Faculty Profiles - TAKEICHI Takuya

A novel splicing CYLD variant associated with trichoepithelioma papulosum multiplex demonstrating intrafamilial severity variability. Reviewed International journal

Ryo Fukaura, Takuya Takeichi, Tatsuhiro Noda, Mariko Seishima, Yoshinao Muro, Masashi Akiyama

The Journal of dermatology 2024.3

Increased JAK activation in cutaneous vasculitis. Reviewed International journal

Aoi Ebata, Mariko Ogawa-Momohara, Ryo Fukaura, Yuta Yamashita, Haruka Koizumi, Takuya Takeichi, Yoshinao Muro, Masashi Akiyama

Journal of the American Academy of Dermatology Vol. 90 ( 3 ) page： 627 - 629 2024.3

Correlation of serum allergen-specific IgE with total serum IgE and IgE specific to other allergens in Atopic dermatitis patients. Reviewed International journal

Norika Akashi, Mariko Ogawa-Momohara, Tomoki Taki, Ryo Fukaura, Keiko Wakahara, Satoshi Kamiya, Yuta Yamashita, Haruka Koizumi, Takuya Takeichi, Yoshinao Muro, Masashi Akiyama

Journal of the European Academy of Dermatology and Venereology : JEADV 2024.2

Panniculitis on the trunk as a possible characteristic feature of anti-SAE1/2 antibody-positive dermatomyositis: A possible cutaneous manifestation of treatment resistance. Reviewed International journal

Mahori Tago, Haruka Koizumi, Satoshi Kamiya, Norika Akashi, Akira Miyazaki, Yuta Yamashita, Mariko Ogawa-Momohara, Takuya Takeichi, Yoshinao Muro, Masashi Akiyama

The Journal of dermatology 2024.2

Localized epidermolysis bullosa simplex caused by a previously unreported substitution in the linker 12 domain of keratin 14. Reviewed International journal

Miyu Misaki, Takuya Takeichi, Michiya Omi, Yasutoshi Ito, Tomoo Ogi, Yoshinao Muro, Masashi Akiyama

The Journal of dermatology 2024.2

The ability of biomarkers to assess the severity of atopic dermatitis. Reviewed International journal

Takeshi Nakahara, Daisuke Onozuka, Satoshi Nunomura, Hidehisa Saeki, Motoi Takenaka, Mai Matsumoto, Yoko Kataoka, Rai Fujimoto, Sakae Kaneko, Eishin Morita, Akio Tanaka, Ryo Saito, Tatsuro Okano, Tomomitsu Miyagaki, Natsuko Aoki, Kimiko Nakajima, Susumu Ichiyama, Makiko Kido-Nakahara, Kyoko Tonomura, Yukinobu Nakagawa, Risa Tamagawa-Mineoka, Koji Masuda, Takuya Takeichi, Masashi Akiyama, Yozo Ishiuji, Michie Katsuta, Yuki Kinoshita, Chiharu Tateishi, Aya Yamamoto, Akimichi Morita, Haruna Matsuda-Hirose, Yutaka Hatano, Hiroshi Kawasaki, Ayano Fukushima-Nomura, Mamitaro Ohtsuki, Koji Kamiya, Yudai Kabata, Riichiro Abe, Hiroshi Mitsui, Tatsuyoshi Kawamura, Gaku Tsuji, Norito Katoh, Masutaka Furue, Kenji Izuhara

The journal of allergy and clinical immunology. Global Vol. 3 ( 1 ) page： 100175 - 100175 2024.2

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

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

DOI： 10.1016/j.jacig.2023.100175

Dual clinical features of fine and rough scales seen in a combined ichthyosis vulgaris and X-linked recessive ichthyosis patient with atopic dermatitis. Reviewed International journal

Yoshimasa Nakane, Takenori Yoshikawa, Takuya Takeichi, Michihiro Kono, Masashi Akiyama

The Journal of dermatology Vol. 51 ( 2 ) page： e49 - e50 2024.2

Cross-sectional nationwide epidemiologic survey on quality of life and treatment efficacy in Japanese patients with congenital ichthyoses. Reviewed International journal

Yuika Suzuki, Kana Tanahashi, Chiaki Terashima-Murase, Takuya Takeichi, Yumiko Kobayashi, Fumie Kinoshita, Masashi Akiyama

Journal of dermatological science Vol. 113 ( 1 ) page： 2 - 9 2024.1

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

BACKGROUND: Congenital ichthyoses sometimes present with severe skin symptoms that significantly affect the patient's quality of life (QOL). Symptomatic treatments are the mainstay therapies, and their efficacy is limited and inadequate. OBJECTIVE: To assess the disease severity and QOL in patients with congenital ichthyoses, and to investigate the effectiveness of current treatments. METHODS: We conducted a questionnaire-based Japan-wide epidemiological survey of patients with congenital ichthyosis who received medical care from 1 January 2016-31 December 2020. Effectiveness of past and current treatments was assessed. The outcomes were the physician's assessment, disease severity assessed using the clinical ichthyosis score (CIS), and the disease burden estimated using the Dermatology Life Quality Index (DLQI), the Children's Dermatology Life Quality Index (CDLQI), and the Infants' Dermatitis Quality of Life Index. RESULTS: One hundred patients with 14 ichthyosis subtypes from 47 institutes were included in the final analysis. The CDLQI score showed a positive correlation with CIS (rs = 0.59, p = 0.004), while the DLQI score showed no significant correlation (rs = 0.13, p = 0.33). All existing medications were effective for many patients. Etretinate improved QOL and reduced CIS, but side effects including bone growth retardation were reported. Decreased treatment willingness was observed in patients with very low and very high CIS. CONCLUSION: QOL scores were found to correlate with CIS in children, but not in adults. Considering the adverse events, it is speculated that etretinate is not indicated for children with mild cases. Petrolatum was the most commonly used medication, even in patients who were reluctant to receive treatment.

DOI： 10.1016/j.jdermsci.2023.11.002

Patients with keratinization disorders due to ABCA12 variants showing pityriasis rubra pilaris phenotypes. Reviewed International journal

Takuya Takeichi, Takahiro Hamada, Mayuko Yamamoto, Yasutoshi Ito, Aya Kawaguchi, Haruka Kobashi, Takenori Yoshikawa, Hiroshi Koga, Norito Ishii, Takekuni Nakama, Yoshinao Muro, Tomoo Ogi, Masashi Akiyama

The Journal of dermatology Vol. 51 ( 1 ) page： 101 - 105 2024.1

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

Pathogenic variants in ABCA12 are important causative genetic defects for autosomal recessive congenital ichthyoses (ARCI), which include congenital ichthyosiform erythroderma (CIE), harlequin ichthyosis, and lamellar ichthyosis. In addition, pathogenic variants in ABCA12 are known to cause a localized nevoid form of CIE due to recessive mosaicism. We previously reported siblings who carried an ABCA12 variant but did not show a "congenital" phenotype. They were considered to have pityriasis rubra pilaris (PRP). Here, we present a further patient with ABCA12 variants whose phenotype was not congenital ichthyosis, in an independent family. Notably, these three patients had geographic unaffected areas. Such areas are not usually found in patients with ARCI who have ABCA12 variants, suggesting mild phenotypes for these patients. Interestingly, the histological features of the ichthyotic lesions in these patients resembled those of PRP. All three patients had homozygous pathogenic missense variants in ABCA12. Our findings expand the phenotypic spectrum of patients with ABCA12 variants.

DOI： 10.1111/1346-8138.16967

Generalized pustular psoriasis that developed in a patient with an NFKB2 variant. Reviewed International journal

Shogo Wada, Takeshi Namiki, Aoi Ebata, Takuya Takeichi, Masashi Akiyama, Masafumi Yamada, Atsushi Hijikata, Yutaka Shimomura, Hirokazu Kanegane, Naoko Okiyama

Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG Vol. 22 ( 1 ) page： 118 - 120 2023.12

Natal teeth, hypoplasia of the first toe, and growth retardation in a patient with severe epidermolysis bullosa simplex. Reviewed International journal

Maiko Shimomura-Ishihara, Takuya Takeichi, Tatsuhiro Noda, Haruka Koizumi, Teruyuki Mitsuma, Tomoo Ogi, Yoshinao Muro, Masashi Akiyama

The Journal of dermatology 2023.12

Two patients with Hailey-Hailey disease with novel pathogenic ATP2C1 variants suggesting possible genotype/phenotype correlations. Reviewed International journal

Michiya Omi, Takuya Takeichi, Yasutoshi Ito, Takenori Yoshikawa, Yuki Mizutani, Miki Nagai, Mariko Seishima, Tomoo Ogi, Yoshinao Muro, Masashi Akiyama

The Journal of dermatology 2023.12

ELISA detection of anti-eIF2B antibodies in Japanese patients with systemic sclerosis. Reviewed International journal

Haruka Koizumi, Yasuhiko Yamano, Yoshinao Muro, Ryo Fukaura, Yuta Yamashita, Satoshi Kamiya, Norika Akashi, Mariko Ogawa-Momohara, Takuya Takeichi, Yasuhiro Kondoh, Masashi Akiyama

Rheumatology (Oxford, England) 2023.12

Lysophospholipase D from Thermocrispum limits psoriatic inflammation by hydrolyzing epidermal lysoplasmalogen produced by group IIF secreted phospholipase A2. Reviewed International journal

Haruka Hakoi, Yoshimi Miki, Saki Nomura, Kimiko Nakajima, Chiaki Terashima-Murase, Takuya Takeichi, Shigetoshi Sano, Masashi Akiyama, Shin-Ichi Sakasegawa, Makoto Murakami, Kei Yamamoto

Biochimie Vol. 215 page： 75 - 87 2023.12

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

Epidermal lipids play important roles in skin homeostasis and diseases. Psoriasis is an inflammatory disease characterized by keratinocyte hyperproliferation and Th17 immune responses. We previously reported that ethanolamine-type lysoplasmalogen (P-LPE), preferentially produced by group IIF secreted PLA2 (sPLA2-IIF/PLA2G2F) that is expressed in the suprabasal epidermis, promotes epidermal hyperplasia in psoriatic inflammation. Herein, we show that forcible degradation of epidermal P-LPE by topical application of recombinant lysophospholipase D (LyPls-PLD) from Thermocrispum, a lysoplasmalogen-specific hydrolase, attenuated epidermal hyperplasia and inflammation in imiquimod-induced and K5.Stat3C-transgenic mouse psoriasis models. In humans, P-LPE levels were elevated in the tape-stripped stratum corneum of patients with psoriasis. Moreover, in primary cultured human epidermal keratinocytes, aberrant cell proliferation and activation by psoriatic cytokines were sPLA2-IIF/P-LPE-dependent and were suppressed by the addition of LyPls-PLD with a decrease in P-LPE. These findings confirm that the sPLA2-IIF/P-LPE axis in the epidermis indeed regulates psoriasis, that P-LPE is a lipid biomarker that predicts the severity of psoriasis, and that pharmacological removal of this bioactive lipid is useful to prevent the disease. Thus, our study may lead to the development of drug discovery and diagnostic techniques based on this pathway.

DOI： 10.1016/j.biochi.2023.09.027

An in-frame 18 bp deletion in linker domain L1 of KRT9 identified in a Japanese patient with epidermolytic palmoplantar keratoderma. Reviewed International journal

Michiya Omi, Takuya Takeichi, Tomoko Chiba, Yoshihide Asano, Yoshinao Muro, Masashi Akiyama

The Journal of dermatology Vol. 50 ( 11 ) page： E370 - E372 2023.11

Diagnosis of acute generalized pustular bacterid facilitated by point-of-care testing. Reviewed International journal

Ryo Fukaura, Chiaki Terashima-Murase, Kana Tanahashi, Takuya Takeichi, Masashi Akiyama

The Journal of dermatology Vol. 50 ( 10 ) page： E347 - E348 2023.10

Allergen-specific IgG4 increase in atopic dermatitis with long-term dupilumab use. Reviewed International journal

Mariko Ogawa-Momohara, Yoshinao Muro, Chiaki Murase, Tomoki Taki, Kana Tanahashi, Yuta Yamashita, Haruka Koizumi, Ryo Fukaura, Takuya Takeichi, Masashi Akiyama

The British journal of dermatology Vol. 189 ( 4 ) page： 472 - 474 2023.9

Treatment of Severe Dermatitis, Multiple Allergies, and Metabolic Wasting With Dupilumab. Reviewed International journal

Yuta Koike, Takuya Takeichi, Norito Ishii, Tomoka Waseda, Naoya Murayama, Masashi Akiyama, Hiroyuki Murota

JAMA dermatology Vol. 159 ( 9 ) page： 1009 - 1011 2023.9

Mild generalised pustular psoriasis patient with a heterozygous hypomorphic MPO variant successfully treated with granulocyte and monocyte adsorption apheresis. Reviewed International coauthorship International journal

Takuya Takeichi, Takenori Yoshikawa, Muhammad Nasir Iqbal, Muhammad Farooq, Tomoki Taki, Yoshinao Muro, Yutaka Shimomura, Mariko Seishima, Masashi Akiyama

Experimental dermatology Vol. 32 ( 9 ) page： 1557 - 1562 2023.9

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

Pathogenic variants in MPO, which encodes the myeloperoxidase, were reported as causative genetic defects in several cases of generalised pustular psoriasis (GPP) in addition to patients with myeloperoxidase deficiency in 2020. However, which clinical subtypes of GPP patients have pathogenic variants in MPO remains largely undetermined, and elucidating this is clinically important. The present report outlines a mild case of GPP with a rare missense heterozygous variant, c.1810C>T p.(Arg604Cys), in MPO. Our structural analysis and functional assays to measure myeloperoxidase activity suggest that the present MPO substitution is a hypomorphic variant in MPO. Thus, the mild phenotype of the present GPP patient might be associated with an incomplete hypomorphic loss-of-function variant in MPO. Additionally, the severe intractable edematous pustules and erythema improved dramatically after five rounds of granulocyte and monocyte adsorption apheresis (GMA) therapy. This is the first report of GMA treatment for GPP associated with a pathogenic variant in MPO, as far as we know. Our findings suggest that GMA might be a useful and powerful tool for controlling GPP in patients with myeloperoxidase deficiency.

DOI： 10.1111/exd.14846

Giant condyloma of Buschke-Löwenstein in a Netherton syndrome patient, successfully treated with cryotherapy and intravenous immunoglobulin. Reviewed International journal

Mirai Sawa, Chiaki Murase, Naoto Yamada, Ryo Fukaura, Nobuyuki Tetsuka, Yoshitaka Sato, Takuya Takeichi, Masashi Akiyama

The Journal of dermatology Vol. 50 ( 9 ) page： E289 - E291 2023.9

Comment on: Successful treatment of rapid progressive interstitial lung disease in a case of anti-Zo antibody positive anti-synthetase syndrome. Reviewed International journal

Haruka Koizumi, Yoshinao Muro, Satoshi Kamiya, Norika Akashi, Satoko Imai, Yuta Yamashita, Mariko Ogawa-Momohara, Takuya Takeichi, Masashi Akiyama

International journal of rheumatic diseases Vol. 26 ( 9 ) page： 1872 - 1873 2023.9

Anti-KIF20B autoantibodies in systemic autoimmune rheumatic diseases: Their high prevalence in systemic lupus erythematosus. Reviewed International coauthorship International journal

Haruka Koizumi, Yoshinao Muro, Yuta Yamashita, Takuya Takeichi, Marvin J Fritzler, Masashi Akiyama

The Journal of dermatology Vol. 50 ( 8 ) page： 990 - 998 2023.8

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

The kinesin superfamily protein 20B (KIF20B), also known as M-phase phosphoprotein-1, is a plus-end-directed motor enzyme for cytokinesis. Anti-KIF20B antibodies have been reported in idiopathic ataxia, but no previous studies have examined anti-KIF20B antibodies in systemic autoimmune rheumatic diseases (SARDs). We aimed to establish methods for detecting anti-KIF20B antibodies and to investigate the clinical significance of these antibodies in SARDs. Serum samples from 597 patients with various SARDs and 46 healthy controls (HCs) were included. Fifty-nine samples that had been examined by immunoprecipitation using the recombinant KIF20B protein produced by in vitro transcription/translation were used for establishing the ELISA cutoff with the same recombinant protein for measuring the anti-KIF20B antibodies. The ELISA performed well, showing close agreement with the immunoprecipitation results (Cohen's κ >0.8). The ELISA results for 643 samples showed the prevalence of anti-KIF20B to be higher in the systemic lupus erythematosus (SLE) patients than in the HCs (18/89 vs. 3/46, P = 0.045). Since no SARD other than SLE had higher frequencies of anti-KIF20B antibodies than those of the HCs, we investigated the clinical characteristics of anti-KIF20B antibody-positive cases in SLE. The score on the SLE Disease Activity Index-2000 (SLEDAI-2K) was significantly higher for the anti-KIF20B-positive SLE patients than for the anti-KIF20B-negative SLE patients (P = 0.013). In a multivariate regression analysis of the anti-single-stranded deoxyribonucleic acid, anti-double-stranded deoxyribonucleic acid, and anti-KIF20B antibodies, the presence of anti-KIF20B antibody was significantly associated with high SLEDAI-2K scores (P = 0.003). Anti-KIF20B antibodies were found in ~20% of patients with SLE and were associated with high SLEDAI-2K scores. Much larger cohort and longitudinal studies are needed to confirm the association between anti-KIF20B antibodies and SLE.

