Neutrophilic epitheliotropism, proposed as an auto-inflammatory condition of neutrophilic urticarial dermatosis including Schnitzler syndrome, is also observed in Japanese cases.

Schnitzler syndrome (SchS) is a rare autoinflammatory disease characterized by bone pain, recurrent fever, leukocytosis, and elevated C-reactive protein, along with an urticaria-like rash and monoclonal immunoglobulin (Ig)M or IgG gammopathy. Notably, the condition is distinguished by a relatively persistent recurrent urticarial-like rash. Histopathological features observed in the skin comprise diffuse neutrophil infiltration into the dermis, absence of dermal edema, and vascular wall degeneration, all of which classify SchS as a neutrophilic urticarial dermatosis (NUD). Accumulated histological data from skin biopsies of patients with NUD have revealed a sensitive histopathological marker for NUD, acknowledged as neutrophilic epitheliotropism, which has been proposed as reflecting an autoinflammatory condition. In this report, we present three SchS patients: two men (ages 55 and 68) and a woman (age 75), all displaying neutrophilic epitheliotropism in their skin biopsy specimens. Additionally, a review of eight previously reported SchS cases in Japan identified neutrophilic epithliotropism in five cases. These findings suggest that the inclination of neutrophils toward the epithelial tissue could aid in confirming diagnoses of NUD in most cases that need to be differentiated from conventional urticaria. Consequently, we emphasize that acknowledging neutrophilic epithelial predilection as a hallmark of NUD is critical for expediting early diagnosis and appropriate treatment for SchS.

Oestrogen inhibits psoriasis-like dermatitis induced by imiquimod in mice in relation to increased IL-10 producing cells despite elevated expression of IL-22, IL-23, IL-17 mRNA.

Sex hormones influence the development and natural course of psoriasis. Here, we examined the effects of female sex hormones, particularly oestrogen, on psoriasis-like dermatitis induced using topical imiquimod in mice that underwent either sham operation (Sham) or ovariectomy (OVX), with (hormone replacement treatment: HRT) or without 17ß-oestradiol targeting the maximum physiological levels. The number of neutrophils in the skin was higher in the order of OVX-, Sham-, and HRT-treated mice. However, no significant difference was detected in the clinical scores among the three groups due to severe erythema and scale in a few mice out of HRT-treated mice in a set of experiments. OVX- and HRT-treated mice showed increased mRNA levels of interleukin (IL)-22 and IL-23 compared with Sham-treated mice; increased IL-10 mRNA levels were found in HRT-treated mice, possibly due to an increased proportion of forkhead box P3 (Foxp3)- and IL-10 positive large cells (possibly macrophages). In addition, HRT-treated mice had a more compact stratum corneum with higher expression of loricrin and involucrin than OVX- and Sham-treated mice. This study suggests that oestrogen has a dual potential in the pathogenesis of psoriasis: suppression of inflammation by enhancing IL-10 production and enhancement of inflammation by induction of IL-22 and IL-23 expression.

Summary of the current status of clinically diagnosed cases of Schnitzler syndrome in Japan.

BACKGROUND: Schnitzler syndrome is a rare disorder with chronic urticaria, and there is no report summarizing the current status in Japan. METHODS: A nationwide survey of major dermatology departments in Japan was conducted in 2019. We further performed a systematic search of PubMed and Ichushi-Web, using the keywords "Schnitzler syndrome" and "Japan" then contacted the corresponding authors or physicians for further information. RESULTS: Excluding duplicates, a total of 36 clinically diagnosed cases were identified from 1994 through the spring of 2022, with a male to female ratio of 1:1. The median age of onset was 56.5 years. It took 3.3 years from the first symptom, mostly urticaria, to reach the final diagnosis. The current status of 30 cases was ascertained; two patients developed B-cell lymphoma. SchS treatment was generally effective with high doses of corticosteroids, but symptoms sometimes recurred after tapering. Colchicine was administered in 17 cases and was effective in 8, but showed no effect in the others. Tocilizumab, used in six cases, improved laboratory abnormalities and symptoms, but lost its efficacy after several years. Rituximab, used in five cases, was effective in reducing serum IgM levels or lymphoma mass, but not in inflammatory symptoms. Four cases were treated with IL-1 targeting therapy, either anakinra or canakinumab, and achieved complete remission, except one case with diffuse large B-cell lymphoma. CONCLUSIONS: Since Schnitzler syndrome is a rare disease, the continuous collection and long-term follow-up of clinical information is essential for its appropriate treatment and further understanding of its pathophysiology.

Possible involvement of type 2 cytokines in alloknesis in mouse models of menopause and dry skin.

Alloknesis, an abnormal itch sensation induced by innocuous stimuli, is a key phenomenon in the vicious itch-scratch cycle in patients with atopic dermatitis. Dry skin and pruritus, including alloknesis, are major health problems in peri- and post-menopausal women. We recently reported permeability barrier dysfunction in ovariectomized (OVX) mice-a model of menopause-and found that the dysfunction was related to dry skin. However, the mechanism of the itch remains unknown. Therefore, we examined touch- and pruritogen-evoked alloknesis and epidermal innervation in OVX mice and acetone, diethyl ether and water (AEW)-treated mice, for the experimental dry skin model. Both alloknesis and epidermal innervation were comparable in OVX and AEW mice. Neutralizing antibodies against IL-4 and IL-13 inhibited alloknesis in both OVX and AEW mice as early as 30 min after intradermal administration. Comparable values close to the measurement limit of IL-4 were found in the skin of HRT and Sham mice as well as AEW and the control mice, but the levels of IL-4 were within the measurement limit in OVX mice. We could not detect mRNAs of IL-4 or IL-13 in any groups of mice. On the other hand, the number of eosinophils and basophils was increased in OVX and AEW mice. These results suggest that impaired barrier function in cooperation with type 2 cytokines derived from eosinophils and basophils in the skin or with endogenous type 2 cytokine may trigger the development of alloknesis, and thus, these cytokines could be a therapeutic target for sensitive skin.

