Norihiro Ikoma

HLA-C*12:02 is a susceptibility factor in late-onset type of psoriasis in Japanese.

Psoriasis is thought to be a multifactorial disease triggered by both genetic and environmental factors. The HLA‐C locus on chromosome 6p21.33 remains the strongest susceptibility candidate locus in psoriasis. The strong association between psoriasis and the HLA‐Cw6 allele has been well documented in various races. It is known that psoriatic patients with early onset are more likely to be familial and associated with HLA‐Cw6. Familial occurrence of Japanese psoriasis is smaller than other populations. Furthermore, males are predominant over females in Japanese psoriasis. We investigated the relation between HLA‐C alleles and age of onset, and in each gender for Japanese psoriasis, and discuss male predominance in the incidence of psoriasis in Japan. Four hundred forty six unrelated Japanese patients with psoriasis vulgaris and 557 sex‐ and age‐matched unrelated Japanese healthy controls were investigated by genotyping. We confirmed the association between early‐onset type of psoriasis with HLA‐C*06:02 allele in Japanese. In addition, we detected the association between the late‐onset type of psoriasis and the HLA‐C*12:02 allele in Japanese. No significant differences in allele frequency were observed between females and males. Our results suggest that there is no genetic factor effect on male predominance in Japanese. In contract, the effect of environmental risk factors on the onset of Japanese psoriatic patients is stronger in males than in females. As a result, male predominant in psoriasis may occur in Japan.

Notch signaling may be involved in the abnormal differentiation of epidermal keratinocytes in psoriasis.

Localization of each keratin isoform differs among epidermal layers. Proliferating basal cells synthesize keratin 14 (K14) and suprabasal cells express keratin 10 (K10) in normal skin. Notch signaling is essential for keratinocyte differentiation. Notch1 is expressed in all epidermal layers, Notch2 in the basal cell layer and Notch3 in basal cell and spinous cell layers in normal epidermis. It has been poorly elucidated how localization and expression levels of Notch molecules are related to epidermal molecular markers K10 and K14 in psoriatic skin with abnormal differentiation of epidermal tissue. This study aimed to investigate the relationship between abnormal differentiation of epidermal cells in psoriatic skin and expression of Notch molecules. We investigated keratins (K14 and K10) and Notches (1, 2, 3 and 4) using immunohistochemistry in psoriatic skin (n=30) and normal skin (n=10). In normal skin, K14 and K10 were discretely observed in the basal cell layer and suprabasal layer, respectively. In psoriatic skin, K14 was expressed in the pan epidermal layer while it and K10 were co-expressed in some middle suprabasal layer cells. Notch1, 2, 3, and 4 localized in all epidermal layers in normal skin. In psoriatic skin, Notch1, 2, and 4 mainly localized in suprabasilar layers and Notch3 is lacalized in pan epidermal, suprabasilar, and basilar layers. Protein and mRNA of Notch1, 2, and 3 isoforms decreased in psoriatic epidermis compared with normal epidermis. These data suggest that decrements in these Notch molecules might cause aberrant expression of K10 and K14 leading to anomalous differentiation of the epidermis in psoriatic lesions.

A novel small compound accelerates dermal wound healing by modifying infiltration, proliferation and migration of distinct cellular components in mice

BACKGROUND Impaired wound healing in skin ulcer is one of the major medical issues in the aged society. Wound healing is a complex process orchestrated by a number of humoral factors and cellular components. TGF-β is known to stimulate collagen production in dermal fibroblasts while inhibiting proliferation of epidermal keratinocyte. A screening of small compounds that suppress type I collagen production in fibroblasts has identified HSc025 that antagonizes the TGF-β/Smad signal. OBJECTIVE We examined the effects of HSc025 on dermal wound healing and elucidated the underlying mechanisms. METHODS Effects of HSc025 on the wound closure process were evaluated in a murine full-thickness excisional wound healing model. Cell proliferation and migration were estimated using primary cultures of human keratinocytes and fibroblasts. Comprehensive analyses of gene expression profiles were performed using untreated and HSc025-treated fibroblasts. RESULTS Oral HSc025 administration suppressed macrophage infiltration and accelerated wound closure as early as at day 2 after the dermal excision. Treatment of cultured keratinocytes with HSc025 counteracted the inhibitory effects of TGF-β on cell proliferation and migration. On the other hand, HSc025 stimulated migration, but not proliferation, of dermal fibroblasts independently of TGF-β. Experiments using an artificial dermis graft revealed that HSc025 stimulated migration of collagen-producing cells into the graft tissue. A cDNA microarray analysis of untreated and HSc025-treated fibroblasts identified pirin as a critical mediator accelerating fibroblast migration. CONCLUSION HSc025 accelerates wound healing by modifying infiltration, proliferation and migration of distinct cellular components, which provides a novel insight into the therapy for intractable skin ulcer.

A novel case of nocardiosis with skin lesion due to Nocardia araoensis.

Nocardiosis is caused by Gram‐positive aerobic actinomycetes that live in soil and are known to be responsible for opportunistic infections. The condition mostly affects the lung, brain or skin. Here, we present a 24‐year‐old Japanese woman who had had systemic lupus erythematosus since the age of 20 years, and lupus nephritis since the age of 23 years. She developed cutaneous lymph duct‐type nocardiosis due to Nocardia araoensis while on immunosuppressant therapy. The patient had cutaneous findings from the right inguinal region to the right lower thigh and did not have lesions on the rest of the body. Minocycline and co‐trimoxazole were co‐administrated, and her condition improved. To our knowledge, this is the first case in which N. araoensis was detected by analysis on rRNA base sequence in skin lesions.