DOI： 10.1111/1346-8138.16813

Plucked scalp hair follicle samples are useful RNA sources for mRNA analysis of most genodermatosis-associated genes. Reviewed International journal

So Takeuchi, Takuya Takeichi, Yoshinao Muro, Teppei Shimamura, Masashi Akiyama

Journal of dermatological science Vol. 111 ( 2 ) page： 68 - 70 2023.8

Loss of RhoE function in dermatofibroma promotes disorganized dermal fibroblast extracellular matrix and increased integrin activation. Reviewed International coauthorship International journal

Sofia Endzhievskaya, Chao-Kai Hsu, Hsing-San Yang, Hsin-Yu Huang, Yu-Chen Lin, Yi-Kai Hong, John Y W Lee, Alexandros Onoufriadis, Takuya Takeichi, Julia Yu-Yun Lee, Tanya J Shaw, John A McGrath, Maddy Parsons

The Journal of investigative dermatology Vol. 143 ( 8 ) page： 1487 - 1497.e9 2023.8

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

Dermatofibromas are common, benign fibrous skin tumors that can occur at any skin site. In most cases, dermatofibromas are solitary and sporadic, but a few are multiple and familial, and the mechanisms leading to these lesions are currently unclear. Using exome sequencing, we have identified a heterozygous variant in a pedigree with autosomal dominant multiple familial dermatofibromas within RND3 (c.692C>T,p.T231M) that encodes for the small GTPase RhoE, a regulator of the actin cytoskeleton. Expression of T231M-RhoE or RhoE depletion using CRISPR in human dermal fibroblasts increased proliferation, adhesion to extracellular matrix via enhanced β1 integrin activation and more disorganized matrix. The enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) was identified as a binding partner for RhoE and formation of this complex was disrupted by T231M-RhoE. PLOD2 promotes collagen crosslinking and activation of β1 integrins, and depleting PLOD2 in T231M-RhoE expressing cells reduced T231M-RhoE-mediated β1 integrin activation and led to increased matrix alignment. Immunohistochemical analysis revealed reduced expression of RhoE but increased expression of PLOD2 in the dermis of dermatofibroma skin samples compared to controls. Our data show loss of RhoE function leads to increased PLOD2 activation, enhancing integrin activation and leading to disorganized extracellular matrix, contributing to dermatofibroma.

DOI： 10.1016/j.jid.2023.01.019

Ichthyotic skin phenotype induced by the chronic activation of Toll-like receptor 2, and autoinflammation. Reviewed International journal

Takuya Takeichi, Yoshinao Muro, Masashi Akiyama

The British journal of dermatology Vol. 189 ( 2 ) page： 252 - 252 2023.7

KLK11 ichthyosis: large truncal hyperkeratotic pigmented plaques underscore a distinct autosomal dominant disorder of cornification. Reviewed International coauthorship International journal

Takuya Takeichi, Yasutoshi Ito, John Y W Lee, Chiaki Murase, Yusuke Okuno, Yoshinao Muro, John A McGrath, Masashi Akiyama

The British journal of dermatology Vol. 189 ( 1 ) page： 134 - 136 2023.7

Cutaneous manifestations of microscopic polyangiitis successfully controlled with avacopan alone. Reviewed International journal

Satoshi Kamiya, Haruka Koizumi, Yuika Suzuki, Satoko Imai, Yuta Yamashita, Mariko Ogawa-Momohara, Takuya Takeichi, Yoshinao Muro, Kazushi Yasuda, Masashi Akiyama

The Journal of dermatology Vol. 50 ( 7 ) page： E206 - E207 2023.7

Recent Advances in Clinical Research on Rare Intractable Hereditary Skin Diseases in Japan. Reviewed

Masashi Akiyama, Takuya Takeichi, Shigaku Ikeda, Akira Ishiko, Michiko Kurosawa, Hiroyuki Murota, Yutaka Shimomura, Tamio Suzuki, Katsuto Tamai, Akio Tanaka, Tadashi Terui, Masayuki Amagai

The Keio journal of medicine 2023.6

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

Our Research Group for Rare and Intractable Skin Diseases operates within the Project for Research on Intractable Diseases of the Ministry of Health, Labour, and Welfare of Japan and is conducting research on eight rare intractable skin diseases. Five of these are monogenic disorders (epidermolysis bullosa, congenital ichthyoses, oculocutaneous albinism, pseudoxanthoma elasticum, and hereditary angioedema), and for a sixth [generalized pustular psoriasis (GPP)], genetic predisposing factors are important. This review introduces our activities for raising public awareness of these six intractable hereditary skin diseases and summarizes our recent achievements in clarifying the situation of medical treatments for these diseases in Japan. We note our current progress in elucidating the pathogeneses of these diseases and in developing new treatment methods, and we discuss our progress in establishing clinical practice guidelines. A nationwide survey on epidermolysis bullosa and a clinical survey on congenital ichthyoses are progressing. The Angioedema Activity Score and the Angioedema Quality-of-Life Questionnaire, the latter of which is a quality-of-life evaluation tool, have been established for hereditary angioedema. Registries of patients with oculocutaneous albinism and pseudoxanthoma elasticum have been created, and the registry for the latter has achieved its target of 170 cases. For GPP, the results of our survey on clinical practice were published in 2021. Information regarding all six of these hereditary skin diseases has been disseminated to academic societies, medical professionals, patients, and the general public.

DOI： 10.2302/kjm.2023-0008-IR

Ichthyotic skin lesions of Conradi-Hünermann-Happle syndrome successfully treated with dupilumab. Reviewed International journal

Ryo Fukaura, Takuya Takeichi, Aoi Ebata, Chiaki Murase, Yoshinao Muro, Masashi Akiyama

Journal of the European Academy of Dermatology and Venereology : JEADV Vol. 37 ( 6 ) page： E732 - E734 2023.6

COVID-19 infection- and vaccination-related exacerbation of Darier's disease in a single patient. Reviewed International journal

Ryo Fukaura, Takuya Takeichi, Aoi Ebata, Yoshinao Muro, Masashi Akiyama

The Journal of dermatology Vol. 50 ( 6 ) page： 833 - 836 2023.6

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

Darier's disease (DD) is a rare autosomal dominantly inherited disorder. DD patients usually present with widespread keratotic eruptions with itching in the seborrheic regions that are exacerbated by various factors, including heat, sweat, and physical trauma. The SARS-CoV-2 (COVID-19) pandemic has stirred confusion among the medical community, including dermatologists, as this infection has been implicated in various skin conditions. Only a handful of reports have documented DD associated with COVID-19. Here, we report a 30-year-old male with Darier's disease whose symptoms were exacerbated following both COVID-19 vaccination and COVID-19 infection. The patient had noticed slight eruptions 7 years prior, but was not particularly concerned. After COVID-19 vaccination and infection, he had erythematous maculopapular lesions in large areas of the trunk and extremities. The previously reported pathogenic variant c.2255_2257del (p.(Ile752_Tyr753delinsAsn)) in ATP2A2 was detected in the present patient. Oral etretinate greatly improved his DD manifestations. As far as we know, the present patient is the first genetically confirmed DD case who showed both COVID-19 infection- and vaccination-related DD exacerbations independently. We think that the further accumulation of DD cases exacerbated by COVID-19 infection/vaccination is needed to clarify the mechanisms of DD aggravation.

DOI： 10.1111/1346-8138.16725

Successful combination therapy of bimekizumab and granulocyte monocyte adsorption apheresis for generalized pustular psoriasis complicated with microscopic polyangiitis. Reviewed International journal

Rie Shukuin, Haruka Koizumi, Aoi Ebata, Satoko Imai, Yuta Yamashita, Mariko Ogawa-Momohara, Takuya Takeichi, Yoshinao Muro, Norito Takami, Masashi Akiyama

The Journal of dermatology Vol. 50 ( 6 ) page： E181 - E182 2023.6

The use of certolizumab pegol to successfully treat generalized pustular psoriasis combined with psoriatic uveitis Reviewed International journal

Kazuki Yatsuzuka, Takuya Matsumoto, Yuri Sakane, Ryo Fukaura, Takuya Takeichi, Masashi Akiyama, Masamoto Murakami

The Journal of Dermatology Vol. 50 ( 6 ) page： E175 - E176 2023.6

Current understanding of the phenotypic spectrum of patients with NLRP1 variants. Reviewed International journal

Takuya Takeichi, Masashi Akiyama

The British journal of dermatology Vol. 188 ( 2 ) page： 160 - + 2023.2

Development of pemphigus vegetans and exacerbation of pemphigus foliaceus after secukinumab loading in a patient with complicated generalized pustular psoriasis and pyoderma gangrenosum. Reviewed International journal

Lisa Minai, Takuya Takeichi, Youichi Ogawa, Akiko Honobe-Tabuchi, Takashi Okamoto, Hiroshi Mitsui, Shinji Shimada, Masashi Akiyama, Tatsuyoshi Kawamura

The Journal of dermatology Vol. 50 ( 2 ) page： 245 - 249 2023.2

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

In dermatology, biologics that block signaling pathways of TNF-α, IL-4/IL13, IL-17s, and IL-23 are widely used for the treatment of several inflammatory skin diseases, such as atopic dermatitis and psoriasis. They have shown excellent efficacy with an acceptable safety profile. However, these biologics targeting pathogenic cytokines and their receptors could modulate immunological balance, leading to the development of other inflammatory or autoimmune skin diseases in some cases. In this study, we present a patient who suffered pemphigus vegetans and showed an exacerbation of pemphigus foliaceus after secukinumab loading for the treatment of complicated generalized pustular psoriasis and pyoderma gangrenosum.

DOI： 10.1111/1346-8138.16563

Prominent dermal accumulation of Russell bodies underlying pseudocarcinomatous hyperplasia with fungal infection. Reviewed

Exploring biomarkers to predict clinical improvement of atopic dermatitis in patients treated with dupilumab (B-PAD study). Reviewed International journal

Takeshi Nakahara, Kenji Izuhara, Daisuke Onozuka, Hidehisa Saeki, Satoshi Nunomura, Motoi Takenaka, Mai Matsumoto, Yoko Kataoka, Rai Fujimoto, Sakae Kaneko, Eishin Morita, Akio Tanaka, Michihiro Hide, Tatsuro Okano, Tomomitsu Miyagaki, Natsuko Aoki, Kimiko Nakajima, Susumu Ichiyama, Makiko Kido-Nakahara, Kyoko Tonomura, Yukinobu Nakagawa, Risa Tamagawa-Mineoka, Koji Masuda, Takuya Takeichi, Masashi Akiyama, Yozo Ishiuji, Michie Katsuta, Yuki Kinoshita, Chiharu Tateishi, Aya Yamamoto, Akimichi Morita, Haruna Matsuda-Hirose, Yutaka Hatano, Hiroshi Kawasaki, Keiji Tanese, Mamitaro Ohtsuki, Koji Kamiya, Yudai Kabata, Riichiro Abe, Hiroshi Mitsui, Tatsuyoshi Kawamura, Gaku Tsuji, Norito Katoh, Masutaka Furue

Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology Vol. 53 ( 2 ) page： 233 - 238 2023.2

Tatsuhiro Noda, Norika Akashi, Maiko Shimomura, Haruka Koizumi, Miyuki Mizuta, Kosei Nakajima, Takuya Takeichi, Teruyuki Mitsuma, Masashi Akiyama

Nagoya journal of medical science Vol. 85 ( 1 ) page： 123 - 126 2023.2

Language：English

Blockade of the secretion of immunoglobulins leads to their accumulation in plasma cells, resulting in condensed immunoglobulins in the rough endoplasmic reticulum of plasma cells, termed Russell bodies. They are sometimes found in lymphoplasmacellular inflammation of the intestinal mucosa and in lymphoid cell malignancies, but only very rarely in skin diseases. Here, we report an 86-year-old female who presented with a lesion with the prominent accumulation of Russell bodies underlying pseudocarcinomatous hyperplasia with fungal infection in the face. Immunohistochemical staining showed the cells containing Russell bodies to be positive for CD138 and the Russell bodies to be positive for immunoglobulin κ and λ light chains. The present case suggests that when inflammatory cell infiltration with abundant round intracellular eosinophilic materials is observed in the dermis, the dermal accumulation of Russell bodies should be considered in cases with reactive pseudocarcinomatous hyperplasia with fungal infection.

DOI： 10.18999/nagjms.85.1.123

Whole-exome sequencing reveals a retinitis pigmentosa-causative PRPH2 variant as a secondary finding in a patient with pseudoxanthoma elasticum. International journal

Akira Miyazaki, Takuya Takeichi, Kana Tanahashi, Tomoki Taki, Yosuke Taki, Yoshinao Muro, Masashi Akiyama

The Journal of dermatology Vol. 50 ( 2 ) page： e85 - e86 2023.2

A case of juvenile amyopathic dermatomyositis with anti-transcription intermediary factor 1-α antibody showing negative anti-TIF1-γ ELISA results: Comment on "Case of pembrolizumab-induced dermatomyositis with anti-transcription intermediary factor 1-γ antibody". Reviewed International journal

Haruka Koizumi, Yoshinao Muro, Satoko Imai, Yuta Yamashita, Mariko Ogawa-Momohara, Takuya Takeichi, Megumi Murakami, Teruyuki Mitsuma, Masashi Akiyama

The Journal of dermatology Vol. 50 ( 1 ) page： E39 - E40 2023.1

Novel homozygous missense mutation c.1654G>T in the ALOX12B gene causing congenital ichthyosiform erythroderma. Reviewed International journal

Kotoe Mae, Yoshio Kawakami, Ai Kajita, Takuya Takeichi, Tatsuhiro Noda, Yoji Hirai, Masashi Akiyama, Shin Morizane

The Journal of dermatology Vol. 50 ( 1 ) page： E37 - E38 2023.1

Comment on: Disease evolution in a long-term follow-up of 104 undifferentiated connective tissue disease patients. Reviewed International journal

Yuta Yamashita, Yoshinao Muro, Haruka Koizumi, Mariko Ogawa-Momohara, Takuya Takeichi, Masashi Akiyama

Clinical and experimental rheumatology Vol. 41 ( 1 ) page： 195 - 196 2023.1

Comment on: Disease evolution in a long-term follow-up of 104 undifferentiated connective tissue disease patients Reviewed International journal

Yamashita Y., Muro Y., Koizumi H., Ogawa-Momohara M., Takeichi T., Akiyama M.