Rectal carcinoma and multiple gastrointestinal stromal tumors (GIST) of the small intestine in a patient with neurofibromatosis type 1: a case report.

BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomally dominant inherited disorder characterized by multiple pigmented skin spots (café-au-lait spots) and neurofibroma. NF1 is associated with a wide variety of benign or malignant tumors. We report a NF1 patient who received surgical treatment for rectal carcinoma and multifocal small intestinal gastrointestinal stromal tumors (GISTs). CASE PRESENTATION: A 70-year-old female patient with NF1 was referred to our hospital after a positive fecal occult blood test. Locally advanced rectal carcinoma was detected in the upper rectum using colonoscopy. A submucosal tumor 20 mm in diameter was detected in the duodenal bulb during the upper gastrointestinal endoscopy. The biopsy specimen from the duodenum was GIST with positive immunostaining of KIT and CD34 microscopically. Laparoscopic low anterior resection for rectal carcinoma and local excision of the duodenal GIST were performed successfully. During the operation, five white small nodules were found on the serosa of the jejunum. One nodule was excised for histological examination. The resected rectal tumor was a well-differentiated adenocarcinoma with multiple lymph nodes metastases according to the histology. The duodenal tumor was found to be low-risk GIST. Moreover, the nodule from the jejunum was very low risk GIST. An excised skin wart was neurofibroma according to the histology. CONCLUSIONS: GIST or carcinomas have been reported to occasionally occur in the digestive tract of the patients with NF1. We present a rare case of a NF1 patient with GISTs and colorectal carcinoma.

Physiological and functional changes in the stratum corneum restored by oestrogen in an ovariectomized mice model of climacterium.

Significant decreases in hormonal levels at menopause induce physiological and functional discomfort in the skin. Representative changes at menopause are based on so-called dry skin. However, there is no evidence to explain the mechanism, even though hydration of the stratum corneum (SC) in women at menopause is comparable with that at premenopause but is enhanced by hormone replacement therapy. This study objective was to evaluate structural and functional changes in the SC in ovariectomized mice model of menopause. Hydration of the SC, recovery of the permeability barrier function, integrity and cohesion of the SC, and irritant dermatitis were analysed in mice that underwent ovariectomy with or without replacement of 17ß-estradiol. In ovariectomized mice, hydration of the SC was reduced, recovery of permeability barrier function after acute disruption was impaired, and integrity of the SC was weakened and was associated with increased cohesion and increased levels of irritant dermatitis. Oestrogen replacement treatment restored all changes. Immunohistochemistry revealed reduced levels of expression of desmoglein-1 and differentiation markers of epidermis in ovariectomized mice compared with control mice and mice with oestrogen replacement treatment. These changes might be directly associated with weakened integrity and impaired permeability barrier function of the SC in ovariectomized mice. This study results reveal that so-called dry skin at menopause is caused by not only lower hydration of the SC but also complicated structural and functional changes in the SC and skin.

Three cases of pigmented cosmetic dermatitis-like eruptions associated with primary Sjögren's syndrome or anti-SSA antibody.

Pigmented cosmetic dermatitis-like (Riehl's melanosis-like) pigmentation was reported in three of 27 patients with primary Sjögren's syndrome. But case reports of such eruptions are rare. We describe three cases of such eruptions associated with primary Sjögren's syndrome or anti-SSA antibody and possible associations with specific types of human leukocyte antigen (HLA) and infiltrating lymphocytes. These middle-aged Japanese women had reticular facial pigmentation and histopathological examination revealed interface dermatitis, melanophages, and dense lymphocytic infiltration around hair follicles and sweat ducts. HLA typing revealed common antigenic equivalents or genetic typing of HLA-A2, DR52, DPA1(02:02) and DPB1(05:01). Immunohistochemical staining revealed major subsets of T cells to be CD8 and CD45RO. Some Foxp3- and few IL17-positive cells were found in strong contrast to the major CD4 subset of infiltrated T cells in annular erythema associated with Sjögren's syndrome. Apparently, our patients' pigmentation represented a specific etiology associated with primary Sjögren's syndrome or anti-SSA antibody.

Results of second-stage screening for skin cancers in Oita Prefecture, Japan.

We performed skin cancer screenings for 2 or 3 days annually from 2006 through 2013 in Oita Prefecture, Japan. Screening of approximately 3000 people in total allowed us to identify and treat several skin cancers, including five cases of malignant melanoma, four of squamous cell carcinoma, 16 of basal cell carcinoma, 11 of Bowen's disease, 17 of actinic keratosis, one of extramammary Paget's disease and one of metastatic breast carcinoma. The sensitivity and specificity for the category defined by an identified lesion associated with risk of cancer and requiring further examination (category C) were 92.7% and 95%, respectively. We cannot estimate the outcome of our skin cancer screenings in terms of cancer mortality because of the small number of subjects examined and the brief follow-up period. However, we did estimate the effectiveness of these screenings in terms of stages or sizes of cancerous lesions. The relative numbers of subjects with malignant melanoma at various clinical stages, identified during skin cancer screenings and during a routine visit to our hospital, were significantly different. We also compared, statistically, the sizes of lesions in Bowen's disease that were found during cancer screenings and during a direct visit to our hospital. The former lesions were smaller than the latter. Our data suggest the benefits of our skin cancer screenings and the importance of campaigns and education to encourage people to visit dermatologists for the detection of skin cancers at an early stage.