的な治療選択が必要である。(著者抄録)

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<p>We developed a questionnaire to determine the findings of cutaneous arteritis (cutaneous polyarteritis nodosa) among dermatological experienced vasculitis specialists as certified by the Committee for guidelines for the management of vasculitis and vascular disorders of the Japanese Dermatological Association. Retrospective data obtained from all patients at 12 dermatological facilities between January of 2012 and December of 2016 were evaluated. Fever, cerebral hemorrhage, and cerebral infarction were found in more than 10% of cases during our follow-up period. Arthralgia and/or arthritis (37%), myalgia and/or myositis (21%), and peripheral neuropathy (33%) were the most prominent findings in the study. Systemic steroid treatment was administered in only half of these cases. We believe that such patients, who are originally diagnosed as having CA, can progress from CA to systemic polyarteritis nodosa if they do not receive appropriate treatment such as systemic steroid therapy.</p>

DOI： 10.14924/dermatol.129.1901

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Squamous cell carcinoma antigens 1 and 2 (SCCA1 and 2, SERPIN B3 and B4), members of the ovalbumin serpin (ov-serpin)/clade B serpin family, were originally discovered as tumor-specific antigens and are used as tumor markers for various kinds of squamous cell carcinomas. Recently, our understanding of the underlying mechanisms of how SCCA1/2 enhance tumor growth has greatly increased. Moreover, it has been shown that SCCA1/2 are involved in the pathogenesis of several inflammatory diseases: asthma, psoriasis, and atopic dermatitis (AD). IL-22 and IL-17, signature cytokines of type 17 inflammation, as well as IL-4 and IL-13, signature cytokines of type 2 inflammation, both of which are positively correlated with the pathogenesis of psoriasis and allergic diseases, respectively, can induce expression of SCCA1/2 in airway epithelial cells and/or keratinocytes, leading to high expression of SCCA1/2 in these diseases. Based on these findings, several trials have been performed to examine the potential of applying SCCA1/2 to biomarkers for these diseases. The findings show that SCCA2 is useful to aid diagnosis, estimate clinical severity and disease type, and assess responses to treatment in psoriasis and AD. These results suggest that SCCA2 has emerged as a novel biomarker for skin inflammatory diseases.

DOI： 10.3390/ijms19041102

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Language：Japanese   Publisher：(公社)日本栄養・食糧学会  

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＜POINT＞▼全身性エリテマトーデス(SLE)の皮疹は多彩であり、特異的皮疹と非特異的皮疹、急性・亜急性・慢性型皮疹を総合して判断することが重要である▼蝶形紅斑として知られるSLE急性型の顔面紅斑は、必ずしも綺麗な蝶形にならないことも多い▼手指の凍瘡様紅斑は特異的・非特異的要素を含むが、SLEの初発症状であることも多く、特に春になっても改善しないものは注意を要する(著者抄録)

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Language：Japanese   Publisher：(一社)日本皮膚アレルギー・接触皮膚炎学会  

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Language：Japanese   Publisher：(一社)日本皮膚アレルギー・接触皮膚炎学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE INC  

Web of Science

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY  

Web of Science

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE INC  

Web of Science

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：金原出版(株)  

70歳女。右側頭部の皮疹を主訴とした。ペット飼育歴はなく、糖尿病、関節リウマチにて内服加療中であり、外用薬と抗真菌薬、抗菌薬の内服を併用するも皮疹は改善しなかった。紹介受診時には右前頭部に血痂を伴うやや隆起した紅色局面と軽度の脱毛がみられ、グロコット染色では毛周囲に黒色に染色される線毛状の菌糸を認めた。培養所見では表面は白みがかった粗い綿毛状、周辺部は淡い黄色色素と放射状の溝を認め、裏面は黄色調であり、スライドカルチャーでは紡錘形で厚い隔壁に分画され、先端の尖った大分生子と棍棒状の小分生子を認めた。以上よりMicrosporum canisによる頭部白癬と診断してテルビナフィン塩酸塩を開始し、3ヵ月後には皮疹は消退した。自験例は動物との接触がなく、原因菌や感染経路の推察において真菌培養の重要性が示された。