CLINICAL AND EXPERIMENTAL RHEUMATOLOGY Vol. 41 ( 1 ) page： 195 - 196 2023.1

Occurrence of cholangiocarcinoma, three years after negative seroconversion of anti-TIF1γ antibody, in a dermatomyositis patient. Reviewed International journal

Ken Horisaki, Yoshinao Muro, Mariko Ogawa-Momohara, Yuta Yamashita, Haruka Koizumi, Takuya Takeichi, Masashi Akiyama

European journal of dermatology : EJD Vol. 33 ( 1 ) page： 48 - 49 2023.1

Appropriate immunoassay systems are needed to evaluate various anticentromere antibodies as biomarkers for disease progression in systemic sclerosis. Reviewed International journal

Yoshinao Muro, Yuta Yamashita, Haruka Koizumi, Mariko Ogawa-Momohara, Takuya Takeichi, Masashi Akiyama

Journal of immunological methods Vol. 512 page： 113400 - 113400 2023.1

Two novel anti-aminoacyl tRNA synthetase antibodies: Autoantibodies against cysteinyl-tRNA synthetase and valyl-tRNA synthetase. Reviewed International journal

Yoshinao Muro, Yuta Yamashita, Haruka Koizumi, Mariko Ogawa-Momohara, Takuya Takeichi, Teruyuki Mitsuma, Masashi Akiyama

Autoimmunity reviews Vol. 21 ( 12 ) page： 103204 - 103204 2022.12

Language：English

Anti-aminoacyl-tRNA synthetase (anti-ARS) antibodies are useful for identifying a clinical subset of patients with inflammatory myopathies. Since the myositis of anti-ARS-positive patients is characterized by a unique set of non-myopathic manifestations, including interstitial lung disease, mechanic's hands, and arthralgia, the patients are classified as having anti-synthetase syndrome. Autoantibodies have been identified to eight kinds of ARSs. Of the other 12 ARSs, eight are components of the "OJ" multi-synthetase complex. Autoantibodies to the four remaining ARSs (CysARS, ValARS, SerARS, and TrpARS) have not been reported to be present in patients with inflammatory myopathies. In this study, we first screened samples from more than 300 Japanese patients majorly consisting of those with dermatomyositis (DM) by our established in-house ELISA to find autoantibodies against the four ARSs described above. Since sera from two DM patients specifically reacted to CysARS or ValARS, we determined their reactivities by immunoprecipitation (IP) with the corresponding recombinant proteins and IP-Western blotting with cellular extract. One patient had several features found in anti-synthetase syndrome, but the other did not. The clinical differences among the various anti-ARS antibodies should be explored in a future work.

DOI： 10.1016/j.autrev.2022.103204

Ceramide analysis in combination with genetic testing may provide a precise diagnosis for self-healing collodion babies. International journal

Takuya Takeichi, Yusuke Ohno, Kana Tanahashi, Yasutoshi Ito, Ken Shiraishi, Ryo Utsunomiya, Satoshi Yoshida, Kenta Ikeda, Hayato Nomura, Shin Morizane, Koji Sayama, Tomoo Ogi, Yoshinao Muro, Akio Kihara, Masashi Akiyama

Journal of lipid research Vol. 63 ( 12 ) page： 100308 - 100308 2022.12

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

Self-healing collodion baby (SHCB), also called "self-improving collodion baby", is a rare mild variant of autosomal recessive congenital ichthyosis and is defined as a collodion baby who shows the nearly complete resolution of scaling within the first 3 months to 1 year of life. However, during the neonatal period, it is not easy to distinguish SHCB from other inflammatory forms of autosomal recessive congenital ichthyosis, such as congenital ichthyosiform erythroderma. Here, we report a case study of two Japanese SHCB patients with compound heterozygous mutations, c.235G>T (p.(Glu79*))/ c.1189C>T (p.(Arg397Cys)) and c.1295A>G (p.(Tyr432Cys))/ c.1138delG (p.(Asp380Thrfs*3)), in CYP4F22, which encodes cytochrome P450, family 4, subfamily F, polypeptide 22 (CYP4F22). Immunohistochemically, inflammation with the strong expression of IL-17C, IL-36γ, and TNF-α was seen in the skin at birth. CYP4F22 is an ultra-long-chain fatty acid (FA) ω-hydroxylase responsible for ω-O-acylceramide (acylceramide) production. Among the epidermal ceramides, acylceramide is a key lipid in maintaining the epidermal permeability barrier function. We found that the levels of ceramides with ω-hydroxy FAs including acylceramides and the levels of protein-bound ceramides were much lower in stratum corneum samples obtained by tape stripping from SHCB patients than in those from their unaffected parents and individuals without SHCB. Additionally, our cell-based enzyme assay revealed that two mutants, p.(Glu79*) and p.(Arg397Cys), had no enzyme activity. Our findings suggest that genetic testing coupled with non-invasive ceramide analyses using tape-stripped stratum corneum samples might be useful for the early and precise diagnosis of congenital ichthyoses, including SHCB.

DOI： 10.1016/j.jlr.2022.100308

Clinical characteristics of systemic sclerosis patients with anti-NOR90 antibodies

Yamashita, Y; Muro, Y; Koizumi, H; Ogawa-Momohara, M; Takeichi, T; Akiyama, M

JOURNAL OF INVESTIGATIVE DERMATOLOGY Vol. 142 ( 12 ) page： S204 - S204 2022.12

Ceramide profiling of stratum corneum in Sjögren-Larsson syndrome. Reviewed International journal

Ayami Arai, Takuya Takeichi, Hiroyuki Wakamoto, Takayuki Sassa, Yasutoshi Ito, Yuya Murase, Tomoo Ogi, Masashi Akiyama, Akio Kihara

Journal of dermatological science Vol. 107 ( 3 ) page： 114 - 122 2022.9

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

BACKGROUND: Sjögren-Larsson syndrome (SLS) is a neurocutaneous disorder whose causative gene is the fatty aldehyde dehydrogenase ALDH3A2 and of which ichthyosis is the major skin symptom. The stratum corneum contains a variety of ceramides, among which ω-O-acylceramides (acylceramides) and protein-bound ceramides are essential for skin permeability barrier formation. OBJECTIVES: To determine the ceramide classes/species responsible for SLS pathogenesis and the enzymes that are impaired in SLS. METHODS: Genomic DNA was collected from peripheral blood samples from an SLS patient and her parents, and whole-genome sequencing and Sanger sequencing were performed. Lipids were extracted from stratum corneum samples from the SLS patient and healthy volunteers and subjected to ceramide profiling via liquid chromatography coupled with tandem mass spectrometry. RESULTS: A duplication (c.55_130dup) and a missense mutation (p.Lys447Glu) were found in the patient's ALDH3A2 gene. The patient had reduced levels of all acylceramide classes, with total acylceramide levels at 25 % of healthy controls. Reductions were also observed for several nonacylated ceramides: ceramides with phytosphingosine or 6-hydroxysphingosine in the long-chain base moiety were reduced to 24 % and 41 % of control levels, respectively, and ceramides with an α-hydroxy fatty acid as the fatty acid moiety were reduced to 29 %. The fatty acid moiety was shortened in many nonacylated ceramide classes. CONCLUSION: These results suggest that reduced acylceramide levels are a primary cause of the ichthyosis symptoms of SLS, but reductions in other ceramide classes may also be involved.

DOI： 10.1016/j.jdermsci.2022.08.003

Comment on: Favourable complete remission of anti-OJ antibody-positive myositis after lung cancer resection. Reviewed International journal

Yoshinao Muro, Kazuki Nishida, Yuta Yamashita, Haruka Koizumi, Takuya Takeichi, Minoru Satoh, Masashi Akiyama

Rheumatology (Oxford, England) Vol. 61 ( 8 ) page： E232 - E234 2022.8

Extremely mild dominant dystrophic epidermolysis bullosa: Genotype information from whole-exome sequencing of salivary gDNA predicts disease severity. Reviewed International journal

Akira Miyazaki, Takuya Takeichi, So Takeuchi, Tomoki Taki, Yoshinao Muro, Masashi Akiyama

The Journal of dermatology Vol. 49 ( 8 ) page： E276 - E277 2022.8

Eosinophilic granulomatosis with polyangiitis complicated with idiopathic thrombocytopenic purpura and sclerosing cholangitis showing eosinophilic infiltration. Reviewed International journal

Yuta Yamashita, Takuya Takeichi, Yoji Ishizu, Nobuaki Suzuki, Takashi Tsuboi, Kentaro Matsuura, Haruka Koizumi, Yoshinao Muro, Masashi Akiyama

The Journal of dermatology Vol. 49 ( 8 ) page： E270 - E271 2022.8

Darier disease successfully treated with a topical agent containing vitamin A (retinyl palmitate), vitamin E, and urea. Reviewed International journal

Akira Miyazaki, Tomoki Taki, Takuya Takeichi, Michihiro Kono, Hiroaki Yagi, Masashi Akiyama

The Journal of dermatology Vol. 49 ( 8 ) page： 779 - 782 2022.8

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

Darier disease (DD), also called keratosis follicularis, is an autosomal dominant hereditary keratinization disorder that manifests as keratotic papules with plaques in seborrheic areas. There are no validated curative treatments for DD, with the majority of cases treated symptomatically. We report the efficacy of a topical over-the-counter agent which contains retinyl palmitate, vitamin E, and urea for a patient with DD. A 13-year-old girl had brown papules on her scalp, neck, shoulders, and axillae since entering elementary school. A skin biopsy revealed hyperkeratosis, suprabasal acantholysis, and dyskeratosis manifested as corps ronds and grains in the epidermis. Sanger sequencing found the previously reported heterozygous mutation c.1484C>T in ATP2A2. The application of an over-the-counter topical agent containing retinyl palmitate 2750 μg/g (5000 IU/g), tocopheryl acetate 20 mg/g, urea 200 mg/g, and monoammonium glycyrrhizinate 5 mg/g twice daily for 2 months improved the papules without serious adverse events. Oral or topical aromatic vitamin A analogs (retinoids) are often used to treat DD. However, several adverse events are associated with retinoid treatment, and many patients only undergo their intermittent use or discontinue the treatments. Retinyl palmitate is more stable and has a lower irritative profile than other retinoic acids. When applied topically, however, retinyl palmitate cannot penetrate the skin as well as retinol can. Some reports have noted that vitamin E increases the biological availability of vitamin A and that urea helps mechanical percutaneous drug delivery. Our case suggests that retinyl palmitate has a sufficient therapeutic effect when combined with vitamin E and urea. In conclusion, we propose that topical agents containing retinyl palmitate, vitamin E, and urea might have a satisfactory effect on the skin lesions of DD patients, without the serious risks of adverse events.

DOI： 10.1111/1346-8138.16395

Case of ichthyosis with confetti caused by KRT10 mutation, complicated with multiple malignant melanomas. Reviewed International journal

Yasutoshi Ito, Takuya Takeichi, Koichi Nakagawa, Kana Tanahashi, Yoshinao Muro, Tomoo Ogi, Masashi Akiyama

The Journal of dermatology Vol. 49 ( 7 ) page： E228 - E229 2022.7

Deep Phenotyping of Superficial Epidermolytic Ichthyosis due to a Recurrent Mutation in KRT2. Reviewed International journal

Yuika Suzuki, Takuya Takeichi, Kana Tanahashi, Yoshinao Muro, Yasushi Suga, Tomoo Ogi, Masashi Akiyama

International journal of molecular sciences Vol. 23 ( 14 ) 2022.7

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

Superficial epidermolytic ichthyosis (SEI) is an autosomal dominant inherited ichthyosis. SEI is caused by mutations in KRT2 and frequently shows erythroderma and widespread blistering at birth. We report the clinical manifestations of two patients from a Japanese family with SEI caused by a hotspot mutation, p.Glu487Lys, in KRT2. In addition, we summarize previous reports on SEI patients with the identical mutation. One of the two patients had disease onset at the age of 7 months. The other patient's age of onset is unknown, but it was in childhood. Neither of the two patients showed erythroderma. To perform deep phenotyping, we studied the age of onset and the frequency of erythroderma in 34 reported SEI cases with the p.Glu487Lys mutation, including the present cases. Among the cases with sufficient clinical information, 44.4% of the cases that were due to p.Glu487Lys in KRT2 occurred at birth. Erythroderma was observed in 11.1% of the cases with p.Glu487Lys in KRT2.

DOI： 10.3390/ijms23147791

UVB-Induced Skin Autoinflammation Due to Nlrp1b Mutation and Its Inhibition by Anti-IL-1β Antibody. Reviewed International journal

Yuya Murase, Takuya Takeichi, Jun Koseki, Yuki Miyasaka, Yoshinao Muro, Tamio Ohno, Teppei Shimamura, Masashi Akiyama

Frontiers in immunology Vol. 13 page： 876390 - 876390 2022.6

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

NLRP1 (NACHT and leucine-rich repeat-containing protein family, pyrin domain-containing protein 1) is an innate immune sensor that is involved in the formation of inflammasome complexes. NLRP1 hyperactivity has been reported to cause inherited autoinflammatory diseases including familial keratosis lichenoides chronica and NLRP1-associated autoinflammation with arthritis and dyskeratosis. We generated Nlrp1b (the mouse homologue of human NLRP1) gain-of-function knock-in (Nlrp1b KI) mice with UVB irradiation-induced autoinflammatory skin lesions. We demonstrated that UVB irradiation induces IL-1β upregulation and IL-1β-dependent inflammation via caspase-1 activation in these Nlrp1b KI mice. RNA sequencing revealed the upregulation of inflammasome pathway-related genes, keratinocyte stress marker genes, and keratinocyte differentiation marker genes in the Nlrp1b KI mice after UVB irradiation. The skin inflammation and hyperkeratosis from UVB irradiation in the Nlrp1b KI mice were inhibited by both intraperitoneal and subcutaneous administration of anti-IL-1β antibodies before UVB irradiation. UVB irradiation and the IL-1β pathway are important in the pathogenesis of NLRP1-associated autoinflammatory skin lesions.

DOI： 10.3389/fimmu.2022.876390

Epithelioid cell granuloma formation in CARD14-associated papulosquamous eruptions. Reviewed International journal

Takuya Takeichi, Kenta Ikeda, Yoshinao Muro, Tomoo Ogi, Shin Morizane, Masashi Akiyama

Journal of the European Academy of Dermatology and Venereology : JEADV Vol. 36 ( 5 ) page： E369 - E371 2022.5

Clinical significance of anti-NOR90 antibodies in systemic sclerosis and idiopathic interstitial pneumonia. Reviewed International journal

Yuta Yamashita, Yasuhiko Yamano, Yoshinao Muro, Mariko Ogawa-Momohara, Takuya Takeichi, Yasuhiro Kondoh, Masashi Akiyama

Rheumatology (Oxford, England) Vol. 61 ( 4 ) page： 1709 - 1716 2022.4

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

OBJECTIVE: Anti-NOR90 antibodies are usually found in patients with systemic sclerosis (SSc); however, their clinical relevance remains obscure. We developed an enzyme-linked immunosorbent assay (ELISA) for measuring them to investigate the clinical features of patients with anti-NOR90 antibodies. METHODS: Serum samples from 1,252 patients with various conditions from Nagoya University Hospital and 244 patients with idiopathic interstitial pneumonia (IIP) from Tosei General Hospital were included. Anti-NOR90 antibodies were assayed by an ELISA using the recombinant protein produced by in vitro transcription/translation. RESULTS: Five (0.4%) patients in the Nagoya University Hospital cohort had anti-NOR90 antibodies. One patient with diffuse cutaneous SSc, 3 with limited cutaneous SSc, and 1 with Raynaud's disease were positive for anti-NOR90 antibodies. Anti-NOR90 antibodies were found more frequently in patients with systemic scleroderma-spectrum disorders (SSDs) than without SSDs (5/316 vs. 0/936, P<0.00101) and were found more frequently in patients with SSc than without SSc (4/249 vs. 0/528, P<0.0104) in the systemic autoimmune rheumatic diseases cohort. Three of the 4 anti-NOR90-positive SSc patients had interstitial lung disease (ILD), and 2 of those 4 had cancer. Three (1.2%) patients in the Tosei General Hospital cohort had anti-NOR90 antibodies. All 3 of the anti-NOR90-positive IIP patients had gastrointestinal tract involvement, and 2 of those 3 had cancer or skin lesions observed in SSc. CONCLUSIONS: Although anti-NOR90 antibodies are rarely found in clinics, our ELISA is useful for their detection. Further studies are needed to confirm the association of anti-NOR90 antibodies with ILD and cancer in SSc and IIP patients.

