Faculty Profiles - TAKEICHI Takuya

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