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Malignant melanoma (MM) is often associated with a poor prognosis due to metastasis and cancer death. The monitoring of prognostic factors is of vital importance, and among these factors, elevated lactate dehydrogenase (LDH) should be closely observed during the disease course. Important factors for predicting the survival of MM patients include tumor thickness, ulceration, the number of lymph node metastases, metastatic lesions, and the sites of metastasis. Weight loss is not generally included in the prognostic factors of MM, but it is monitored in other cancers, such as lung cancer and gastrointestinal cancer. The objective of this study was to investigate the association between weight loss and MM prognosis. Using data from MM patients who had been treated at our institution, we assessed the prognoses of two groups: weight loss of at least 5% body weight or weight loss not exceeding 5% body weight within a 12‐month period. As a result, a higher mortality rate was found for the former group. Furthermore, the loss of at least 5% of body weight within a month was found to almost always adversely affect the patient's prognosis. The present study indicates that there may be an association between MM prognosis and weight loss of at least 5% within a year, and body weight could potentially serve as an informative factor for MM survival. [ABSTRACT FROM AUTHOR]

Epidermolysis bullosa (EB) is a group of inherited blistering disorders that primarily affect the skin and mucous membranes of the digestive tract, which can lead to poor nutritional status. Dietary supplements and nutritional support methods, such as nasogastric tubes and gastrostomy, have been employed to improve the nutritional status of patients with EB; however, few foods are suitable for enjoyable eating with family and friends. Here, we introduce a nutritionally balanced, melt‐in‐the‐mouth chocolate called andew, which was specifically designed for patients with EB. The andew chocolate is nutritionally superior and melts more easily than traditional chocolates, thus it is suitable for patients with EB, who are prone to oral erosions. Patients responded more favorably to the taste and texture of andew than to those of other dietary supplements. Not only does andew provide nutritional benefits, but it also promotes enjoyable eating with family members and friends, which could positively impact patients' mental health. [ABSTRACT FROM AUTHOR]

Bullous pemphigoid (BP) is an autoimmune disease characterized by itchy erythema and tense blisters on the whole body. Recent reports have unveiled the pathogenic roles of eosinophils in BP (e.g., dermal‐epidermal separation, generation of pruritus). Thus, eosinophils are considered a therapeutic target. Benralizumab is an anti‐IL‐5 receptor alpha (IL‐5Rα) monoclonal antibody (mAb) that is widely used to treat severe eosinophilic asthma. By affecting IL‐5Rα, benralizumab depletes eosinophils and basophils due to apoptosis through antibody‐dependent cell‐mediated cytotoxicity. The efficacies of benralizumab and other biologics, including bertilimumab (anti‐eotaxin‐1 mAb) and mepolizumab (anti‐IL‐5 mAb), were evaluated in several clinical trials. Also, reslizumab, an anti‐IL‐5 mAb, was reported as a successful treatment option in a case of BP. We present a case of severe asthma treated with benralizumab at 8‐week intervals for 3 years before BP developed. Histologically, subepidermal blisters without eosinophilic infiltration were observed. Methylprednisolone pulse therapy followed by 40 mg/day (1 mg/kg/day) of oral prednisolone (PSL) was initiated, but the skin lesions worsened. Additional intravenous immunoglobulin and oral azathioprine enabled the oral PSL to be tapered. The benralizumab was discontinued after the onset of BP because the asthma did not worsen. To the best of our knowledge, there have been no reports of BP developing during anti‐eosinophil therapy. BP may occur paradoxically via various pathways during treatment with drugs that are typically effective against BP. [ABSTRACT FROM AUTHOR]

Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative condition. Skin biopsies taken from the lower leg were reported to be a standard diagnostic procedure for NIID; however, no studies have addressed the optimal skin biopsy locations. We retrospectively analyzed 12 cases in which skin biopsies were performed for diagnosing NIID. We collected clinical information including age, sex, skin biopsy site, the presence of nuclear inclusion bodies, the results of p62 immunostaining, the final diagnosis from the department of neurology, and the presence of abnormal GGC repeats in the NOTCH2NLC gene. Four of the 12 cases had a final diagnosis of NIID. One of the four cases was biopsied from the lower leg, whereas the other three cases were biopsied from the abdomen or thigh. Biopsy specimens of the four definite NIID cases revealed the average rates of nuclear inclusion body‐positive cells in adipocytes, sweat gland cells, and fibroblasts to be 13.2%, 10.3%, and 6.3%, respectively. GGC repeat abnormalities in the NOTCH2NLC gene were observed in two of the four cases. The present study indicates that sites with ample subcutaneous fat tissue could be promising for diagnostic skin biopsies for NIID. [ABSTRACT FROM AUTHOR]

Bullous pemphigoid (BP) is a subepidermal blistering disease induced by autoantibodies to type XVII collagen (COL17, also called BP180) and BP230. Previous studies using patients' samples and animal disease models elucidated the complement‐dependent and complement‐independent pathways of blister formation, the pathogenic roles of immune cells (T and B cells, macrophages, mast cells, neutrophils, eosinophils), and the pathogenicity of IgE autoantibodies in BP. This review introduces the recent progress on the mechanism behind the epitope‐spreading phenomenon in BP, which is considered to be important to understand the chronic and intractable disease course of BP, and the pathogenicity of anti‐BP230 autoantibodies, mainly focusing on studies that used active disease models. To clarify the pathogenesis of BP, the mechanism behind the breakdown of immune tolerance to BP antigens should be investigated. Recent studies using various experimental models have revealed important roles for regulatory T cells in the maintenance of self‐tolerance to COL17 and BP230 as well as in the suppression of inflammation triggered by the binding of antibodies to COL17. Notably, physical stresses such as trauma, thermal burns, bone fractures, irradiation and ultraviolet exposure, some pathologic conditions such as neurological diseases and hematological malignancies, and the use of dipeptidyl peptidase‐IV inhibitors and immune checkpoint inhibitors have been reported as triggering factors for BP. These factors and certain underlying conditions such as genetic background, regulatory T‐cell dysfunction or aging might synergistically affect some individuals and eventually induce BP. Further studies on the breakdown of self‐tolerance and on the identification of key molecules that are relevant to blister formation and inflammation may expand our understanding of BP's etiology and may lead to the development of novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

This was a multicenter clinical trial of rituximab, a chimeric monoclonal IgG antibody directed against CD20, for the treatment of refractory pemphigus vulgaris and pemphigus foliaceus. In total, 20 patients were treated with two doses of rituximab (1000 mg; 2 weeks apart) on days 0 and 14. The primary end point was the proportion of patients who achieved complete or partial remission on day 168 following the first rituximab dose. Of the 20 enrolled patients, 11 (55%) and four (20%) achieved complete and partial remission, respectively; therefore, remission was achieved in a total of 15 patients (75.0% [95% confidence interval, 50.9%–91.3%]). It was demonstrated that the remission rate was greater than the prespecified threshold (5%). In addition, a significant improvement in clinical score (Pemphigus Disease Area Index) and decrease in serum anti‐desmoglein antibody level were observed over time. Four serious adverse events (heart failure, pneumonia, radial fracture, and osteonecrosis) were recorded in two patients, of which only pneumonia was considered causally related with rituximab. The level of peripheral blood CD19‐positive B lymphocytes was decreased on day 28 after rituximab treatment and remained low throughout the study period until day 168. Our results confirm the efficacy and safety of rituximab therapy for refractory pemphigus in Japanese patients. [ABSTRACT FROM AUTHOR]