DOI： 10.1093/rheumatology/keab575

Mutations in SAM syndrome and palmoplantar keratoderma patients suggest genotype/phenotype correlations in DSG1 mutations Reviewed

Case of harlequin ichthyosis in preterm infant with a compound heterozygous ABCA12 missense mutation. Reviewed International journal

Moeka Miyazaki, Natsuki Ohkawa, Kazuki Miyabayashi, Hiromichi Shoji, Takuya Takeichi, Masato Kantake, Masashi Akiyama, Toshiaki Shimizu

The Journal of dermatology Vol. 49 ( 4 ) page： E137 - E139 2022.4

S. Takeuchi, T. Takeichi, Y. Koike, H. Takama, K. Tanahashi, Y. Okuno, N. Ishii, Y. Muro, T. Ogi, Y. Suga, M. Akiyama

Journal of the European Academy of Dermatology and Venereology Vol. 36 ( 3 ) page： E215 - E218 2022.3

Anti-Zo antibodies in Japanese myositis patients detected by a newly developed ELISA Reviewed

Muro Y., Hashimoto T., Izumi S., Ogawa-Momohara M., Takeichi T., Yamashita H., Yasuoka H., Akiyama M.

Clinical and experimental rheumatology Vol. 40 ( 2 ) page： 219 - 223 2022.2

Differential pathomechanisms of desmoglein-1 transmembrane domain mutations in skin disease. Reviewed International journal

Stephanie E Zimmer, Takuya Takeichi, Daniel E Conway, Akiharu Kubo, Yasushi Suga, Masashi Akiyama, Andrew P Kowalczyk

The Journal of investigative dermatology Vol. 142 ( 2 ) page： 323 - + 2022.2

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Dominant and recessive mutations in the desmosomal cadherin, desmoglein-1 (DSG1), cause the skin diseases palmoplantar keratoderma (PPK) and severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome, respectively. Here, we compare two dominant missense mutations in the DSG1 transmembrane domain (TMD), G557R and G562R, causing PPK (DSG1PPK-TMD) and SAM syndrome (DSG1SAM-TMD), respectively, to determine the differing pathomechanisms of these mutants. Expressing the DSG1TMD mutants in a DSG-null background, we use cellular and biochemical assays to reveal differences in the mechanistic behavior of each mutant. Super resolution microscopy and functional assays showed a failure by both mutants to assemble desmosomes due to reduced membrane trafficking and lipid raft targeting. DSG1SAM-TMD maintained normal expression levels and turnover relative to DSG1WT, but DSG1PPK-TMD lacked stability, leading to increased turnover through lysosomal and proteasomal pathways and reduced expression levels. These results differentiate the underlying pathomechanisms of these disorders, suggesting that DSG1SAM-TMD acts dominant negatively while DSG1PPK-TMD is a loss-of-function mutation causing the milder PPK disease phenotype. These mutants portray the importance of the DSG TMD in desmosome function and suggest that a greater understanding of the desmosomal cadherin TMDs will further our understanding of the role that desmosomes play in epidermal pathophysiology.

DOI： 10.1016/j.jid.2021.07.154

Long-term risk of cancer development among anti-Th/To antibody-positive systemic sclerosis patients: comment on the article by Mecoli et al. Reviewed International journal

Yuta Yamashita, Yasuhiko Yamano, Yoshinao Muro, Haruka Koizumi, Takuya Takeichi, Yasuhiro Kondoh, Masashi Akiyama

Arthritis & rheumatology (Hoboken, N.J.) Vol. 74 ( 2 ) page： 368 - 369 2022.2

Language：English Publisher：WILEY

We read the report by Mecoli et al on the relationship between cancer and anti-Th/To antibodies (AThAs) in patients with systemic sclerosis (SSc) (1). It is interesting that the presence of AThAs was reported to confer a protective effect against cancer development in those patients. However, cancer development in AThA-positive patients was significantly suppressed only within the first 3 years after SSc onset, and there was no significant difference in the number of deceased between the AThA-positive and AThA-negative patients.

DOI： 10.1002/art.41945

Anti-Zo antibodies in Japanese myositis patients detected by a newly developed ELISA Reviewed

Muro Y., Hashimoto T., Izumi S., Ogawa-Momohara M., Takeichi T., Yamashita H., Yasuoka H., Akiyama M.

CLINICAL AND EXPERIMENTAL RHEUMATOLOGY Vol. 40 ( 2 ) page： 219 - 223 2022.2

Autoinflammatory Keratinization Disease With Hepatitis and Autism Reveals Roles for JAK1 Kinase Hyperactivity in Autoinflammation. Reviewed International coauthorship International journal

Takuya Takeichi, John Y W Lee, Yusuke Okuno, Yuki Miyasaka, Yuya Murase, Takenori Yoshikawa, Kana Tanahashi, Emi Nishida, Tatsuya Okamoto, Komei Ito, Yoshinao Muro, Kazumitsu Sugiura, Tamio Ohno, John A McGrath, Masashi Akiyama

Frontiers in immunology Vol. 12 page： 737747 - 737747 2022.1

Language：English Publishing type：Research paper (scientific journal) Publisher：FRONTIERS MEDIA SA

Heterozygous mutations in JAK1 which result in JAK-STAT hyperactivity have been implicated in an autosomal dominant disorder that features multi-organ immune dysregulation. This study identifies another previously unreported heterozygous missense JAK1 mutation, H596D, in an individual with a unique autoinflammatory keratinization disease associated with early-onset liver dysfunction and autism. Using CRISPR-Cas9 gene targeting, we generated mice with an identical Jak1 knock-in missense mutation (Jak1 H595D/+;I596I/+;Y597Y/+ mice) that recapitulated key aspects of the human phenotype. RNA sequencing of samples isolated from the Jak1 H595D/+;I596I/+;Y597Y/+ mice revealed the upregulation of genes associated with the hyperactivation of tyrosine kinases and NF-κB signaling. Interestingly, there was a strong correlation between genes downregulated in Jak1 H595D/+;I596I/+;Y597Y/+ mice and those downregulated in the brain of model mice with 22q11.2 deletion syndrome that showed cognitive and behavioral deficits, such as autism spectrum disorders. Our findings expand the phenotypic spectrum of JAK1-associated disease and underscore how JAK1 dysfunction contributes to this autoinflammatory disorder.

DOI： 10.3389/fimmu.2021.737747

FOXA1 mutations in extramammary Paget's disease

Takeichi T.

Nishinihon Journal of Dermatology Vol. 84 ( 1 ) page： 9 - 12 2022

A Case of Family with Vörner-type Palmoplantar Keratoses Confirmed by Genetic Analysis

Matsumoto K., Kaneko S., Takeuchi S., Takeichi T., Akiyama M.

Nishinihon Journal of Dermatology Vol. 84 ( 5 ) page： 418 - 421 2022

Pitfalls in establishing mouse model of female infertility by immunization with human centromere protein. Reviewed International journal

Yoshinao Muro, Yuta Yamashita, Haruka Koizumi, Takuya Takeichi, Masashi Akiyama

Immunology letters Vol. 239 page： 20 - 22 2021.11

Extensive multiple organ involvement in VEXAS syndrome. Reviewed International journal

Noriyuki Takahashi, Takuya Takeichi, Tetsuya Nishida, Yasuhiro Takahashi, Juichi Sato, Masahiro Yamamura, Tomoo Ogi, Masashi Akiyama

Arthritis & rheumatology (Hoboken, N.J.) Vol. 73 ( 10 ) page： 1896 - 1897 2021.10

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

A 55-year-old Japanese man was diagnosed with VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, which is a newly documented adult-onset autoinflammatory disease caused by somatic UBA1 mutations [1], after four years of symptoms. He had suffered from recurrent fever after the onset of systemic arthralgia, scleritis, periorbital/orbital inflammation, optic perineuritis (A, B, T1-weighted contrast-enhanced magnetic resonance imaging in C and D, arrow in D), and myelodysplastic syndrome.

DOI： 10.1002/art.41775

Successful dupilumab treatment for ichthyotic and atopic features of Netherton syndrome Reviewed

Murase C., Takeichi T., Taki T., Yoshikawa T., Suzuki A., Ogi T., Suga Y., Akiyama M.

JOURNAL OF INVESTIGATIVE DERMATOLOGY Vol. 141 ( 10 ) page： S177 - S177 2021.10

A case of generalised pustular psoriasis with bullous pemphigoid showing spongiform pustule of Kogoj with eosinophils. Reviewed International journal

Hiroyoshi Nozaki, Shin Iinuma, Shigetsuna Komatsu, Yoshio Hashimoto, Hikaru Shibaki, Takuya Takeichi, Norito Ishii, Masashi Akiyama, Masaru Honma, Akemi Ishida-Yamamoto

European journal of dermatology : EJD Vol. 31 ( 5 ) page： 660 - 662 2021.9

Case of annular pustular psoriasis/circinate erythematous psoriasis induced by hydroxychloroquine in a patient with systemic lupus erythematosus: Possible association with CARD-14 mutation. Reviewed International journal

Hirotaka Midorikawa, Yukiko Kiniwa, Akane Minagawa, Kana Osawa, Takushi Shirai, Tasuku Sano, Kenta Nakamura, Atsuko Ashida, Ken-Ichi Ueno, Takuya Takeichi, Masashi Akiyama, Ryuhei Okuyama

The Journal of dermatology Vol. 48 ( 9 ) page： E440 - E442 2021.9

Intravenous allogeneic multilineage-differentiating stress-enduring cells in adults with dystrophic epidermolysis bullosa: a phase 1/2 open-label study. Reviewed International journal

Y Fujita, T Nohara, S Takashima, K Natsuga, M Adachi, K Yoshida, S Shinkuma, T Takeichi, H Nakamura, O Wada, M Akiyama, A Ishiko, H Shimizu

Journal of the European Academy of Dermatology and Venereology : JEADV Vol. 35 ( 8 ) page： E528 - E531 2021.8

Cutaneous malignant melanoma in an elderly patient with intermediate junctional epidermolysis bullosa. Reviewed International journal

Yuta Yamashita, Tomoki Taki, Takuya Takeichi, Mao Okumura, Shoichiro Mori, Yasutoshi Ito, Tomoo Ogi, Motohito Yamada, Masashi Akiyama

The Journal of dermatology Vol. 48 ( 8 ) page： E384 - E385 2021.8

Immune recognition of lysyl-tRNA synthetase and isoleucyl-tRNA synthetase by anti-OJ antibody-positive sera. Reviewed International journal

Yoshinao Muro, Yasuhiko Yamano, Ken Yoshida, Yohsuke Oto, Kimiko Nakajima, Teruyuki Mitsuma, Shiori Kikuchi, Akihiro Matsumae, Mariko Ogawa-Momohara, Takuya Takeichi, Yasuhiro Kondoh, Masao Katayama, Yasuyuki Todoroki, Yoshiya Tanaka, Minoru Satoh, Masashi Akiyama

Journal of autoimmunity Vol. 122 page： 102680 - 102680 2021.8

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

OBJECTIVE: Anti-aminoacyl-tRNA synthetase (anti-ARS) antibodies are useful for identifying a clinical subset of patients with idiopathic inflammatory myopathies (IIMs). Anti-OJ antibodies, which recognize multi-enzyme synthetase complexes including isoleucyl-tRNA synthetase (IARS) and lysyl-tRNA synthetase (KARS), are among the anti-ARS antibodies. Although testing antibodies to other ARSs have been used clinically, no validated immunoassays for detecting anti-OJ antibodies are available. We aimed to establish an anti-OJ ELISA. METHODS: Serum samples were collected from 279 patients with IIMs and 22 patients with idiopathic interstitial pneumonia. Sixty-four of the samples that had been confirmed to be negative for anti-OJ by standard immunoprecipitation were used as the negative control, and 12 anti-OJ-positive reference sera were used as the positive control. Antibodies to IARS and KARS were assayed by ELISA using biotinylated recombinant proteins generated by in vitro transcription/translation. RESULTS: The anti-OJ-positive sera strongly reacted with the KARS and IARS recombinant proteins in ELISA. Although all 12 reference sera were positive in the anti-KARS ELISA, 4 of the 64 anti-OJ-negative sera were also weakly positive. The sensitivity and the specificity were 100% and 93.8%, respectively. Since our anti-KARS ELISA performed well, showing a high agreement with the results for immunoprecipitation (Cohen's κ > 0.8), the remaining 237 samples were also tested. Thirteen anti-KARS-positive sera were newly found by ELISA, all of which were anti-OJ positive by immunoprecipitation. CONCLUSION: Immunoassays for detecting anti-OJ antibodies using KARS and IARS recombinant proteins were developed. Our ELISAs performed well, with very high agreement of the results by immunoprecipitation and can be applied to the first reliable, easy-to-use measurement assays for anti-OJ antibodies.

DOI： 10.1016/j.jaut.2021.102680

Updated allele frequencies of SERPINB7 founder mutations in Asian patients with Nagashima-type palmoplantar keratosis/keratoderma. Reviewed International journal

Yasutoshi Ito, Takuya Takeichi, Kenta Ikeda, Kana Tanahashi, Takenori Yoshikawa, Yuya Murase, Yoshinao Muro, Yoshio Kawakami, Yasuo Nakamura, Kanako Matsuyama, Jun Muto, Naoki Oiso, Shin Morizane, Kazumitsu Sugiura, Yasushi Suga, Mariko Seishima, Akira Kawada, Tomoo Ogi, Masashi Akiyama

Journal of dermatological science Vol. 103 ( 2 ) page： 116 - 119 2021.8

Paradoxical Reaction in a Patient with Hidradenitis Suppurativa Undergoing Adalimumab Treatment. Reviewed International journal

Soichiro Ikeya, Takuya Takeichi, Tomoki Taki, Yoshinao Muro, Tomoo Ogi, Masashi Akiyama

Acta dermato-venereologica Vol. 101 ( 6 ) page： adv00484 2021.6

Establishment of in-hospital clinical network for patients with neurofibromatosis type 1 in Nagoya University Hospital. Reviewed International journal

Yoshihiro Nishida, Kunihiro Ikuta, Atsushi Natsume, Naoko Ishihara, Maki Morikawa, Hiroyuki Kidokoro, Yukako Muramatsu, Norie Nonobe, Kanako Ishizuka, Takuya Takeichi, Miki Kanbe, Seiji Mizuno, Shiro Imagama, Norio Ozaki

Scientific reports Vol. 11 ( 1 ) page： 11933 - 11933 2021.6

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

Neurofibromatosis type 1 (NF1) is a genetic multisystem disorder. Clinicians must be aware of the diverse clinical features of this disorder in order to provide optimal care for it. We have set up an NF1 in-hospital medical care network of specialists regardless of patient age, launching a multidisciplinary approach to the disease for the first time in Japan. From January 2014 to December 2020, 246 patients were enrolled in the NF1 patient list and medical records. Mean age was 26.0 years ranging from 3 months to 80 years. The number of patients was higher as age at first visit was lower. There were 107 males (41%) and 139 females. After 2011, the number of patients has increased since the year when the medical care network was started. Regarding orthopedic signs, scoliosis was present in 60 cases (26%), and bone abnormalities in the upper arm, forearm, and tibia in 8 cases (3.5%). Neurofibromas other than cutaneous neurofibromas were present in 90 cases (39%), and MPNST in 17 cases (7.4%). We launched a multidisciplinary NF1 clinic system for the first time in Japan. For patients with NF1, which is a hereditary and systemic disease associated with a high incidence of malignant tumors, it will be of great benefit when the number of such clinics in Japan and the rest of Asia is increased.