Case of generalized pustular psoriasis with end-stage renal disease successfully treated with granulocyte monocyte apheresis in combination with hemodialysis

Granulocyte monocyte apheresis (GMA) is an extracorporeal apheresis instrument that removes activated neutrophils and monocytes. Generalized pustular psoriasis (GPP) is characterized by neutrophil infiltration into the epidermis that causes Kogojs spongiotic pustule. Thus, GMA is one of the useful therapies for GPP, and it was approved for the treatment in 2012 in Japan. Herein, we report a case of GPP with end‐stage renal disease (ESRD) successfully treated with GMA in combination with hemodialysis (HD). A 54‐year‐old Japanese female visited our outpatient clinic because of erythema with pustules on her trunk and extremities over the past 4 months. Histopathological examination showed an intraepidermal pustule filled with numerous neutrophils and spongiosis. These findings led to the diagnosis of GPP. She had ESRD and had been treated with HD twice a week for approximately 4 years. During maintenance HD twice a week, weekly GMA was started at Tokai University Hospital. The skin symptoms disappeared after five administrations of GMA. We suggest that GMA is an effective therapy for GPP patients with ESRD who are treated with HD.

A novel splicing variant of CADM2 as a protective transcript of psoriasis

CADM2, a candidate gene for psoriasis, was identified by a genome-wide association study using microsatellites in the Japanese population (561 cases and 561 controls). Moreover, haplotype analysis included an additional 68 SNPs and indicated that a 110-kb haplotype block was detected for the protective risk haplotype of psoriasis. We also identified an initial exon of novel splicing variants in this haplotype block. A functional analysis by qRT-PCR using RNAs from the blood of 56 cases and 64 controls significantly demonstrated an inverse correlation between expression frequencies in a novel splicing variant and the number of alleles associated with psoriasis. To confirm these results, we must perform replication studies using other ethnic groups and more functional analysis particularly for skin tissues.

Pediatric case of anaplastic lymphoma kinase-positive anaplastic large cell lymphoma forming a solitary skin tumor on the forearm

A 5‐year‐old girl noticed a rapidly growing reddish nodule on her right forearm. Although oral antibiotics had been administrated for 2 weeks, the tumor enlarged. Skin biopsy revealed excessive infiltration of atypical neoplastic cells expressing CD4, CD30 and anaplastic lymphoma kinase (ALK). These histological and immunohistochemical findings were consistent with anaplastic large cell lymphoma (ALCL). Computed tomography showed multiple lymphadenopathy, but lymph node biopsy and bone marrow examination did not show any evidence of systemic dissemination. However, due to the positive results for ALK and multiple lymphadenopathy, we diagnosed ALK‐positive ALCL forming a solitary skin tumor on the forearm. The patient received chemotherapy and presented marked improvement. This paper discusses the difficulty of diagnosing pediatric ALK‐positive ALCL limited to the skin and reviews the medical published work.

Long-term efficacy of psoriasis vulgaris treatments: Analysis of treatment with topical corticosteroid and/or vitamin D3 analog, oral cyclosporin, etretinate and phototherapy over a 35-year period, 1975–2010

Various therapies have been tried for psoriasis. In Japan, biologics began to be used for psoriasis treatment in January 2010. Their clinical efficacy is well known, but biologics cannot be used in all psoriasis patients for reasons such as side‐effects and cost. It is necessary to evaluate the effect of long‐term psoriasis treatment, but there have been no reports evaluating long‐term treatment. Therefore, the outcomes of patients who had been treated at the Tokai University Hospital for more than 5 years, before biological agents were released, were examined. Three categories, classified by initial severity, changes in severity by method of treatment and background characteristics, were investigated. In conclusion, cases of long‐term treatment with a combination of topical corticosteroid and topical vitamin D3 analog or oral cyclosporin were found to be effective therapies. Patients with a history of diabetes mellitus or cardiovascular disease of psoriasis were likely to be treatment resistant.

Diagnostic usefulness of findings in Doppler sonography for amelanotic melanoma

To evaluate the diagnostic usefulness of Doppler sonography for amelanotic melanoma (AM), the correspondence between the findings of dermoscopy and Doppler sonography was investigated in AM in comparison with other hypopigmented tumors. Seven cases with AM and 11 cases with squamous cell carcinoma (SCC), 10 cases with non‐ or hypopigmented basal cell carcinoma (NP‐BCC) and six cases with eccrine poroma (EP) as hypopigmented tumors were investigated. EP is readily recognized by differences from AM and SCC based on a single vertical and non‐torvtuous vessels. NP‐BCC is distinguished from AM based on tortuosity running in a vertical direction. Though findings of tortuosity in vessels and heterogeneity of vessel size are recognized both in AM and SCC: (i) abundant blood flow was recognized more clearly in AM; (ii) total blood flow was more than 40% in most cases of AM (average, 60.9%); and (iii) more vessels which flow into a tumor are found in AM (85.7%). There is no relationship between dermoscopic findings of vessel types and Doppler sonography findings of vessels. In this study, the diagnostic usefulness of the above‐mentioned specific findings in examination may suggest using Doppler sonography for AM as one non‐invasive method.

Development of psoriasis 10 years after allogeneic hematopoietic cell transplantation from non‐psoriatic donor: Further evidences for genetics and immunopathogenesis of psoriasis

Japan and only five instances from other countries. This scarcity of papers on adalimumab for GPP highlights the significance of our report. The case we experienced was rare in that GPP developed in a PsA patient, who refused infusion. Adalimumab elicited a favorable response to the concomitant GPP. No similar reports have been published except for a case reported by Zangrilli et al. More case records should be collected to establish evidence that adalimumab is a safe and effective treatment, even for GPP patients judged as having primary or secondary failure to infliximab therapy.