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Journal of Dermatology | 2014

Defective barrier function accompanied by structural changes of psoriatic stratum corneum

Hidetoshi Takahashi; Hitomi Tsuji; Masako Minami-Hori; Yuki Miyauchi; Hajime Iizuka

Although barrier function of psoriatic skin is shown to be decreased by measuring transepidermal water loss (TEWL), few reports exist examining other physical skin properties and components including stratum corneum hydration, natural moisturizing factor (NMF), free fatty acids (FFA), β‐sheet and α‐helix ratio of structural protein(s), and sebum content. We compared the skin properties and components of normal, involved and uninvolved skin of psoriasis. Using a corneometer and attenuated total reflection‐infrared spectrometer, we measured TEWL, stratum corneum hydration, NMF, FFA, β/α ratio and sebum in psoriasis vulgaris patients and healthy controls. TEWL and β/α ratio of involved psoriatic skin were significantly increased compared with uninvolved skin and normal control skin. In contrast, stratum corneum hydration, NMF and FFA, but not sebum, are significantly decreased in the involved skin compared with uninvolved skin and normal skin. TEWL and stratum corneum hydration returned to the normal levels following clinical improvement of the lesion. Barrier function and hydration of psoriatic skin are defective and secondary structure in stratum corneum protein is altered in the involved psoriatic skin.


Journal of Investigative Dermatology | 2014

IL36RN mutations underlie impetigo herpetiformis.

Kazumitsu Sugiura; Naoki Oiso; Shin Iinuma; Hiromasa Matsuda; Masako Minami-Hori; Akemi Ishida-Yamamoto; Akira Kawada; Hajime Iizuka; Masashi Akiyama

TO THE EDITOR Impetigo herpetiformis (IH) is a rare pustular dermatosis that typically occurs in pregnant women sporadically with unknown etiology (Sauer and Geha, 1961). Early diagnosis is essential, as IH is life-threatening and is associated with placental insufficiency and electrolyte abnormalities. IH appears to have the same clinical and histologic appearance as generalized pustular psoriasis (GPP), which is also a rare severe episodic pustular dermatosis that occurs repeatedly in both sexes at any age. However, some researchers have regarded IH as an entity distinct from GPP, because some patients are affected by IH only in the gestational period (Lotem et al., 1989). Recently, we reported that the majority of GPP that is not accompanied by psoriasis vulgaris (PV; GPP alone) is caused by homozygous or compound heterozygous mutations of IL36RN, which encodes IL-36 receptor antagonist (IL36RN), although only a small number of cases with GPP preceding or accompanied by PV (GPP with PV) were found to have IL36RN mutations (Sugiura et al., 2013). Very recently, we reported that CARD14 c.526G4C is a significant risk factor for GPP with PV, but not for GPP alone in the Japanese cohort, which further supports the idea that GPP with PV differs genetically from GPP alone (Sugiura et al., 2014a). However, to our knowledge, there have been no reports of IH with IL36RN mutations. Here we report two cases of IH with homozygous and heterozygous IL36RN mutations. Cases 1 and 2 were a 23-year-old woman and a 28-year-old Japanese woman who were admitted to our hospitals for pustular lesions in the 29 week and the 20 week of their first pregnancies, respectively (Figure 1a and b). There was no family history of GPP, no IH, and no consanguinity in their families. Case 1 had no previous history of GPP. Her pustular lesions had begun to develop at the 21 week of pregnancy, and she had been hospitalized in a maternity hospital. Oral prednisolone at a dose of 15 mg per day had been administered, but the eruptions had persisted. A skin biopsy from a pustular eruption on the trunk revealed a spongiform pustule of Kogoj in the epidermis consistent with IH (Figure 1c). Case 2 had suffered from GPP from the age of 8 to 18 years. Skin biopsies from pustular eruptions on the trunk revealed spongiform pustules of Kogoj in the epidermis at the age of 8 and 28 years (Figure 1d). She had been admitted to hospitals four times for GPP flare-ups. She had been treated with cyclosporine or etretinate. In the ten years leading up to her pregnancy, her GPP had been in remission without any treatment. Both cases had erythema with pustules over the whole body and fever of over 38 1C. Blood examinations from Cases 1 and 2, respectively, revealed white blood cell counts of 12,000ml 1 and 21,170ml , and C-reactive protein concentrations of 6.5 and 14.9 mg dl 1 (normal range: o0.3 mg dl ). Bacterial cultures of the pustules were negative. Thus, Cases 1 and 2 were, respectively, diagnosed as having IH and IH with a previous history of GPP. Following ethical approval, written informed consent was obtained in compliance with the Declaration of Helsinki Principles. The entire coding regions of IL36RN including the exon/intron boundaries were sequenced using genomic DNA samples from the patients. Case 1 had the homozygous mutation c.115þ6T4C, which was proven to result in p.Arg10ArgfsX1 in IL36RN by us previously, and Case 2 had the heterozygous mutation c.28C4T (p.Arg10X) in IL36RN. Both of these are GPP-causing founder mutations in the Japanese cohort (Sugiura et al., 2013, 2014b; Figure 1e and f, and Figure 2). A search for a second IL36RN mutation in all intron and putative promoter regions in Case 2 revealed no other IL36RN mutations (Supplementary Figure S1 online and Supplementary Table S1 online). However, there is still the possibility of a second unidentified IL36RN mutation in Case 2. More than 10 cases of GPP with heterozygous IL36RN mutations have been reported (Capon, 2013; Korber et al., 2013; Li et al., 2013; SettaKaffetzi et al., 2013; Sugiura et al., 2013). Moreover, in some patients, heterozygous IL36RN mutations are associated with palmoplantar pustulosis, a type of pustular psoriasis, and acute generalized exanthematous pustulosis, a severe cutaneous drug reaction (Navarini et al., 2013; SettaKaffetzi et al., 2013). IL-36 is absent in normal skin but is induced by inflammatory cytokines such as tumor necrosis factor-a, IL-17A, and IL-22 (Carrier et al., 2011). When functional IL-36RN is absent or underproduced, overexpressed IL-36 can induce neutrophilrich infiltration. Tumor necrosis factor-a is often elevated in the blood of pregnant women, whereby it induces various serious diseases (Mallmann et al., 1991). As for skin diseases, tumor necrosis factor-a sometimes causes exacerbation of PV lesions in pregnant women (Puig et al., 2010). Hence, it is very likely that a pregnant woman who has the IL36RN mutation occasionally cannot produce enough IL-36RN to adequately antagonize IL-36 excessively induced by inflammatory cytokines, and this imbalance results in IH. After longstanding controversy over whether IH is an independent disease Accepted article preview online 9 April 2014; published online 1 May 2014 Abbreviations: GPP, generalized pustular psoriasis; IH, impetigo herpetiformis; IL-36RN, IL-36 receptor antagonist; PV, psoriasis vulgaris K Sugiura et al. IL36RN Mutations and IH