DOI： 10.1038/s41598-021-91345-6

Altered replication stress response due to CARD14 mutations promotes recombination-induced revertant mosaicism. Reviewed International journal

Toshinari Miyauchi, Shotaro Suzuki, Masae Takeda, Jin Teng Peh, Masayuki Aiba, Ken Natsuga, Yasuyuki Fujita, Takuya Takeichi, Taiko Sakamoto, Masashi Akiyama, Hiroshi Shimizu, Toshifumi Nomura

American journal of human genetics Vol. 108 ( 6 ) page： 1026 - 1039 2021.6

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

Revertant mosaicism, or "natural gene therapy," refers to the spontaneous in vivo reversion of an inherited mutation in a somatic cell. Only approximately 50 human genetic disorders exhibit revertant mosaicism, implicating a distinctive role played by mutant proteins in somatic correction of a pathogenic germline mutation. However, the process by which mutant proteins induce somatic genetic reversion in these diseases remains unknown. Here we show that heterozygous pathogenic CARD14 mutations causing autoinflammatory skin diseases, including psoriasis and pityriasis rubra pilaris, are repaired mainly via homologous recombination. Rather than altering the DNA damage response to exogenous stimuli, such as X-irradiation or etoposide treatment, mutant CARD14 increased DNA double-strand breaks under conditions of replication stress. Furthermore, mutant CARD14 suppressed new origin firings without promoting crossover events in the replication stress state. Together, these results suggest that mutant CARD14 alters the replication stress response and preferentially drives break-induced replication (BIR), which is generally suppressed in eukaryotes. Our results highlight the involvement of BIR in reversion events, thus revealing a previously undescribed role of BIR that could potentially be exploited to develop therapeutics for currently intractable genetic diseases.

DOI： 10.1016/j.ajhg.2021.04.021

Odontogenic keratocysts are an important clue for diagnosing basal cell nevus syndrome. Reviewed

Hereditary Mucoepithelial Dysplasia and Autosomal-Dominant IFAP Syndrome Is a Clinical Spectrum Due to SREBF1 Variants. Reviewed International journal

Chiaki Murase, Takuya Takeichi, Toshifumi Nomura, Tomoo Ogi, Masashi Akiyama

The Journal of investigative dermatology Vol. 141 ( 6 ) page： 1596 - 1598 2021.6

Autoantibody profiles in patients' sera associated with distribution patterns of dermatomyositis skin symptoms. Reviewed International journal

Mariko Ogawa-Momohara, Fumie Kinoshita, Yoshinao Muro, Yumiko Kobayashi, Takuya Takeichi, Masashi Akiyama

Journal of the American Academy of Dermatology Vol. 84 ( 6 ) page： 1720 - + 2021.6

MEDNIK-like syndrome due to compound heterozygous mutations in AP1B1 Reviewed

Ito Y., Takeichi T., Igari S., Mori T., Ono A., Suyama K., Takeuchi S., Muro Y., Ogi T., Hosoya M., Yamamoto T., Akiyama M.

JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY Vol. 35 ( 5 ) page： E345 - E347 2021.5

Successful dupilumab treatment for ichthyotic and atopic features of Netherton syndrome. Reviewed International journal

Chiaki Murase, Takuya Takeichi, Tomoki Taki, Takenori Yoshikawa, Akiko Suzuki, Tomoo Ogi, Yasushi Suga, Masashi Akiyama

Journal of dermatological science Vol. 102 ( 2 ) page： 126 - 129 2021.5

Kaori Kaibuchi-Ando, Takuya Takeichi, Yasutoshi Ito, So Takeuchi, Yuta Yamashita, Motohito Yamada, Yoshinao Muro, Tomoo Ogi, Masashi Akiyama

Nagoya journal of medical science Vol. 83 ( 2 ) page： 393 - 396 2021.5

Language：English

Basal cell nevus syndrome (BCNS) is an autosomal dominant skin disorder characterized by multiple basal cell nevi. Patients with BCNS tend to develop basal cell carcinoma (BCC) and frequently show skeletal abnormalities. Most cases of BCNS are caused by mutations in patched 1 (PTCH1). PTCH1 encodes a transmembrane receptor protein for the secreted molecule sonic hedgehog, which plays a key role in the development of animals ranging from insects to mammals. We analyzed two Japanese BCNS patients from two independent families. Both of our patients had multiple jaw keratocysts. In one patient, these were the key to noticing his BCNS, as he had no skin tumors. The early detection of PTCH1 mutations would enable BCNS patients to be carefully followed up for the occurrence of BCC. The diagnosis of BCC at the early stage leads to prompt surgical treatments, resulting in a good prognosis. The present cases suggest that keratocysts of the jaw might be an important clue for diagnosing BCNS.

DOI： 10.18999/nagjms.83.2.393

Darier's disease with epilepsy in an elderly patient after surgery for aortic dissection. Reviewed International journal

Yuya Murase, Takuya Takeichi, Tomoyuki Shibata, Yoshinao Muro, Masashi Akiyama

The Journal of dermatology Vol. 48 ( 4 ) page： E169 - E170 2021.4

Cutaneous extramedullary hematopoiesis in a patient with secondary myelofibrosis due to MPL gene mutation. Reviewed International journal

Yuya Murase, Takuya Takeichi, Kana Tanahashi, Yoshiaki Marumo, Yuka Suzuki, Shigeo Nakamura, Masashi Akiyama

Journal of the European Academy of Dermatology and Venereology : JEADV Vol. 35 ( 4 ) page： E257 - E259 2021.4

Language：English

Dermal extramedullary hematopoiesis (EMH) is seen as a normal process from the first to the fifth month of gestation, and it is a process in which undifferentiated dermal mesenchymal cells retain their hematopoietic potential.1 However, after sixth months of gestation, hematopoiesis does not occur in the dermis except in a few conditions, such as in myeloproliferative disorders.1-3.

DOI： 10.1111/jdv.16990

ANCA-associated neuropathy in systemic sclerosis: A case report and review of literature Reviewed

Kayo Takenaka, Takuya Takeichi, Ryoji Nishi, Masashi Suzuki, Haruki Koike, Masahisa Katsuno, Mariko Ogawa-Momohara, Yoshinao Muro, Masashi Akiyama

JOURNAL OF CUTANEOUS IMMUNOLOGY AND ALLERGY Vol. 4 ( 2 ) page： 34 - 36 2021.4

Language：English Publisher：JOHN WILEY & SONS LTD

Systemic sclerosis (SSc) is a multi-system autoimmune disease. Anti-neutrophil cytoplasmic antibodies (ANCA) are autoantibodies directed against enzymes found within primary granules of neutrophils and lysosomes in monocytes. Although up to 12% of SSc patients have ANCA, only a minority of these patients develop an overlap syndrome with ANCA-associated vasculitis. We summarize previous reports on SSc patients with ANCA-associated neuropathy. In all the reported cases, the SSc diagnosis preceded the ANCA-associated neuropathy diagnosis. Seven of the eight patients with limited cutaneous SSc had interstitial lung disease (ILD). Thus, patients with ANCA-associated neuropathy in lSSc may be prone to complication with ILD.

DOI： 10.1002/cia2.12153

Acute generalized exanthematous pustulosis triggered by acetaminophen in an IL36RN variant heterozygote. Reviewed International journal

Chiaki Murase, Takuya Takeichi, Kazumitsu Sugiura, Masashi Akiyama

The Journal of dermatology Vol. 48 ( 4 ) page： E186 - E187 2021.4

Identification of a novel causative mutation in KRT1 in diffuse palmoplantar keratoderma, facilitated by whole-exome sequencing. Reviewed International journal

So Takeuchi, Takuya Takeichi, Yasutoshi Ito, Kana Tanahashi, Yoshinao Muro, Tomoo Ogi, Masashi Akiyama

European journal of dermatology : EJD Vol. 31 ( 2 ) page： 264 - 265 2021.3

Two Cases of Porokeratosis with MVD Mutations, in Association with Bullous Pemphigoid. Reviewed International journal

Yuki Arisawa, Yasutoshi Ito, Kana Tanahashi, Yoshinao Muro, Tomoo Ogi, Takuya Takeichi, Masashi Akiyama

Acta dermato-venereologica Vol. 101 ( 3 ) page： adv00423 2021.3

A case with overlapping features of IgG4-related autoimmune pancreatitis, Sjögren's syndrome and anti-aminoacyl-tRNA synthetase syndrome. Reviewed International journal

Masato Yoshikawa, Yoshinao Muro, Mariko Ogawa-Momohara, Satoru Ito, Takuya Takeichi, Masashi Akiyama

Modern rheumatology case reports Vol. 5 ( 1 ) page： 82 - 86 2021.1

Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS LTD

A 55-year-old man who had been diagnosed with autoimmune pancreatitis five years earlier was referred to our department because of finger swelling, finger stiffness and the presence of interstitial lung disease (ILD). The patient was diagnosed with Sjögren's syndrome according to the pathological findings of minor salivary glands and positive anti-SS-A antibodies. Later, at age 58, he was hospitalised due to the exacerbation of the ILD. Serum IgG4 level was checked and was found to be elevated (417 mg/dL). After the introduction of cyclosporine in addition to the prednisolone, at age 60, the ILD disease activity stabilised. However, at age 62, fever, myalgia and mechanic's hands appeared. His serum creatine kinase level was high, and magnetic resonance imaging showed inflammatory findings of muscle. In-house ELISA clarified that his serum carried anti-PL-7 antibody among anti-aminoacyl-tRNA synthetase antibodies. This is a unique case who had overlapping features of IgG4-related autoimmune pancreatitis, Sjögren's syndrome and anti-synthetase syndrome. Although the aetiology of the complications in this patient is obscure, autoimmunity might have played a significant role in the disease conditions and prognosis of the present case with IgG4-related disease.

DOI： 10.1080/24725625.2020.1816675

A patient with CARD14-associated papulosquamous eruptions showing atopic dermatitis-like features. Reviewed International journal

Takuya Takeichi, Shiho Terawaki, Yumiko Kubota, Yasutoshi Ito, Kana Tanahashi, Yoshinao Muro, Masashi Akiyama

Journal of the European Academy of Dermatology and Venereology : JEADV Vol. 35 ( 1 ) page： E58 - E59 2021.1

Language：English

Caspase recruitment domain family member 14 (CARD14) is an activator of nuclear factor kappa-light-chain-enhancer in activated B cells (NF-κB) and contributes to inflammatory responses within the epidermis. CARD14 mutations are associated with autoinflammatory keratinization diseases, such as psoriasis and familial pityriasis rubra pilaris (PRP). Recently, Craiglow et al. proposed CARD14-associated papulosquamous eruption (CAPE), a spectrum that includes clinical features of psoriasis and PRP. Characteristic features of patients with CAPE include early onset, prominent facial involvement, and favorable response to ustekinumab therapy. Here, we describe a unique CAPE patient with atopic dermatitis (AD)-like features and extend the spectrum of CAPE.

DOI： 10.1111/jdv.16799

Generalized pustular psoriasis associated with systemic lupus erythematosus successfully treated with secukinumab. Reviewed International journal

Kazuya Akaji, Yukinobu Nakagawa, Kasumi Kakuda, Madoka Takafuji, Eiji Kiyohara, Chiaki Murase, Takuya Takeichi, Masashi Akiyama, Manabu Fujimoto

The Journal of dermatology Vol. 48 ( 1 ) page： E43 - E44 2021.1

Systemic inflammatory diseases due to germ line EGFR mutations, with features suggestive of autoinflammatory keratinization diseases. Reviewed International journal

Takuya Takeichi, Masashi Akiyama

The Journal of dermatology Vol. 48 ( 1 ) page： E24 - E25 2021.1

Morphea in a Crohn's disease patient undergoing ustekinumab treatment. Reviewed International journal

Misako Makihara-Inukai, Takuya Takeichi, Mariko Ogawa-Momohara, Yoshinao Muro, Masashi Akiyama

European journal of dermatology : EJD Vol. 31 ( 1 ) page： 96 - 97 2021.1

A heterozygous SERPINB7 mutation is a possible modifying factor for epidermolytic palmoplantar keratoderma. Reviewed International journal

Takenori Yoshikawa, Takuya Takeichi, Tomoo Ogi, Yasushi Suga, Yoshinao Muro, Masashi Akiyama

Journal of dermatological science Vol. 100 ( 2 ) page： 148 - 151 2020.11

Anti-Zo antibodies in Japanese myositis patients detected by a newly developed ELISA. Reviewed International journal

Yoshinao Muro, Takako Hashimoto, Shinyu Izumi, Mariko Ogawa-Momohara, Takuya Takeichi, Hiroyuki Yamashita, Hidekata Yasuoka, Masashi Akiyama

Clinical and experimental rheumatology Vol. 40 ( 2 ) page： 219 - 223 2020.10

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

OBJECTIVES: The myositis-specific autoantibodies that characterise certain forms of idiopathic inflammatory myopathy (IIM) are useful for diagnosing dermatomyositis (DM) / polymyositis (PM) and predicting its prognosis. The autoantibody to phenylalanyl-tRNA synthetase (anti-Zo) has been identified as a disease marker antibody for anti-synthetase syndrome only in a UK cohort. Here we aim to establish an ELISA for the measurement of anti-Zo and to characterise the clinical features of Japanese patients who have this autoantibody. METHODS: Anti-Zo was investigated by immunoprecipitation with recombinant phenylalanyl-tRNA synthetase α/β proteins. The results were confirmed by immunoprecipitation-Western blotting with cell extract. Sera from patients with DM/PM (n=224) were screened by an ELISA with the recombinant proteins. Medical records were retrospectively reviewed to obtain detailed information on the clinical phenotypes of the anti-Zo-positive patients. RESULTS: Only two male patients were confirmed to have anti-Zo. Both patients had fever, myopathy, interstitial lung disease, and mechanic's hands, and these clinical features are consistent with those of anti-synthetase syndrome. Another patient's serum showed a higher level than the cut-off value for anti-phenylalanyl-tRNA synthetase α by our in-house ELISA, but was judged to be negative for anti-Zo by immunoprecipitation-Western blotting. CONCLUSIONS: This is the first report of anti-Zo-positive IIM patients from Asia. Although Japanese patients with anti-Zo have a clinical phenotype similar to that of Caucasian patients, further large cohort studies are necessary to confirm the frequency of anti-Zo in Japanese IIM patients. Our newly developed ELISA should be validated for sensitivity and specificity in large cohorts.

DOI： 10.55563/clinexprheumatol/q70vmh

Reducing immunosuppressant use in patients with chronic inflammation during the COVID-19 pandemic: Risks versus benefits

Acquired reactive perforating collagenosis with chondrodermatitis nodularis chronica helicis. International journal

Yuya Murase, Takuya Takeichi, Kana Tanahashi, Hiroyuki Takama, Masashi Akiyama

The Journal of dermatology Vol. 47 ( 10 ) page： E362 - E364 2020.10

Mariko Ogawa-Momohara, Yoshinao Muro, Takuya Takeichi, Masashi Akiyama

JOURNAL OF CUTANEOUS IMMUNOLOGY AND ALLERGY Vol. 3 ( 5 ) page： 120 - 121 2020.10

Language：English Publisher：JOHN WILEY & SONS LTD

During the COVID-19 pandemic, clinicians are facing a difficult but important question: Should we try to reduce immunosuppressant use or postpone immunosuppressant therapies for newly diagnosed autoimmune disease patients with mild to moderate symptoms? We would like to alert your readership that although potential chronic inflammation itself is not always critical, it can trigger a hyper-inflammatory condition in patients who become infected with COVID-19. We should be careful when reducing immunosuppressant use.

