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Abstract Pyoderma gangrenosum is a rare inflammatory skin disease classified within the group of neutrophilic dermatoses, and clinically characterised by painful, rapidly evolving cutaneous ulcers with undermined, irregular, erythematous‐violaceous edges. Underlying diseases include rheumatoid arthritis, inflammatory bowel disease, haematopoietic malignancy, and aortitis syndrome. However, there was a limited number of cases of concomitant pyoderma gangrenosum and IgA vasculitis. Herein, we report a case presenting persistent large skin wounds as a diagnosis of pyoderma gangrenosum in the setting of IgA cutaneous vasculitis, which was successfully treated by a TNF‐α inhibitor. A 67‐year‐old obese female presented palpable purpura on her lower extremities. A skin biopsy taken from the purpuric eruption showed leukocytoclastic vasculitis with IgA and C3 depositions in the vessel walls of the upper dermis, leading to the diagnosis of IgA vasculitis. Small skin ulcers rapidly expanded in several days, eventually developing perforating skin ulcers with irregular erythematous and violaceous edges on both lower extremities following the tapered oral prednisolone at a dose of 25 mg per day. Based on the clinical manifestation and histological analysis, we diagnosed her skin wound as pyoderma gangrenosum. After the adalimumab administration, the spreading ulceration was dampened, leading to the acceleration of wound epithelialisation.

Abstract Biological agents targeting inflammatory skin diseases have dramatically overcome many of the limitations of older oral therapeutic options. Among the various biological agents, ixekizumab is a humanised monoclonal antibody that blocks the biological activity of IL‐17A, which exhibited high efficacy against psoriasis. Although there are a limited number of cutaneous adverse reactions, biologic‐induced type I allergic reactions are rare. Herein, we report a case of ixekizumab‐induced urticaria.

Abstract The coronavirus disease 2019 (COVID‐19) vaccine is positively changing the health crises of this pandemic and is currently essential to overcome the COVID‐19 pandemic. The vaccine shows high efficacy against the infection and impairs the severity of symptoms. However, this vaccination is associated with concerns, such as vaccine‐associated adverse reactions, which are currently highlighted issues for clinicians. We experienced two cases of mild cutaneous adverse reaction following COVID‐19 vaccine administration, which was successfully controlled by prior administration of the antihistamine agent fexofenadine 3 days before COVID‐19 vaccination for 7 days.

Abstract Mycosis fungoides is recognized as an indolent cutaneous malignant T-cell lymphoma. In contrast, there are few therapeutic options for advanced forms of mycosis fungoides. Since immunotherapy is desirable as an alternative therapeutic option, identifying candidate molecules is an important goal for clinicians. Although tumor-derived negative immunomodulatory molecules, such as PD-1/PD-L1, have been identified in various malignancies, the useful positive immunological drivers of mycosis fungoides are largely unknown. We found that the stimulator of interferon (IFN) genes (STING) was highly upregulated in early-stage mycosis fungoides. Immunohistochemical examination revealed different STING staining patterns in patients with mycosis fungoides. Although there were no significant differences in clinical factors’ characteristics, STING expression was associated with the survival of patients with mycosis fungoides. The survival rate was significantly poor in patients with low STING-expressing mycosis fungoides. Univariate and multivariate analyses revealed that low STING expression was associated with an increased hazard ratio. Our results indicate that STING expression independently influences the prognosis of mycosis fungoides.

Abstract Psoriasis is a chronic inflammatory skin disease that involves various systemic organs and tissues and is characterized by scaly erythematous skin. Among the different types of psoriasis, psoriatic arthritis (PsA) is frequently reported, and occasionally develops into severe arthritis leading to joint dysfunction. There are various tools, especially questionnaires, to identify the presence of PsA in European and American populations; however, little is known about the utility of these tools in the Asian population. In this study, we investigated the utility of a representative tool, the psoriasis epidemiology screening tool (PEST) questionnaire, to identify PsA among Japanese patients with psoriasis. A total of 143 patients with psoriasis were enrolled in this study. Among them, 29 patients were diagnosed with PsA. The frequency of PsA was significantly increased in patients with PEST scores > 3, with a sensitivity of 93.1% and a specificity of 78.9%. Among the questions in the PEST questionnaire, “Have you ever had a swollen joint?” showed the highest frequency to answer “Yes” among patients with PsA. Univariate and multivariate analyses revealed that high PEST scores (> 3) was an independent variable in PsA patients. Taken together, our study suggests that the PEST questionnaire is a useful tool to identify PsA among Japanese patients with psoriasis.