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE INC  

Web of Science

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(株)北隆館  

乾癬の治療薬であるはずのTNFα阻害剤の使用によって、乾癬様・掌蹠膿疱症様の皮疹が誘発される、もしくは既存の乾癬が悪化する現象は、"Paradoxical reaction(逆説的反応)"として知られてきた。その臨床型は、典型的乾癬とはやや異なる特徴を持つ。この奇妙な現象のメカニズムは明らかとは言えないが、広く知られる仮説としては、TNFαとIFNαのサイトカインバランスがTNFα阻害により不均衡となり、乾癬発症に重要とされるIFNαが優位になるというものである。治療法は、外用剤で軽快する例も多いが、TNFα阻害剤を中止して、他の全身性治療を必要とすることもあり、症状に合わせた適切な対処が必要である。(著者抄録)

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(株)メディカルレビュー社  

エリテマトーデス(LE)の病態において、形質細胞様樹状細胞(pDC)の活性化とI型インターフェロン(I型IFN)が重要な働きをしていることが明らかとなっているが、その発症メカニズムはいまだ不明な点が多い。遺伝的素因のほか、紫外線曝露などの環境要因が重要であり、とくに紫外線曝露は、アポトーシスの誘導や細胞内自己抗原の表出、サイトカイン産生などを引き起こし、LE発症の重要なトリガー因子となり得る。また近年は、過剰なNETosisによる細胞内自己抗原の放出や、TLR7を介した核酸自己抗原に対する免疫応答とその制御が注目されており、新たな病態解明が進んでいる。(著者抄録)

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Language：Japanese  

CiNii Books

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：Japanese Dermatological Association  

<p>Molecular targeting agents are widely used to treat various inflammatory and immune diseases and tumors. Unlike the adverse reactions induced by conventional drugs, these drugs induce various new types of adverse reactions. Anti-PD-1 antibody has clearly induced survival benefits in patients with metastatic melanoma. However, immune checkpoint inhibitors sometimes induce various kinds of immune-related adverse events (irAE). It is very important for clinicians to know the prevalence, clinical types, and severity of irAE in these drugs.</p><p>We analyzed the clinical characteristics of the adverse cutaneous effects of anti-PD-1 antibody in melanoma patients. The 7 patients studied were referred to Yokohama City University Hospital between October of 2014 and March of 2016. Vitiligo, cutaneous pruritus, lichenoid eruptions, psoriasiform eruptions, and bullae on the extremities were observed. All of these patients were able to be managed without discontinuation of the drug.</p><p>Larger clinical studies of this drug would help to predict and manage the characteristics of cutaneous adverse reactions. Dermatologists should be careful to detect and treat irAE induced by the newly developed immune checkpoint inhibitors.</p>

DOI： 10.14924/dermatol.126.2419

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Language：Japanese   Publisher：(株)全日本病院出版会  

リウマチ性多発筋痛症(polymyalgia rheumatica;PMR)や線維筋痛症(fibromyalgia;FM)は、ともに高齢者に好発し、全身の筋骨格系の疼痛を訴える原因不明の疾患である。PMRは、全身の炎症所見が高値となり、ステロイドが著効するものの再発が多く、いかにステロイドの漸減を行うかが重要となる。FMは、特徴的な圧痛点を伴った全身の疼痛のほか、さまざまな随伴症状が出現する一方で特異的所見を認めず、診断に苦慮する場合も多い。高齢化社会を迎え、両疾患に遭遇する機会も増えると予想されるが、正確な診断のためには疑う眼を持つことと、しっかりとした鑑別診断が必要である。(著者抄録)

CiNii Books

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY  

Web of Science

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本栄養・食糧学会  

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Language：Japanese   Publisher：金原出版(株)  