DOI： 10.1002/cia2.12132

Clinical and serological features of dermatomyositis and systemic lupus erythematosus patients with autoantibodies to ADAR1. International journal

Yoshinao Muro, Mariko Ogawa-Momohara, Takuya Takeichi, Shusaku Fukaya, Hidekata Yasuoka, Michihiro Kono, Masashi Akiyama

Journal of dermatological science Vol. 100 ( 1 ) page： 82 - 84 2020.10

Classical Vohwinkel syndrome with heterozygous p.Asp66His mutation in GJB2 gene: Second Asian case. International journal

Kenta Ikeda, Takuya Takeichi, Yasutoshi Ito, Yoshio Kawakami, Yuki Nakagawa, Seiko Naito, Osamu Yamasaki, Masashi Akiyama, Shin Morizane

The Journal of dermatology Vol. 47 ( 10 ) page： E352 - E354 2020.10

Association of Topical Minoxidil With Autosomal Recessive Woolly Hair/Hypotrichosis Caused by LIPH Pathogenic Variants. Reviewed International journal

Tomoki Taki, Kana Tanahashi, Takuya Takeichi, Takenori Yoshikawa, Yuya Murase, Kazumitsu Sugiura, Masashi Akiyama

JAMA dermatology Vol. 156 ( 10 ) page： 1030 - 1032 2020.10

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER MEDICAL ASSOC

This nonrandomized clinical trial evaluates the association of topical minoxidil with hypotrichosis in patients with autosomal recessive woolly hair/hypotrichosis carrying LIPH pathogenic variants.

DOI： 10.1001/jamadermatol.2020.2195

Exploration of biomarkers to predict clinical improvement of atopic dermatitis in patients treated with dupilumab: A study protocol. Reviewed International journal

Takeshi Nakahara, Kenji Izuhara, Daisuke Onozuka, Satoshi Nunomura, Risa Tamagawa-Mineoka, Koji Masuda, Susumu Ichiyama, Hidehisa Saeki, Yudai Kabata, Riichiro Abe, Mamitaro Ohtsuki, Koji Kamiya, Tatsuro Okano, Tomomitsu Miyagaki, Yozo Ishiuji, Akihiko Asahina, Hiroshi Kawasaki, Keiji Tanese, Hiroshi Mitsui, Tatsuyoshi Kawamura, Takuya Takeichi, Masashi Akiyama, Emi Nishida, Akimichi Morita, Kyoko Tonomura, Yukinobu Nakagawa, Koji Sugawara, Chiharu Tateishi, Yoko Kataoka, Rai Fujimoto, Sakae Kaneko, Eishin Morita, Akio Tanaka, Michihiro Hide, Natsuko Aoki, Shigetoshi Sano, Haruna Matsuda-Hirose, Yutaka Hatano, Motoi Takenaka, Hiroyuki Murota, Norito Katoh, Masutaka Furue

Medicine Vol. 99 ( 38 ) page： e22043 2020.9

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

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

DOI： 10.1097/MD.0000000000022043

A case of systemic lupus erythematosus/systemic sclerosis overlap syndrome successfully treated with belimumab. International journal

Mami Hara, Mariko Ogawa-Momohara, Yoshinao Muro, Takuya Takeichi, Masashi Akiyama

European journal of dermatology : EJD Vol. 30 ( 5 ) page： 615 - 617 2020.9

Mild epidermolytic ichthyosis with palmoplantar keratoderma due to the KRT1 mutation p.lle479Thr. Reviewed International journal

Yuya Murase, Kana Tanahashi, Takuya Takeichi, Kazumitsu Sugiura, Akiteru Aiyama, Keigo Nishida, Teruyuki Mitsuma, Masashi Akiyama

The Journal of dermatology Vol. 47 ( 9 ) page： E336 - E339 2020.9

Late-onset Langerhans cell histiocytosis without extracutaneous involvement Reviewed

Iwata, M; Takeichi, T; Muro, Y; Akiyama, M

JOURNAL OF CUTANEOUS IMMUNOLOGY AND ALLERGY Vol. 3 ( 4 ) page： 94 - 95 2020.8

A case of pemphigus with anti-desmoglein 3 and anti-desmocollin 2 and 3 autoantibodies, associated with follicular lymphoma and bronchiolitis obliterans. Reviewed International journal

Masato Yoshikawa, Takuya Takeichi, Tomoki Taki, Fumihiko Hayakawa, Norito Ishii, Takashi Hashimoto, Yoshinao Muro, Masashi Akiyama

European journal of dermatology : EJD Vol. 30 ( 4 ) page： 424 - 425 2020.7

Recurrent KRT10 Variant in Ichthyosis with Confetti. Reviewed International coauthorship International journal

Takuya Takeichi, Yasushi Suga, Takashi Mizuno, Yusuke Okuno, Daisuke Ichikawa, Michihiro Kono, John Y W Lee, John A McGrath, Masashi Akiyama

Acta dermato-venereologica Vol. 100 ( 14 ) page： adv00209 - 2 2020.7

SDR9C7 plays an essential role in skin barrier function by dehydrogenating acylceramide for covalent attachment to proteins International journal

Takuya Takeichi

Journal of Dermatological Science Vol. 98 ( 2 ) page： 82 - 87 2020.5

Language：English Publisher：ELSEVIER IRELAND LTD

© 2020 Japanese Society for Investigative Dermatology Among the components of the barrier structure of the stratum corneum in human skin, the corneocyte lipid envelope (CLE) is extremely important for the skin barrier. The importance of the CLE and esterified ω-hydroxy sphingosine (CerEOS), its main precursor, has been suggested from the fact that mutations in a number of genes involved in CerEOS synthesis and CLE formation have been identified as genetic causes of congenital ichthyoses, which are severe genetic skin disorders. However, the molecule/mechanism involved in the covalent binding of CerEOS to proteins on the outer surface of the cornified cell envelope had been a missing part. Very recently, we proposed new potential modes of protein binding by covalent reactions of CerEOS-epoxy-enone. We revealed the biochemical function of short-chain dehydrogenase/reductase family 9C member 7 (SDR9C7), encoded by SDR9C7, as catalyzing the dehydrogenation of the lipoxygenase products that are esterified in CerEOS. Epoxy-enone produced by SDR9C7 covalently binds to proteins on the outer extracellular surface of the cornified cell envelope. Importantly, our recent striking findings were derived from the detailed lipid analysis of only one ARCI patient with SDR9C7 mutation. The combination of detailed analyses of precious samples from a rare patient and the establishment of corresponding animal models is an effective and powerful tool for analyzing rare inherited diseases. This review summarizes this newly revealed mechanism in skin barrier formation, describes the characteristic features of patients with SDR9C7 mutations, and introduces the clinical value of non-invasive analyses for patients with very rare intractable skin diseases.

DOI： 10.1016/j.jdermsci.2020.03.005

長島型掌蹠角化症とアトピー性皮膚炎が併存した1例

垣生美奈子, 武藤潤, 藤井由美子, 吉川剛典, 武市拓也, 秋山真志, 佐山浩二

日本皮膚科学会雑誌 Vol. 130 ( 5 ) page： 1191 - 1191 2020.5

KLICK Syndrome Linked to a POMP Mutation Has Features Suggestive of an Autoinflammatory Keratinization Disease International journal

Takuya Takeichi, Masashi Akiyama

Frontiers in Immunology Vol. 11 page： 641 - 641 2020.4

Language：English Publisher：FRONTIERS MEDIA SA

© Copyright © 2020 Takeichi and Akiyama. Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) syndrome is a rare autosomal recessive skin disorder characterized by palmoplantar keratoderma, linear hyperkeratotic plaques, ichthyosiform scaling, circular constrictions around the fingers, and numerous papules distributed linearly in the arm folds and on the wrists. Histologically, the affected skin shows hypertrophy and hyperplasia of the spinous, granular, and horny epidermal layers with mild infiltration of inflammatory cells in the upper dermis. There are 14 patients with KLICK syndrome described in the literature, and they all carry the same nucleotide deletion. Proteasome maturation protein (POMP), encoded by POMP, is an ubiquitously expressed protein that functions as a chaperone for proteasome maturation. KLICK syndrome is caused by a reduction in POMP levels that leads to proteasome insufficiency in differentiating keratinocytes. It is noteworthy that POMP is also known to be the causative gene for proteasome-associated autoinflammatory syndrome-2 (PRAAS2). It is considered that the disrupted proteasome assembly caused by the POMP mutation might lead to both skin inflammation and then hyperkeratosis in KLICK syndrome. Inflammation caused by the hyperactivation of innate immunity occasionally leads to inflammatory diseases of the skin, recently denoted as autoinflammatory keratinization diseases (AiKDs). We propose that KLICK syndrome caused by the specific 1-bp nucleotide deletion mutation in the regulatory region of POMP might be in a spectrum of proteasome-associated phenotypes.

DOI： 10.3389/fimmu.2020.00641

Frequent FOXA1-activating mutations in extramammary Paget’s disease Reviewed International journal

Takuya Takeichi, Yusuke Okuno, Takaaki Matsumoto, Nobuyuki Tsunoda, Kyogo Suzuki, Kana Tanahashi, Michihiro Kono, Toyone Kikumori, Yoshinao Muro, Masashi Akiyama

Cancers Vol. 12 ( 4 ) 2020.4

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

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Extramammary Paget’s disease (EMPD) is a neoplastic skin disease of indeterminate origin with an unknown genetic cause. We performed a comprehensive genetic analysis or targeted gene sequencing in 48 patients with EMPD. We identified FOXA1 mutations, a GAS6–FOXA1 fusion gene, and somatic hotspot mutations in the FOXA1 promoter region in 11 of the 48 EMPD patients (11/48, 23%). Additional mutations were identified in PIK3CA (six patients) and in HIST1H2BB, HIST1H2BC, and SMARCB1 (one patient each), but none were found in other frequently mutated genes in cancer. A global gene expression analysis using EMPD clinical samples found the upregulation of PI3 kinase–AKT–mTOR signaling. ABCC11, which is specifically expressed in the apocrine secretory cells and is necessary for their sweat secretion, was upregulated in the EMPD samples. This upregulation suggests that Paget cells originate from apocrine secretory cells. Immunohistochemical staining revealed that FOXA1 expression was prevalent in all of the EMPD samples analyzed and was associated with estrogen receptor expression. Our genetic analysis indicates that EMPD frequently involves FOXA1 mutations. FOXA1 is a transcriptional pioneer factor for the estrogen receptor, and the present results suggest that certain treatments for hormone-dependent cancers could be effective for EMPD.

DOI： 10.3390/cancers12040820

Generalized Pustular Psoriasis: Clinical Management and Update on Autoinflammatory Aspects International journal

Takuya Takeichi, Masashi Akiyama

American Journal of Clinical Dermatology Vol. 21 ( 2 ) page： 227 - 236 2020.4

Language：English

© 2019, Springer Nature Switzerland AG. Generalized pustular psoriasis (GPP) is a chronic, systemic inflammatory disease accompanied by high fever and general malaise. Diffuse erythema and swelling of the extremities occur, with multiple sterile pustules all over the body in GPP patients. GPP often relapses over the lifetime and can be life-threatening. Recent discoveries of the underlying molecular genetic basis of many cases of this disorder have provided major advances to clinicians and researchers towards an understanding of the pathomechanism of GPP. However, the therapeutic management of GPP still faces many challenges and much uncertainty, and an evidence-based review summarizing the available clinical data on the management of this heterogeneous disease is needed. The present review addresses challenges regarding the precise clinical diagnosis and evaluation of clinical symptoms in GPP. In addition, we update and briefly summarize the current understanding of molecular pathomechanisms behind GPP as an autoinflammatory keratinization disease. Recent publications have clarified the genetic backgrounds of patients with GPP and ethnic differences in predisposing factors. Although there are ethnic differences in the prevalences of these pathogenic alleles, from recent reports, at most 60.5% (IL36RN), 5.9% (CARD14), and 10.8% (AP1S3) of GPP patients have the mutations/variations of these genes. All the reported biologics studied seemed effective and relatively well tolerated. Although it is difficult to evaluate therapeutic efficacy from studies on just a few cases, recent findings suggest that biologics can be a useful, powerful tool for controlling skin and systemic inflammation in GPP and for improving the quality of life of GPP patients.

DOI： 10.1007/s40257-019-00492-0

Deep phenotyping of ichthyosis follicularis with atrichia and photophobia syndrome associated with MBTPS2 mutations International journal

Chiaki Murase, Takuya Takeichi, Yusuke Okuno, Kyoko Ikumi, Akimichi Morita, Masashi Akiyama

Journal of Dermatology Vol. 47 ( 3 ) page： E87 - E88 2020.3

Successful secukinumab treatment of recalcitrant juvenile generalized pustular psoriasis International journal

Marina Nishida, Takuya Takeichi, Michihiro Kono, Akiko Imanishi, Naoki Maekawa, Masashi Akiyama, Kazuyoshi Fukai

Journal of Dermatology Vol. 47 ( 3 ) page： E77 - E78 2020.3

血清学的に抗BP230抗体単独陽性で、粘膜病変を有した水疱性類天疱瘡の1例

滝奉樹, 武市拓也, 河野通浩, 秋山真志, 杉浦一充, 椙村有里子, 石井文人, 橋本隆

日本皮膚科学会雑誌 Vol. 130 ( 3 ) page： 411 - 412 2020.3

A case of brain metastasis in HER2-negative extramammary Paget's disease. Reviewed International journal

Yuki Maki-Inoue, Takuya Takeichi, Masaki Sawada, Shigeru Fujitani, Akiko Ohashi, Masashi Akiyama

European journal of dermatology : EJD 2020.2

SDR9C7 catalyzes critical dehydrogenation of acylceramides for skin barrier formation Reviewed International journal

Takuya Takeichi, Tetsuya Hirabayashi, Yuki Miyasaka, Akane Kawamoto, Yusuke Okuno, Shijima Taguchi, Kana Tanahashi, Chiaki Murase, Hiroyuki Takama, Kosei Tanaka, William E. Boeglin, M. Wade Calcutt, Daisuke Watanabe, Michihiro Kono, Yoshinao Muro, Junko Ishikawa, Tamio Ohno, Alan R. Brash, Masashi Akiyama

Journal of Clinical Investigation Vol. 130 ( 2 ) page： 890 - 903 2020.2

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

© 2020, American Society for Clinical Investigation. The corneocyte lipid envelope, composed of covalently bound ceramides and fatty acids, is important to the integrity of the permeability barrier in the stratum corneum, and its absence is a prime structural defect in various skin diseases associated with defective skin barrier function. SDR9C7 encodes a short-chain dehydrogenase/reductase family 9C member 7 (SDR9C7) recently found mutated in ichthyosis. In a patient with SDR9C7 mutation and a mouse Sdr9c7-KO model, we show loss of covalent binding of epidermal ceramides to protein, a structural fault in the barrier. For reasons unresolved, protein binding requires lipoxygenase-catalyzed transformations of linoleic acid (18:2) esterified in ω-O-acylceramides. In Sdr9c7-/- epidermis, quantitative liquid chromatography-mass spectometry (LC-MS) assays revealed almost complete loss of a species of ω-Oacylceramide esterified with linoleate-9,10-trans-epoxy-11E-13-ketone; other acylceramides related to the lipoxygenase pathway were in higher abundance. Recombinant SDR9C7 catalyzed NAD+-dependent dehydrogenation of linoleate 9,10-trans-epoxy-11E-13-alcohol to the corresponding 13-ketone, while ichthyosis mutants were inactive. We propose, therefore, that the critical requirement for lipoxygenases and SDR9C7 is in producing acylceramide containing the 9,10-epoxy- 11E-13-ketone, a reactive moiety known for its nonenzymatic coupling to protein. This suggests a mechanism for coupling of ceramide to protein and provides important insights into skin barrier formation and pathogenesis.