Journal of Dermatology | 2014

Biologics are more potent than other treatment modalities for improvement of quality of life in psoriasis patients

Hidetoshi Takahashi; Shin Iinuma; Hitomi Tsuji; Masaru Honma; Hajime Iizuka

Although mental health is hampered in various skin disorders, few studies regarding anxiety in psoriasis patients are available, and specifically, no evaluation exists between mental health and psoriasis severity or the patients quality of life. To examine the relation between mental health, psoriasis severity and patients quality of life, 119 psoriasis vulgaris patients were assessed for anxiety using the General Health Questionnaire (GHQ)‐30. Psoriasis area and severity index (PASI) and Dermatological Life Quality Index (DLQI) scores were also measured. The average total GHQ‐30 score was significantly decreased from 4.41 to 2.11 (52.2% decrease) in biologics‐treated patients. That of patients treated with other systemic agents decreased from 4.36 to 3.32 (23.9% decrease) and that of those treated with topical agents from 4.21 to 3.48 (17.3% decrease). In the biologics‐treated group five of the six categories of GHQ‐30, i.e. general illness, somatic symptoms, sleep disturbance, social dysfunction, and anxiety and dysphoria, were significantly decreased after the treatment. In contrast, in the other systemic treatment and topical treatment groups, three of the six categories, general illness, somatic symptoms, and sleep disturbance were significantly decreased. There was a significant correlation between GHQ‐30 and DLQI, but not with PASI. The psoriasis patients show impaired mental health and among various treatment modalities biologics are superior to other systemic or topical treatments for improving the defective mental state.