Abstract Telaprevir used as a protease inhibitor against hepatitis C virus is frequently associated with cutaneous adverse reactions. To explore a histological biomarker of cutaneous adverse events induced by telaprevir, we systematically searched for genes that were dysregulated by telaprevir in normal human epidermal keratinocytes (NHEKs). Microarray analysis and real-time polymerase chain reaction (PCR) revealed the significant increase in the expression of S100 calcium-binding protein A2 (S100A2) gene following treatment of NHEKs with telaprevir. Immunohistochemical analysis demonstrated that the expression of S100A2 was dominant in the spinous layer of the epidermis in patients with telaprevir-mediated severe-type drug eruptions and limited to the basal layer of the epidermis in healthy subjects. Furthermore, S100A2 expression increased after treatment with trichloroethylene and other medications, and the degree of S100A2 expression correlated with the severity of cutaneous adverse events. S100A2 expression also significantly increased in the skin of patients with atopic dermatitis and psoriasis. Taken together, S100A2 is highly expressed in the epidermis under inflammatory conditions and drug eruptions and may serve as a marker for keratinocyte damage in response to any inflammatory or toxic condition.

Atypical lipomatous tumor (ALT) has been defined as a well-differentiated liposarcoma exhibiting a higher frequency of a local recurrence after surgical resection. ALT is mainly classified into deep type and superficial type. Compared with deep type ALT, superficial type ALT is rarely observed. One of the most important issues is that little has been known about superficial type ALT and it is not easy to predict the presence of superficial type ALT before surgical resection. To clarify the clinical manifestations of superficial type ALT, we examined 15 cases with superficial type ALT and 118 cases with benign lipoma, and analyzed their differences in clinical characteristics and the findings of MRI test. In clinical characteristics, the tumor size of superficial type ALT was significantly greater than that of benign lipoma, and superficial type ALT showed a significantly higher frequency of the tumor size of more than 4 cm. Superficial type ALT exhibited poor tumor mobility and hardness with elastic soft. In addition, a significantly higher frequency of tumor location of superficial type ALT was observed in extremities. Among tumor sites at the trunk, buttocks, and shoulder were high frequent location in superficial type ALT. In an MRI examination, superficial type ALT exhibited a significantly higher frequency of the septal structures compared with benign lipoma. The combinations of clinical characteristics, including physical examinations, MRI, and histological examinations, are helpful for the diagnosis of superficial type ALT.

Immune checkpoint inhibitors (ICIs), such as nivolumab and ipilimumab, have drastically changed treatments of advanced melanoma. However, ICI-related enterocolitis is often the most common adverse event, and represents the main reason for ICI discontinuation and mortalities. Here, we report the case of a metastatic melanoma treated with vedolizumab for ICI-induced colitis. A 67-year-old man treated with ipilimumab and nivolumab developed ICI-induced colitis and grade 3 diarrhea refractory to methylprednisolone and infliximab. After his third dose of vedolizumab, oral prednisolone ceased, and the colitis had completely resolved with no recurrence. This case report supports vedolizumab use in treating severe colitis which failed to resolve with first- and second-line immunosuppressive therapy.

Abstract The anti-inflammatory effect of omega 3 polyunsaturated fatty acids has been confirmed in various inflammatory disease models. Maresin-1 (MaR1) is a lipid mediator derived from the omega-3 fatty acid docosahexaenoic acid (DHA) that has displayed strong anti-inflammatory effects in various inflammatory disease models. However, the effect of topical MaR1 on cutaneous inflammation remains unclear. Therefore, we initially examined the anti-inflammatory effects of topical Maresin-1 using an imiquimod (IMQ)-induced psoriasis-like mouse model of inflammation. Topical MaR1 reduced the ear swelling response as seen in histological findings. RT-PCR and flow cytometry analyses revealed MaR1 had no inhibitory effect on IL-23, but MaR1 suppressed IL-17A production by γδTCRmid+ and CD4+ cells in the skin. These inhibitory effects were also observed in a subcutaneous IL-23-injected psoriasis model. MaR1 downmodulated IL-23 receptor (IL-23R) expression by suppressing retinoic acid-related orphan receptor γt (RORγt) expression and internalization in a clathrin-dependent manner in γδTCRmid+ and CD4+ cells. These results lead to assumptions that topical MaR1 may be a new therapeutic agent for psoriasis and other IL-17-mediated cutaneous inflammatory diseases.