DOI： 10.1172/JCI130675

A novel NCSTN missense mutation in the signal peptide domain causes hidradenitis suppurativa, which has features characteristic of an autoinflammatory keratinization disease

T. Takeichi, T. Matsumoto, T. Nomura, M. Takeda, H. Niwa, M. Kono, H. Shimizu, T. Ogi, M. Akiyama

British Journal of Dermatology Vol. 182 ( 2 ) page： 491 - 493 2020.2

Multifaceted analyses of epidermal serine protease activity in patients with atopic dermatitis Reviewed International journal

Hayato Nomura, Mutsumi Suganuma, Takuya Takeichi, Michihiro Kono, Yuki Isokane, Ko Sunagawa, Mina Kobashi, Satoru Sugihara, Ai Kajita, Tomoko Miyake, Yoji Hirai, Osamu Yamasaki, Masashi Akiyama, Shin Morizane

International Journal of Molecular Sciences Vol. 21 ( 3 ) 2020.2

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

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. The serine proteases kallikrein-related peptidase (KLK) 5 and KLK7 cleave cell adhesion molecules in the epidermis. Aberrant epidermal serine protease activity is thought to play an important role in the pathogenesis of atopic dermatitis (AD). We collected the stratum corneum (SC) from healthy individuals (n = 46) and AD patients (n = 63) by tape stripping and then measuring the trypsin-and chymotrypsin-like serine protease activity. We also analyzed the p.D386N and p.E420K of SPINK5 variants and loss-of-function mutations of FLG in the AD patients. The serine protease activity in the SC was increased not only in AD lesions but also in non-lesions of AD patients. We found, generally, that there was a positive correlation between the serine protease activity in the SC and the total serum immunoglobulin E (IgE) levels, serum thymus and activation-regulated chemokine (TARC) levels, and peripheral blood eosinophil counts. Moreover, the p.D386N or p.E420K in SPINK5 and FLG mutations were not significantly associated with the SC's serine protease activity. Epidermal serine protease activity was increased even in non-lesions of AD patients. Such activity was found to correlate with a number of biomarkers of AD. Further investigations of serine proteases might provide new treatments and prophylaxis for AD.

DOI： 10.3390/ijms21030913

A juvenile male case of dermatofibrosarcoma protuberans on the breast

Y. Murase, T. Takeichi, T. Matsumoto, A. Sakakibara, M. Akiyama

Clinical and Experimental Dermatology Vol. 45 ( 1 ) page： 111 - 113 2020.1

Reduced stratum corneum acylceramides in autosomal recessive congenital ichthyosis with a NIPAL4 mutation Reviewed International journal

Yuya Murase, Takuya Takeichi, Akane Kawamoto, Kana Tanahashi, Yusuke Okuno, Hiroyuki Takama, Eri Shimizu, Junko Ishikawa, Tomoo Ogi, Masashi Akiyama

Journal of Dermatological Science Vol. 97 ( 1 ) page： 50 - 56 2020.1

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

© 2019 Japanese Society for Investigative Dermatology Background: NIPAL4, encoding the NIPA-like domain containing 4 protein (NIPAL4), is one of the causative genes of autosomal recessive congenital ichthyosis (ARCI). The physiological role of NIPAL4 and the pathogenetic mechanisms of ARCI caused by NIPAL4 mutations remain unclear. Objective: To clarify the changes of ceramide components in the lesional stratum corneum (SC) and the gene expression profile in the lesional skin of an ARCI patient with a novel frameshift mutation in NIPAL4. Methods: We performed ultrastructural and immunohistochemical analyses of the skin. We used RNA sequencing to determine the mRNA expression in the skin of the patient and healthy individuals. We investigated ceramide components using tape stripped SC samples from the patient. Results: mRNA expression profiling in the patient's skin showed significant upregulation of IL-17/TNFα-related genes (IL17C, IL36A, IL36G, S100A7A, S100A9) and psoriasis hallmark genes (VNN3, LCE3D, PLA2G4D), and significant downregulation of lipid-associated genes (GAL, HAO2, FABP7). Ceramide analysis in the patient's SC revealed amounts of CER[NS] with carbon chain-length (C) 32–52 were increased, while amounts of most acylceramide with C66:2 - C72:2 were reduced relatively to those in healthy individuals. After the retinoid treatment, CER[NS] with carbon chains C46–54, CER[EOH] and CER[EOP] increased. Conclusion: IL-17C and IL-36 family cytokines might be involved in the pathogenetic process of ARCI with NIPAL4 mutations. Reduced amounts of the acylceramides in the SC are associated with the skin phenotype due to NIPAL4 mutations. Efficacy of the oral retinoid treatment might be due to restored amounts of CER[EOH] and CER[EOP] in the SC.

DOI： 10.1016/j.jdermsci.2019.12.001

Unique reticular hyperkeratotic eruptions seen in a patient with Darier's disease and attention deficit hyperactivity disorder

Case of erythrokeratodermia variabilis successfully treated with narrowband ultraviolet B International journal

Kayoko Okuda, Emi Nishida, Kan Tori, Akihiro Matubara, Yoko Sagawa, Takuya Takeichi, Masashi Akiyama, Akimichi Morita

Journal of Dermatology Vol. 47 ( 1 ) page： E30 - E31 2020.1

A patient with bullous pemphigoid with mucosal involvement serologically positive for anti-BP230 autoantibodies only International journal

T. Taki, T. Takeichi, M. Kono, K. Sugiura, Y. Sugimura, N. Ishii, T. Hashimoto, M. Akiyama

British Journal of Dermatology Vol. 182 ( 1 ) page： 221 - 223 2020.1

T. Yoshikawa, T. Takeichi, Y. Suga, Y. Kitajima, M. Akiyama

Journal of the European Academy of Dermatology and Venereology Vol. 34 ( 1 ) page： E41 - E43 2020.1

Oculodentodigital Dysplasia Diagnosed from Severe Hypotrichosis. Reviewed International journal

Tomoki Taki, Takuya Takeichi, Kazumitsu Sugiura, Masashi Akiyama

Acta dermato-venereologica Vol. 99 ( 13 ) page： 1307 - 1308 2019.12

A case of pustular psoriasis possibly precipitated by periodic oestrogen/gestagen therapy for Turner syndrome

T. Shiratori, T. Takeichi, M. Kono, M. Nishida, A. Imanishi, N. Maekawa, N. Kawamura, K. Fukai

Clinical and Experimental Dermatology Vol. 44 ( 7 ) page： E240 - E241 2019.10

Drug-induced acute eosinophilic pneumonia due to hydroxychloroquine in a chilblain lupus patient International journal

Yuri Ishiguro, Yoshinao Muro, Chiaki Murase, Takuya Takeichi, Michihiro Kono, Runa Adachi, Kazuomi Takahashi, Masashi Akiyama

Journal of Dermatology Vol. 46 ( 10 ) page： E356 - E357 2019.10

Roles of aberrant hemichannel activities due to mutant connexin26 in the pathogenesis of KID syndrome Reviewed

Taki T., Takeichi T., Sugiura K., Akiyama M.

JOURNAL OF INVESTIGATIVE DERMATOLOGY Vol. 139 ( 9 ) page： S248 - S248 2019.9

Brooke–Spiegler syndrome with chronic obstructive pulmonary disease and chronic sinusitis International journal

Yuki Hattori, Takuya Takeichi, Masashi Akiyama, Mariko Seishima

Journal of Dermatology Vol. 46 ( 6 ) page： E200 - E202 2019.6

Unilateral case of multiple minute digitate hyperkeratosis International journal

Satoko Okochi, Michihiro Kono, Hiromichi Takama, Takuya Takeichi, Yoshinao Muro, Masashi Akiyama

Journal of Dermatology Vol. 46 ( 6 ) page： E210 - E211 2019.6

Acrodermatitis continua of Hallopeau with dense infiltration of IgG4-positive cells in the lesional dermis. Reviewed International journal

Ogawa-Momohara M, Muro Y, Nakaguro M, Takeichi T, Kono M, Akiyama M

The British journal of dermatology Vol. 180 ( 4 ) page： 941 - 942 2019.4

Aberrant CARD14 function might cause defective barrier formation International journal

Yuya Murase, Takuya Takeichi, Masashi Akiyama

Journal of Allergy and Clinical Immunology Vol. 143 ( 4 ) page： 1656 - 1657 2019.4

Familial or sporadic porokeratosis as an autoinflammatory keratinization disease International journal

Takuya Takeichi, Masashi Akiyama

Journal of Dermatology Vol. 46 ( 4 ) page： E125 - E126 2019.4

Case of adult-onset Still's disease with psoriasiform eruptions. Reviewed International journal

Yasutoshi Ito, Takuya Takeichi, Toshiko Koide, Masashi Akiyama

The Journal of dermatology Vol. 46 ( 3 ) page： E109 - E110 2019.3

Hyaline vascular-type unicentric Castleman disease presenting as a subcutaneous nodule in a child. Reviewed International journal

Takuya Hanamura, Michihiro Kono, Kenji Yokota, Takuya Takeichi, Kei Kohno, Shigeo Nakamura, Teruyuki Mitsuma, Kosei Nakajima, Yoshinao Muro, Masashi Akiyama

The Journal of dermatology Vol. 46 ( 3 ) page： E97 - E99 2019.3

The lipoxygenase-hepoxilin pathway is activated in cutaneous plaque lesions of psoriasis Reviewed

Takeichi, T; Kinoshita, F; Tanaka, H; Fujita, S; Kobayashi, Y; Nakatochi, M; Sugiura, K; Akiyama, M

JOURNAL OF CUTANEOUS IMMUNOLOGY AND ALLERGY Vol. 2 ( 1 ) page： 15 - 24 2019.2

Authorship：Lead author Language：Japanese Publisher：Journal of Cutaneous Immunology and Allergy

Psoriasis is a common skin disorder that is characterized by hyperkeratosis, epidermal hyperplasia, T-cell and neutrophil recruitment, and changes in the vascular endothelial system. The several upregulated variable lipid mediators, including the eicosanoids, in psoriatic keratinocytes were described previously, although some results were contradictory. Since hepoxilin is less stable than other eicosanoids such as hydroxyeicosatetraenoic acid (HETE), the measurement of hepoxilin is difficult. In this study, to clarify the relationship between hepoxilin/hepoxilin-related fatty acid derivatives and psoriasis vulgaris, we evaluated the amount of production of lipid mediators including hepoxilins in skin tissues of patients with psoriasis vulgaris in comparison with normal controls by high-performance liquid chromatography/mass spectrometry. Most of the hepoxilins and related lipids evaluated in this study tended to be more abundant in the lesional skin from the psoriasis patient group (PPG) than in the skin from controls. Interestingly, 12R-HETE was markedly higher in the skin samples from the PPG. In addition, the lipids produced in the lipoxygenase pathway, including hepoxilin, were elevated in the skin lesions of the PPG compared with those of normal controls, whereas the lipids produced in the cyclooxygenase pathway were decreased in the skin lesions from the PPG. Our results suggest that an imbalance between the lipoxygenase and cyclooxygenase pathways may contribute to psoriatic pathomechanisms.

DOI： 10.1002/cia2.12039

A novel missense mutation in the ABCA12 gene in Japanese siblings with congenital ichthyosis erythroderma Reviewed

Kobashi H., Ishimoto T., Yamamoto M., Nakajima K., Takeichi T., Akiyama S., Sano S.

Nishinihon Journal of Dermatology Vol. 81 ( 5 ) page： 382 - 386 2019

[Successful treatment of pre-engraftment disseminated fusariosis with high-dose liposomal amphotericin B in a cord blood transplant recipient]. Reviewed

Yasuhiko Harada, Makoto Murata, Akane Matsumoto, Daizo Kato, Tetsuya Yagi, Takashi Yaguchi, Takenori Yoshikawa, Takuya Takeichi, Masashi Akiyama, Yohei Yamaguchi, Daisuke Koyama, Seitaro Terakura, Tetsuya Nishida, Hitoshi Kiyoi

[Rinsho ketsueki] The Japanese journal of clinical hematology Vol. 60 ( 12 ) page： 1641 - 1646 2019

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

A 47-year-old man with acute myeloid leukemia and myelodysplastic-related changes relapsed after an allogenic bone marrow transplant and received a cord blood transplant as salvage therapy. The patient developed febrile neutropenia that was resistant to broad-spectrum antibiotics and multiple, painful, nodular skin lesions on his trunk and extremities before engraftment. A skin biopsy and blood culture found mold, and the subsequent microscopic examination, mass spectrometry, and DNA sequencing of the fungal colonies identified Fusarium solani. The patient's fever and skin lesions began to improve with the administration of liposomal amphotericin B at 5 mg/kg/day. Neutrophilic engraftment occurred on day 19. Stage 3 acute skin graft-versus-host disease was cured by the application of topical steroid. Unexpectedly, a change from liposomal amphotericin B to voriconazole on day 38 exacerbated the Fusarium infection. The Fusarium infection was finally cured by the administration of liposomal amphotericin B for a total of 19 weeks. Neutrophilic engraftment, an immediate definitive diagnosis, the sufficient and long-term administration of appropriate antifungal medication, and avoidance of the systemic administration of steroids might have contributed to the successful outcome of this patient.

DOI： 10.11406/rinketsu.60.1641

Reduction of stratum corneum ceramides in Neu-Laxova syndrome caused by phosphoglycerate dehydrogenase deficiency. Reviewed International journal

Takuya Takeichi, Yusuke Okuno, Akane Kawamoto, Takeshi Inoue, Eiko Nagamoto, Chiaki Murase, Eri Shimizu, Kenichi Tanaka, Yuichi Kageshita, Satoshi Fukushima, Michihiro Kono, Junko Ishikawa, Hironobu Ihn, Yoshiyuki Takahashi, Masashi Akiyama

Journal of lipid research Vol. 59 ( 12 ) page： 2413 - 2420 2018.12

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

Neu-Laxova syndrome (NLS) is a very rare autosomal recessive congenital disorder characterized by disturbed development of the central nervous system and the skin and caused by mutations in any of the three genes involved in de novo l-serine biosynthesis: PHGDH, PSAT1, and PSPH l-Serine is essential for the biosynthesis of phosphatidylserine and sphingolipids. The extracellular lipid of the stratum corneum, of which sphingolipid constitutes a significant part, plays a primary role in skin barrier function. Here, we describe a Japanese NLS pedigree with a previously unreported nonsense mutation in PHGDH and a unique inversion of chromosome 1. In addition, the levels of 11 major ceramide classes in the tape-stripped stratum corneum of the NLS patient's skin were assessed by LC/MS. Notably, lower amounts of ceramides of all classes were found in the patient's stratum corneum than in those of controls. This is the first report to demonstrate the reduction of ceramides in the stratum corneum of an NLS patient due to PHGDH mutations. The clinical findings and a detailed analysis of ceramides from the stratum corneum in the family extend the spectrum of clinical anomalies and give us a clue to the pathomechanisms of ichthyosis in NLS patients with phosphoglycerate dehydrogenase deficiency.