Journal of Dermatology | 2014

Increased serum C-reactive protein level in Japanese patients of psoriasis with cardio- and cerebrovascular disease

Hidetoshi Takahashi; Shin Iinuma; Masaru Honma; Hajime Iizuka

Psoriasis is a chronic inflammatory skin disease, which may be associated with metabolic syndrome accompanied by cardio‐ and cerebrovascular diseases. We investigated the relation between serum C‐reactive protein (CRP) and cardio‐ and cerebrovascular diseases in Japanese psoriasis vulgaris patients. Ninety‐seven psoriasis vulgaris patients and 79 healthy controls were assessed for serum CRP levels by immunoturbidimetry. The data were analyzed in terms of Psoriasis Area and Severity Index (PASI) scores, and comorbidity of cardio‐ and cerebrovascular disease and metabolic syndrome. Serum CRP levels in psoriasis vulgaris patients were significantly higher than those of healthy controls. There was no significant difference between male and female CRP levels in either psoriasis or healthy controls. No correlation was detected between PASI scores and serum CRP levels, either. Psoriasis with cardio‐ and cerebrovascular disease showed significantly higher CRP levels compared with those without the diseases. Furthermore, psoriasis with metabolic syndrome showed significantly higher serum CRP levels than those without the metabolic syndrome. In conclusion, serum CRP level is increased in psoriasis, and may be a useful marker for the prediction of the future risk of cardio‐ and cerebrovascular disease.


Journal of Dermatological Science | 2014

Developmental alterations of physical properties and components of neonatal-infantile stratum corneum of upper thighs and diaper-covered buttocks during the 1st year of life.

Masako Minami-Hori; Masaru Honma; Mizue Fujii; Wakana Nomura; Kyoko Kanno; Tokinaka Hayashi; Eiki Nakamura; Ken Nagaya; Yuki Miyauchi; Tsutomu Fujimura; Mitsuyuki Hotta; Yutaka Takagi; Takashi Kitahara; Yoshinori Takema; Hajime Iizuka

BACKGROUNDnAlthough physical properties of neonatal-infantile stratum corneum (SC) change drastically after birth, precise developmental alterations of specific sites have not been fully elucidated.nnnOBJECTIVEnTo determine the longitudinal alterations of neonatal-infantile SC functions and components of upper thighs and diaper-covered buttocks during the first year of life. The data were compared with those of adults.nnnMETHODSnNineteen full-term neonates and their mothers were subjected to the measurements. Skin hydration, water sorption/retention capacity, TEWL were measured. Superficial SC analyses for NMF, ester binding sebum, and free fatty acids were performed by ATR-FTIR spectrometer. Total amount of ceramides (CERs) and CER subclasses were analyzed by NPLC-ESI-MS.nnnRESULTSnSC hydration of neonatal thighs was lower than that of their mothers, which rapidly increased during the 1st month. Skin hydration of neonatal buttocks was similar to that of their mothers. This also rapidly increased during the 1st month. The neonatal TEWL was less than those of their mothers indicating more efficient barrier function at both sites, which significantly increased during the 1st year development. This was mostly correlated decreased in the ω-hydroxy fatty acid-esterified CERs. Superficial ester-binding sebum content of neonates was similar to that of their mothers, which significantly decreased during the measurement; the decrease was more marked on buttocks. Neither NMF nor FFA of the superficial SC showed significant alteration during the 1-year development.nnnCONCLUSIONnOur results indicate that physical functions and components of neonatal-infantile SC show considerable alterations between diaper-covered buttocks and upper thighs during the 1st year development.


Journal of Dermatology | 2016

Novel postzygotic KRAS mutation in a Japanese case of epidermal nevus syndrome presenting with two distinct clinical features, keratinocytic epidermal nevi and sebaceous nevi.

Satomi Igawa; Masaru Honma; Masako Minami-Hori; Etsushi Tsuchida; Hajime Iizuka; Akemi Ishida-Yamamoto

Dear Editor, Epidermal nevus syndrome (ENS) is a heterogeneous congenital disorder characterized by the presence of epidermal nevi associated with systemic involvement. Keratinocytic epidermal nevus (KEN) syndrome and sebaceous nevus (SN) syndrome are included in ENS which share the same postzygotic HRAS and KRAS gene mutations that are relevant for cell proliferation. A HRAS mutation can induce nevus marginatus, a combined nevus of KEN and SN, and this suggests an identical genetic background of KEN and SN. Here, we report a case of ENS exhibiting both KEN and SN characteristics caused by a novel postzygotic KRAS mutation. A 3-year-old Japanese girl presented with multiple nevoid lesions along Blaschko lines on the left side of her body that she had had since birth. The skin lesions, which were light red at the neonatal stage (Fig. 1a), had transformed into two distinct types: yellowish plaques suggesting SN on the sebaceous gland-rich craniofacial area, and brownish verrucous lesions suggesting KEN on the trunk and extremities (Fig. 1b). Histological evaluation showed papillomatosis and acanthosis with overlying laminated hyperkeratosis (Fig. 1c,d).