63歳男。3ヵ月前より右大腿部に紅斑を伴う皮下結節が出現し、前医にて細菌感染を疑われ、抗菌薬投与を受けるも改善しなかった。1ヵ月前には同部位が潰瘍・膿瘍化し、右鼠径にも皮下結節が出現したため、精査加療目的で当科初診となった。初診時、右大腿部外側に紅斑を伴う硬結があり、中心に13mm大の潰瘍を伴っていた。また、右鼠径部周辺に小指頭大、弾性硬の可動性に乏しい紅色結節を認めた。当初、細菌感染症や真菌感染を考え、MINO内服やスルファジアジン銀クリーム外用を開始するも改善せず、初診20日目に入院となった。入院後は穿刺排膿を施行し、皮膚Mycobacterium abscessus感染症と診断された。MINOに加え、CAMの内服投与を開始し、右大腿部感染巣切除術および右鼠径皮下結節切除術を施行した。術後経過良好であったが、切除2週間後に右大腿創周囲に感染の再燃を認め、CAMの増量とともにアミカシン・セフメタゾールを併用し、感染巣切除術を再度行った。術後3年7ヵ月の現在、再発はみられない。

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J01266&link_issn=&doc_id=20160323060028&doc_link_id=10.18888%2FJ01266.2016208992&url=https%3A%2F%2Fdoi.org%2F10.18888%2FJ01266.2016208992&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

Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(株)全日本病院出版会  

生物学的製剤の登場により乾癬治療は新たな時代を迎えた。多種ある治療オプションのなかで、シクロスポリンは依然不可欠な存在である。投与量の増減や投与のタイミング、間歇的投与やパルス的な使用など、その投与方法においては多彩な工夫ができ、皮膚科医の腕の見せ所となる。それにより、即効性を生かした寛解導入のほか、間歇的に上手に使うことで病勢コントロールが可能である。使用に際しては、腎障害や血圧上昇など代表的な副作用に留意するほか、歯肉腫脹などの頻度の低い副作用にも気をつける。高脂血症のリスクも上がるため、まず生活習慣病の改善を心がける。漫然とした継続投与は避け、薬剤の切れのよさを生かした短期的、間歇的使用を行う。副作用や効果の指標となる薬剤血中濃度も参考にしたい。(著者抄録)

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(株)日本臨床社  

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Language：Japanese   Publisher：(一社)日本皮膚アレルギー・接触皮膚炎学会  

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Language：Japanese   Publisher：(株)全日本病院出版会  

皮膚科外来で小児の膠原病を診断することは稀であるが、見逃すことのできない疾患である。皮膚症状を伴う頻度は高いため、初診科が皮膚科ということも少なくない。皮膚科医は膠原病を疑うべき皮疹の特徴をよく理解し、疑ったら詳細な問診としかるべき検査を施行する。具体的には、発熱や関節痛を伴った皮疹、循環障害を疑う皮疹、レイノー症状などが疑うヒントになりうるが、いずれにせよ主訴となる皮疹部の診察だけではなく、頭部、顔面、手指足趾、爪周囲などの好発部位の診察、詳細な問診を行い、患児の全体像を把握することが疾患の発見に重要となる。(著者抄録)

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Language：Japanese   Publisher：金原出版(株)  

慢性C型肝炎に対しテラプレビルを含むペグインターフェロンα-2b、リバビリンの3剤併用療法を行い、Grade 2以上の薬疹を認めた11例を対象に、重症度と治療、C型肝炎治療の継続の有無を含めたその後の経過を解析した。その結果、重症度はGrade 2が5例、Grade 3が6例であった。Grade 2の症例は薬剤開始後比較的早期に皮膚症状が出現し、ステロイド内服治療を行い、全例テラプレビルによる治療を中止することなく終了した。1例でテラプレビルを中断したが、減量して再開が可能であった。一方、Grade 3の症例はGrade 2の症例よりも皮膚症状の出現が遅く、4例で中等量のステロイドが全身投与され、うち2例ではテラプレビルの継続が可能であった。残りの4例は皮疹出現時にテラプレビル中止となったが、うち1例はいったん中止後に少量のステロイド投与とともに減量して再開可能であった。最終的に治療中止後再開されなかった3例中2例は腎障害合併と粘膜障害であった。

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：NATURE PUBLISHING GROUP  

Web of Science

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2015-4371

Web of Science

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Language：Japanese   Publisher：(株)北隆館  