DOI： 10.1194/jlr.P087536

Sterol profiles are valuable biomarkers for phenotype expression of Conradi-Hünermann-Happle syndrome with EBP mutations. Reviewed

Autosomal dominant progressive hyperpigmentation and lentigines in a Japanese pedigree due to a missense mutation near the C-terminus of KIT. Reviewed International journal

T Takeichi, K Sugiura, K Tanahashi, K Noda, M Kono, M Akiyama

The British journal of dermatology Vol. 179 ( 5 ) page： 1210 - 1211 2018.11

Takeichi T, Honda A, Okuno Y, Kojima D, Kono M, Nakamura Y, Tohyama M, Tanaka T, Aoyama Y, Akiyama M

The British journal of dermatology Vol. 179 ( 5 ) page： 1186 - 1188 2018.11

Mild Hailey-Hailey disease cases with aberrant splicing variants of ATP2C1 successfully controlled with excimer light. Reviewed

Kono M, Niizawa M, Takeichi T, Muro Y, Akiyama M

Journal of the European Academy of Dermatology and Venereology : JEADV Vol. 32 ( 11 ) page： E413 - E416 2018.11

Hearing impairment: A secondary symptom in a congenital ichthyosiform erythroderma patient with ABCA12 mutations. Reviewed International journal

Chiaki Murase, Takuya Takeichi, Kazumitsu Sugiura, Miki Kobayashi, Kozue Shiomi, Kaichiro Ikebuchi, Yutaka Tsutsumi, Masashi Akiyama

The Journal of dermatology Vol. 45 ( 11 ) page： E303 - E304 2018.11

Dyschromatosis symmetrica hereditaria may be successfully controlled by topical sunscreen. Reviewed International journal

Michihiro Kono, Takashi Okamoto, Takuya Takeichi, Yoshinao Muro, Masashi Akiyama

European journal of dermatology : EJD Vol. 28 ( 6 ) page： 840 - 841 2018.11

Cross-sectional survey on disease severity in Japanese patients with harlequin ichthyosis/ichthyosis: Syndromic forms and quality-of-life analysis in a subgroup. Reviewed International journal

Chiaki Murase, Takuya Takeichi, Akitaka Shibata, Masahiro Nakatochi, Fumie Kinoshita, Akiharu Kubo, Kimiko Nakajima, Norito Ishii, Hiroo Amano, Koji Masuda, Hiroshi Kawakami, Takuro Kanekura, Ken Washio, Masayuki Asano, Kazuya Teramura, Eijiro Akasaka, Mikiko Tohyama, Yutaka Hatano, Toyoko Ochiai, Shinichi Moriwaki, Tomotaka Sato, Akemi Ishida-Yamamoto, Mariko Seishima, Michiko Kurosawa, Shigaku Ikeda, Masashi Akiyama

Journal of dermatological science Vol. 92 ( 2 ) page： 127 - 133 2018.11

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

BACKGROUND: Congenital ichthyoses (CIs) adversely affect quality of life (QOL) in patients. However, the effects of CIs on patient QOL have not been studied sufficiently. OBJECTIVE: To investigate the association between disease severity and QOL in patients with harlequin ichthyosis (HI) and ichthyosis: syndromic forms (ISFs) METHODS: Clinical information of patients with HI and ISFs from 2010 to 2015 were obtained from 100 dermatology departments/divisions of principal institutes/hospitals throughout Japan. We examined the relationship between disease severity and QOL in patients with HI and ISFs. Patients who were aged 8 years or older and participated in a multicenter retrospective questionnaire survey in Japan were assessed by dermatology life quality index (DLQI, range of 0-30) and clinical ichthyosis score (range of 0-100). RESULTS: Netherton syndrome patients had a significantly higher risk of allergy to food or environmental allergens than patients with other phenotypes. Keratitis-ichthyosis-deafness (KID) syndrome patients showed a significantly higher risk of skin infections than patients with other phenotypes. Complete data on DLQI were obtained from 13 patients, whose median age was 21 (8-71) years. Nine patients were male, and 4 were female. Systemic retinoids were administrated to 2 of the 3 HI patients. The Spearman's correlation coefficient between the clinical ichthyosis score and DLQI was 0.611 (P < 0.05). CONCLUSION: We confirmed that Netherton syndrome and KID syndrome patients have a higher risk of allergy to food or environmental allergens and of skin infections, respectively. QOL impairment correlates with disease severity in HI and ISFs patients.

DOI： 10.1016/j.jdermsci.2018.08.008

Roles of aberrant hemichannel activities due to mutant connexin26 in the pathogenesis of KID syndrome. Reviewed

Deficiency of the interleukin-36 receptor antagonist dramatically improved by secukinumab. Reviewed International journal

Manao Kinoshita, Takashi Okamoto, Shinya Sano, Hiroshi Mitsui, Takuya Takeichi, Kazumitsu Sugiura, Masashi Akiyama, Shinji Shimada, Tatsuyoshi Kawamura

The Journal of dermatology Vol. 45 ( 10 ) page： E280 - E281 2018.10

Dyschromatosis symmetrica hereditaria with chilblains due to a novel two-amino-acid deletion in the double-stranded RNA-binding domain of ADAR1. Reviewed International journal

Kono M, Suganuma M, Shimada T, Ishikura Y, Watanabe S, Takeichi T, Muro Y, Akiyama M

Journal of the European Academy of Dermatology and Venereology : JEADV Vol. 32 ( 10 ) page： E394 - E396 2018.10

Taki T, Takeichi T, Sugiura K, Akiyama M

Scientific reports Vol. 8 ( 1 ) page： 12824 2018.8

Bilateral striatal necrosis and dyschromatosis symmetrica hereditaria: A-I editing efficiency of ADAR1 mutants and phenotype expression. Reviewed International journal

Kono M, Suganuma M, Dutta A, Ghosh SK, Takeichi T, Muro Y, Akiyama M

The British journal of dermatology Vol. 179 ( 2 ) page： 509 - 511 2018.8

Two cases of generalized pustular psoriasis complicated by IgG4-related disease. Reviewed

Miyazawa H, Fujita Y, Iwata H, Ishikawa Y, Nishio S, Ishijima K, Shinmei Y, Takeichi T, Goto K, Oi R, Akiyama M, Shimizu H

The British journal of dermatology Vol. 179 ( 2 ) page： 537 - 539 2018.8

Eosinophilia and systemic symptoms with transient ageusia: a drug reaction caused by zonisamide. Reviewed International journal

Runa Adachi, Michihiro Kono, Takuya Takeichi, Yoshinao Muro, Masashi Akiyama

European journal of dermatology : EJD Vol. 28 ( 4 ) page： 523 - 524 2018.7

Filaggrin gene mutations may influence the persistence of food allergies in Japanese primary school children. Reviewed International journal

M Kono, M Akiyama, Y Inoue, T Nomura, A Hata, Y Okamoto, T Takeichi, Y Muro, W H I McLean, H Shimizu, K Sugiura, Y Suzuki, N Shimojo

The British journal of dermatology Vol. 179 ( 1 ) page： 190 - 191 2018.7

Analysis of genotype/phenotype correlations in Japanese patients with dyschromatosis symmetrica hereditaria. Reviewed

Tomoko Kobayashi, Michihiro Kono, Mutsumi Suganuma, Hirotaka Akita, Ayaka Takai, Kiyohiro Tsutsui, Yu Inasaka, Takuya Takeichi, Yoshinao Muro, Masashi Akiyama

Nagoya journal of medical science Vol. 80 ( 2 ) page： 267 - 277 2018.5

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

Dyschromatosis symmetrica hereditaria (DSH) is one of the genetic pigmentation disorders and shows characteristic mixture of hyper- and hypo-pigmented small macules on the extremities. Heterozygous mutations in the adenosine deaminase acting on RNA1 gene (ADAR1) cause DSH. In the present study, we report five cases of DSH and identify a distinct known mutation in each patient. Furthermore, we review previously described cases with the five ADAR1 mutations found in the present study. We reviewed clinical and molecular findings in the present and previously reported cases and found an identical mutation can result in various phenotypic severities, even in one family. We found novel phenotype-genotype correlations between the presence/absence of facial lesions and the ADAR1 mutation c.3286C>T. The absence of freckle-like macules in the face was found to be more commonly associated with the mutation c.3286C>T than with the other 4 ADAR1 mutations (odds ratio = 0.056 [95% CI: 0.007-0.47, p < 0.005]). We objectively evaluated the severity of skin manifestations in the extremities using our definition of severity levels for such manifestations. This is the first semi-quantitative evaluation of skin manifestations in DSH. Using our definition, we found that patients with facial lesions with or without hypopigmented macules tend to show more severe symptoms on the extremities than patients without facials lesions show. Furthermore, no significant difference in the severity of the skin lesions was observed between the upper and the lower extremities, suggesting that sun exposure does not affect significantly the pathogenesis of DSH skin lesions.

DOI： 10.18999/nagjms.80.2.267

National survey of quality of life and disease severity in patients with congenital ichthyosis

Murase C., Takeichi T., Shibata A., Nakatochi M., Kinoshita F., Ikeda S., Kurosawa M., Akiyama M.

JOURNAL OF INVESTIGATIVE DERMATOLOGY Vol. 138 ( 5 ) page： S44 - S44 2018.5

Impetigo herpetiformis with IL-36RN mutation successfully treated with secukinumab. Reviewed International journal

Manao Kinoshita, Youichi Ogawa, Takuya Takeichi, Takashi Okamoto, Atsushi Osada, Shinji Shimada, Kazumitsu Sugiura, Masashi Akiyama, Tatsuyoshi Kawamura, Katsuhiko Tsukamoto

European journal of dermatology : EJD Vol. 28 ( 3 ) page： 381 - 382 2018.5

Case of mild X-linked ichthyosis complicated with paroxysmal supraventricular tachycardia and anemia.

Maki Y, Takeichi T, Kono M, Tanaka Y, Akiyama M

The Journal of dermatology 2018.3

An infant with generalized pustular psoriasis and geographic tongue had a heterozygous IL36RN mutation and IgG2 deficiency.

Oi R, Takeichi T, Okuno Y, Kojima D, Sugawara K, Kono M, Muramatsu H, Akiyama M

Journal of dermatological science 2018.2

Autoinflammatory keratinization diseases: An emerging concept encompassing various inflammatory keratinization disorders of the skin.

Akiyama M, Takeichi T, McGrath JA, Sugiura K

Journal of dermatological science 2018.2

A novel IFIH1 mutation in the pincer domain underlies the clinical features of both Aicardi-Goutières and Singleton-Merten syndromes in a single patient. Reviewed International journal

T Takeichi, C Katayama, T Tanaka, Y Okuno, N Murakami, M Kono, K Sugiura, Y Aoyama, M Akiyama

The British journal of dermatology Vol. 178 ( 2 ) page： E111 - E113 2018.2

Multiple keratotic papules and plaques on the trunk in Cowden's disease with MALT lymphoma. Reviewed International journal

Sayaka Mizuno, Takuya Takeichi, Junichi Sato, Masanao Nakamura, Hidemi Goto, Kazumitsu Sugiura, Masashi Akiyama

The Journal of dermatology Vol. 45 ( 2 ) page： 238 - 240 2018.2

Trichothiodystrophy, complementation group A complicated with squamous cell carcinoma Reviewed

T. Takeichi, S. Tomimura, Y. Okuno, M. Hamada, M. Kono, K. Sugiura, M. Akiyama

Journal of the European Academy of Dermatology and Venereology Vol. 32 ( 2 ) page： E75 - E77 2018.2

Mild case of Hailey-Hailey disease caused by a novel ATP2C1 mutation.

Hanamura T, Takeichi T, Okuno Y, Ichikawa D, Kono M, Akiyama M

The Journal of dermatology 2018.1

Hailey-Hailey disease due to ATP2C1 splice site mutation, successfully treated with minocycline hydrochloride Reviewed

M. Kono, M. Niizawa, T. Takeichi, Y. Muro, M. Akiyama

Journal of the European Academy of Dermatology and Venereology Vol. 32 ( 1 ) page： E19 - E20 2018.1

Autoinflammatory keratinization diseases. Reviewed

Akiyama M, Takeichi T, McGrath JA, Sugiura K.

J Allergy Clin Immunol. Vol. 140 ( 6 ) page： 1545-1547 2017.12

Granulocyte and monocyte apheresis can control juvenile generalized pustular psoriasis with mutation of IL36RN Reviewed

Y. Koike, M. Okubo, T. Kiyohara, R. Fukuchi, Y. Sato, S. Kuwatsuka, T. Takeichi, M. Akiyama, K. Sugiura, A. Utani

British Journal of Dermatology Vol. 177 ( 6 ) page： 1732 - 1736 2017.12

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

© 2017 British Association of Dermatologists Patients with deficiency of interleukin-36 receptor antagonist (DITRA), due to mutation of IL36RN, exhibit psoriatic phenotypes, typically generalized pustular psoriasis (GPP). We report a paediatric patient with DITRA, whose cutaneous lesions varied from psoriasis vulgaris in infancy to annular pustular psoriasis with acute exacerbation to GPP at 13 years of age. Conventional systemic treatments for GPP, which include oral retinoids, ciclosporin and methotrexate, are controversial in paediatric cases, because of their adverse effects and uncertain long-term consequences. Granulocyte monocyte apheresis, a process associated with few adverse events, promptly controlled the GPP of our paediatric patient, and has potential as a suitable alternative treatment for paediatric patients with DITRA.

DOI： 10.1111/bjd.15509

Biallelic mutations in KDSR disrupt ceramide synthesis and result in a spectrum of keratinization disorders associated with thrombocytopenia. Reviewed

Takeichi T, Torrelo A, Lee JYW, Ohno Y, Lozano ML, Kihara A, Liu L, Yasuda Y, Ishikawa J, Murase T, Rodrigo AB, Fernández-Crehuet P, Toi Y, Mellerio J, Rivera J, Vicente V, Kelsell DP, Nishimura Y, Okuno Y, Kojima D, Ogawa Y, Sugiura K, Simpson MA, McLean WHI, Akiyama M, McGrath JA.

J Invest Dermatol. Vol. 137 ( 11 ) page： 2344-2353 2017.11

Autosomal dominant familial generalized pustular psoriasis caused by a CARD14 mutation. Reviewed

Takeichi T, Kobayashi A, Ogawa E, Okuno Y, Kataoka S, Kono M, Sugiura K, Okuyama R, Akiyama M.

Br J Dermatol. Vol. 177 ( 4 ) page： e133-e135 2017.10

A combination of low-dose systemic etretinate and topical calcipotriol/betamethasone dipropionate treatment for hyperkeratosis and itching in Olmsted syndrome associated with a TRPV3 mutation. Reviewed International journal

Takuya Takeichi, Katsuhiko Tsukamoto, Yusuke Okuno, Daiei Kojima, Michihiro Kono, Yasushi Suga, Masashi Akiyama

Journal of dermatological science Vol. 88 ( 1 ) page： 144 - 146 2017.10

Phosphorylated signal transducer and activator of transcription 3 in the epidermis in adult-onset Still's disease. Reviewed International journal

Takuya Takeichi, Naoki Watanabe, Yoshinao Muro, Shiho Teshigawara, Motoki Sato, Nobutaro Ban, Masashi Akiyama

The Journal of dermatology Vol. 44 ( 10 ) page： 1172 - 1175 2017.10

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

Adult-onset Still's disease (AOSD) is characterized by multiple systemic inflammation of unknown etiology. Although the typical eruption of AOSD is salmon-pink rheumatoid rash on the trunk and extremities, persistent pruritic papules and plaques have also been reported. Correlations between serum cytokines, including interleukin-6 and -18, and disease activity in AOSD have been reported. Activated signal transducer and activator of transcription 3 (STAT3) is transported into the nucleus, where it functions as a transcription factor that regulates genes involved in cell survival and inflammation. To assess whether STAT3 was phosphorylated in skin samples from AOSD patients, we conducted immunohistochemical analysis of affected and unaffected lesions from four AOSD patients in comparison with 10 normal controls. Quantitative analysis was conducted by measuring the ratio of epidermal keratinocytes with phosphorylated STAT3 (p-STAT3)-positive nuclei to total epidermal keratinocytes. p-STAT3 was found to be more strongly expressed in the nuclei in the epidermis of AOSD than in normal controls. Quantification of the data revealed significant differences in staining for p-STAT3 between AOSD and normal skin. Our findings suggest that phosphorylation of STAT3 may be a potential therapeutic target for AOSD.

DOI： 10.1111/1346-8138.13888