Extramammary Paget’s disease is recognized as an apocrine-origin cutaneous tumor and is localized in the intraepithelial skin lesion. However, its advanced form is intractable, and there is currently no therapeutic option with a satisfactory level of clinical outcome. Therefore, it is of great importance to identify a potential biomarker to estimate tumor advancement in extramammary Paget’s disease. Dermcidin is an antimicrobial peptide derived from the eccrine gland and is identified as a biomarker in various malignancies. To investigate the potential of dermcidin in extramammary Paget’s disease, we investigated dermcidin expression in tumors using the immunostaining technique. Although previous studies have reported that extramammary Paget’s disease has no positive staining against dermcidin, 14 out of 60 patients showed positive staining of dermcidin in our study. To clarify the characteristics of positive dermcidin in extramammary Paget’s disease, we investigated the clinical characteristics of positive dermcidin extramammary Paget’s disease patients. Positive dermcidin patients showed a significantly high frequency of lymph node metastasis. We next investigated the impact of positive dermcidin on overall survival. Univariate analysis identified that positive dermcidin showed a significantly increased hazard ratio in overall survival, suggesting that dermcidin might be a prognostic factor for extramammary Paget’s disease.

Cell adhesion molecular 1 (CADM1) is a multifunctional cell adhesion molecule belonging to the immunoglobulin superfamily, which suppresses malignant solid tumor development. However, the correlation between CADM1 expression and prognosis in cutaneous squamous cell carcinoma (cSCC) patients remains unclear. In a retrospective analysis of 88 patients diagnosed with cSCC at our institution between January 2006 and December 2016, the degree of CADM1 expression in tumor cells was evaluated by immunostaining. Fifty-five and 33 patients had tumors with high and low CADM1 expression, respectively. Low CADM1 expression on the tumor was associated with poor differentiation, whereas the Kaplan–Meier curve and log-lank test indicated a favorable prognosis with high CADM1 expression. Multivariate analysis excluding the effect of the degree of differentiation and clinical stages showed that the hazard ratio (HR) of survival was significantly increased with low CADM1 expression. Thus, CADM1 expression is an independent prognostic factor for cSCC patients.

We have established an immune cell therapy with immortalized induced pluripotent stem-cell–derived myeloid lines (iPS-ML). The benefits of using iPS-ML are the infinite proliferative capacity and ease of genetic modification. In this study, we introduced 4-1BBL gene to iPS-ML (iPS-ML-41BBL). The analysis of the cell-surface molecules showed that the expression of CD86 was upregulated in iPS-ML-41BBL more than that in control iPS-ML. Cytokine array analysis was performed using supernatants of the spleen cells that were cocultured with iPS-ML or iPS-ML-41BBL. Multiple cytokines that are beneficial to cancer immunotherapy were upregulated. Peritoneal injections of iPS-ML-41BBL inhibited tumor growth of peritoneally disseminated mouse melanoma and prolonged survival of mice compared to that of iPS-ML. Furthermore, the numbers of antigen-specific CD8+ T cells were significantly increased in the spleen and tumor tissues treated with epitope peptide-pulsed iPS-ML-41BBL compared to those treated with control iPS-ML. The number of CXCR6-positive T cells were increased in the tumor tissues after treatment with iPS-ML-41BBL compared to that with control iPS-ML. These results suggest that iPS-ML-41BBL could activate antigen-specific T cells and promote their infiltration into the tumor tissues. Thus, iPS-ML-41BBL may be a candidate for future immune cell therapy aiming to change immunological “cold tumor” to “hot tumor”.