アトピー性皮膚炎(AD)患者におけるペリオスチン測定の臨床的意義を検討した。ELISA法を用いて測定した血清ペリオスチン値は健常人と比較してADで有意に上昇していた。重症ADでは軽症・中等度と比較して高値を示し、臨床症状の改善に伴い低下した。その値はTARC、好酸球数、LDHと相関した。ADの臨床系では紅皮症型ADの血清、皮膚でペリオスチンの発現が有意に高く重症型と相関した。慢性皮疹である苔癬化病変を伴う症例ではペリオスチン発現が上昇していた。ペリオスチンはAD重症化、慢性病変形成に関与していると考えられた。(著者抄録)

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

昨今、悪性腫瘍、乾癬、自己免疫疾患など多彩な分野において分子標的薬が使用されるようになった。その新薬開発はまさに百花繚乱の勢いで、標的分子に関連する多種の病態において幅広く使用され、有効な成績を収めている。同時に、薬理作用や薬剤アレルギーによって引き起こされる皮膚障害の診断、治療、予防管理は皮膚科専門医にとって重要な役割となってきた。本稿では、分子標的薬を理解するための基本的なヒントと、頻度の高い皮膚障害の診断治療について概説する。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J01174&link_issn=&doc_id=20150703290002&doc_link_id=10.14924%2Fdermatol.125.1401&url=https%3A%2F%2Fdoi.org%2F10.14924%2Fdermatol.125.1401&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Language：Japanese   Publisher：(株)医学書院  

42歳,女性.初診の2ヵ月半前に飼いイヌに右手背を咬まれ,その後,同部に出現した紅斑が徐々に拡大し,硬結を認めるようになったため受診した.病理組織像で真皮に肉芽腫性炎症を認めた.組織のZiehl-Neelsen染色,PAS染色は陰性であったが,培養にて抗酸菌が陽性であり,DNA-DNA hybridization法によりMycobacterium chelonaeと同定した.クラリスロマイシンで治療開始したが改善せず,レボフロキサシンとアミカシンを追加投与し温熱療法を併用した.皮疹は徐々に改善傾向を示したが,紅斑が消失しないため外科的切除を施行し,治癒した.動物咬傷後の皮膚M.chelonae感染症の報告は稀であるが,動物咬傷後に遷延する皮膚病変が出現した場合は本症も念頭に置く必要があると考えた.(著者抄録)

DOI： 10.11477/mf.1412204356

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J01559&link_issn=&doc_id=20150224160018&doc_link_id=10.11477%2Fmf.1412204356&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1412204356&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

Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(株)協和企画  

＜症例のポイント＞成人Still病は、発熱、関節症状、皮疹を主要症状とする原因不明の全身性炎症性疾患である。本症の定型疹は発熱時に紅斑が出現し、解熱とともに消褪する。病理組織学的所見は真皮浅層血管周囲のリンパ球、好中球浸潤といった、非特異的な所見を認める。自験例では、scratch dermatitis様の皮疹を呈し、さらに経過中に定型疹も合併した。scratch dermatitis様の皮疹部の病理組織学的所見で、表皮内個細胞壊死が散見され、成人Still病のpersistent pruritic eruptions(PPE)と考えた。(著者抄録)

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：公益社団法人 日本皮膚科学会  

昨今，悪性腫瘍，乾癬，自己免疫疾患など多彩な分野において分子標的薬が使用されるようになった．その新薬開発はまさに百花繚乱の勢いで，標的分子に関連する多種の病態において幅広く使用され，有効な成績を収めている．同時に，薬理作用や薬剤アレルギーによって引き起こされる皮膚障害の診断，治療，予防管理は皮膚科専門医にとって重要な役割となってきた．本稿では，分子標的薬を理解するための基本的なヒントと，頻度の高い皮膚障害の診断治療について概説する．

DOI： 10.14924/dermatol.125.1401

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Language：Japanese  

J-GLOBAL

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J-GLOBAL

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Language：Japanese   Publisher：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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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY-BLACKWELL  

Web of Science

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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