Journal of Dermatology | 2014

Cutaneous necrotizing vasculitis as a manifestation of familial Mediterranean fever

Shigetsuna Komatsu; Masaru Honma; Satomi Igawa; Hitomi Tsuji; Akemi Ishida-Yamamoto; Kiyoshi Migita; Hiroaki Ida; Hajime Iizuka

Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory disease, which is characterized by recurrent and paroxysmal fever, peritonitis, arthritis, myalgia, and skin rashes. Although various skin lesions such as “erysipelas‐like erythema”, urticaria, nonspecific purpura, and subcutaneous nodules have been described, cutaneous vasculitis is rare. We report a Japanese case of sporadic FMF accompanied by cutaneous arteritis at the time of febrile attacks of FMF. Gene analysis revealed M694I mutation in a single allele of the MEFV gene, and oral colchicine successfully controlled both periodic fever and subcutaneous nodules of arteritis. Cutaneous necrotizing vasculitis repeatedly emerging with febrile attacks should be included among the skin manifestations of FMF.


Journal of Dermatology | 2014

Antifungal effect of TONS504-photodynamic therapy on Malassezia furfur.

Hidetoshi Takahashi; Susumu Nakajima; Isao Sakata; Hajime Iizuka

Numerous reports indicate therapeutic efficacy of photodynamic therapy (PDT) against skin tumors, acne and for skin rejuvenation. However, few reports exist regarding its efficacy for fungal skin diseases. In order to determine the antifungal effect, PDT was applied on Malassezia furfur. M. furfur was cultured in the presence of a novel cationic photosensitizer, TONS504, and was irradiated with a 670‐nm diode laser. TONS504‐PDT showed a significant antifungal effect against M. furfur. The effect was irradiation dose‐ and TONS504 concentration‐dependent and the maximal effect was observed at 100 J/cm2 and 1 μg/mL, respectively. In conclusion, TONS504‐PDT showed antifungal effect against M. furfur in vitro, and may be a new therapeutic modality for M. furfur‐related skin disorders.


Journal of Dermatology | 2014

Cutaneous Langerhans cell histiocytosis in elderly with chronic myelomonocytic leukemia

Takeshi Iwasaki; Ichiro Takahashi; Takahiro Nagashima; Satomi Igawa; Shigetsuna Komatsu; Masaru Honma; Akemi Ishida-Yamamoto; Hajime Iizuka

Langerhans cell histiocytosis (LCH) is a rare histiocytic neoplasm characterized by clonal proliferation of Langerhans cells in multi‐organ systems including skin, bone, pituitary gland, liver and spleen. Skin‐limited involvement of LCH usually indicates an indolent clinical course; however, in rare cases, LCH is accompanied by other myeloproliferative disorders, which may determine the prognosis. An 82‐year old Japanese man presented with numerous asymptomatic facial papules clinically simulating rhinophyma. Although findings of histopathology and general examination including bone marrow biopsy led to the diagnosis of cutaneous LCH, he died from chronic myelomonocytic leukemia, which emerged 10 months after the initial diagnosis of LCH. The previously reported cases of LCH concomitant with other hematological disorders are also summarized and described compared with the present case.


Journal of Dermatology | 2014

Drug-induced hypersensitivity syndrome due to minocycline complicated by severe myocarditis

Kyoko Kanno; Hiroyuki Sakai; Yutaka Yamada; Hajime Iizuka

A 60‐year‐old woman presented with a 13‐day history of a generalized erythematous rash accompanied by fever, periorbital edema and axillary lymphadenopathy. Prior to the appearance of the rash, the patient had been treated with intermittent courses of oral minocycline for cystitis. The patient was diagnosed with drug‐induced hypersensitivity syndrome (DIHS) due to minocycline. During the admission, infectious endocarditis was suspected and the patient was treated with i.v. gammaglobulin (0.4 g/kg per day). The following day, the patient suffered from systemic deterioration and symptomatic low blood pressure that prompted repeat echocardiography which revealed an ejection fraction of 10%. DIHS‐associated myocarditis was suspected and management with circulation assistance devices and steroid pulse therapy were started, resulting in satisfactory resolution. A rise in titer of human herpesvirus‐6, cytomegalovirus and Herpes simplex virus‐1 antibodies was detected. Although minocycline‐induced myocarditis is rare, this severe drug reaction should be considered with DIHS.

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Masaru Honma

Asahikawa Medical University

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Masako Minami-Hori

Asahikawa Medical University

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Hitomi Tsuji

Asahikawa Medical University

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Kyoko Kanno

Asahikawa Medical University

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Satomi Igawa

Asahikawa Medical University

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Shin Iinuma

Asahikawa Medical University

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Shigetsuna Komatsu

Asahikawa Medical University

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