Carotenoderma is a yellow‐orange coloration of the skin caused by high levels of serum carotenoids, mostly due to the excessive intake of carotenoid‐rich foods. The yellowish coloration is typically observed on the palms, soles, and nasolabial folds. Although the physical appearance is prominent, the condition itself is benign and harmless. Diagnosing carotenoderma is not difficult because of its unique manifestations, but its pathophysiology remains unclear. We report a relatively rare case of carotenoderma due to lycopenemia caused by the excessive intake of lycopene‐rich vegetables and fruits. Lycopene is a carotenoid component that is distinguished by the high absorption of light around 488 nm. Given these characteristics, we examined a hematoxylin–eosin‐stained specimen from the patient and tape‐stripped samples by fluorescent microscopy with 488 nm wavelength emission and compared them with normal skin samples. Notably, the patient's samples showed a weaker autofluorescence in the stratum corneum and sweat glands. Furthermore, we measured carotenoid concentrations in the patient's skin noninvasively with Vegecheck® and found a higher score than the average of 24 healthy volunteers. These results support the long‐held hypothesis that carotenoids are secreted in sweat and are deposited in the stratum corneum. To the best of our knowledge, no previous reports have measured skin carotenoid levels nor detailed the pathological findings of carotenoderma patients. This case further highlights that the excessive intake of lycopene causes carotenoderma and demonstrates that carotenoid deposition is particularly pronounced in the stratum corneum of the skin. [ABSTRACT FROM AUTHOR]

Cutaneous angiosarcoma (CAS) is a rare malignant tumor with a poor prognosis for which neither basic research on molecular pathomechanisms nor clinical prospective studies have progressed. A retrospective study of 28 CAS cases reported that chemoradiotherapy with taxanes was superior to conventional surgery. Since that time, chemoradiotherapy with paclitaxel (PTX + RT) has become a standard treatment. In this paper, we retrospectively investigate 21 cases of CAS that had been treated in the Department of Dermatology at Hokkaido University Hospital. Patients initially treated with PTX + RT followed by maintenance taxane chemotherapy showed better prognosis in overall survival (OS) and progression‐free survival (PFS) (median OS, 28 months; median PFS, 12 months) compared to others (median OS, 10 months; median PFS, 5 months) (OS and PFS: p < 0.05, log–rank test). Our results are consistent with those of a previous study that suggested that PTX + RT followed by maintenance taxane chemotherapy is a better therapeutic option than other interventions, including surgery. [ABSTRACT FROM AUTHOR]

Psoriasis, an immune‐mediated inflammatory disease, is characterized by keratinocyte hyperproliferation. Tumor necrosis factor (TNF)‐α, interleukin (IL)‐23, and IL‐17A play critical roles in the pathogenesis of psoriasis. IL‐17A secreted by T‐helper 17 acts more directly against keratinocytes than TNF‐α or IL‐23 do. Regarding the receptors of cytokines, fibroblasts also express receptors against IL‐17A and TNF‐α, and induce the production of growth factors. Epiregulin (EREG), an epidermal growth factor receptor ligand, is produced by both keratinocytes and fibroblasts. EREG enhances keratinocyte proliferation and differentiation. We hypothesized that fibroblasts stimulated with IL‐17A and/or TNF‐α may play a role in epidermal hyperproliferation through the production of epidermal growth factors in psoriasis. The mRNA expression of EREG was found to be significantly upregulated by co‐stimulation with IL‐17A and TNF‐α (mean, 49.2‐fold). Furthermore, the stimulation with TNF‐α alone, but not IL‐17A alone, induced significant increases. Immunofluorescent staining demonstrated that the protein expression level of EREG was also increased in fibroblasts stimulated with these cytokines. Stimulation with EREG significantly enhanced keratinocyte proliferation in vitro. In human psoriatic patients' skin, immunofluorescence staining of EREG showed significantly high intensity in the dermis of lesional skin. In conclusion, cytokine stimulation with TNF‐α and IL‐17A induces the overexpression of EREG from dermal fibroblasts in the lesional skin of psoriasis, and plays a role in epidermal hyperproliferation. [ABSTRACT FROM AUTHOR]

Bullous pemphigoid (BP) varies in severity and stratified treatments are needed. However, there are no definitive standards for choosing appropriate treatments. To elucidate the factors involved in choosing treatments and the clinical outcomes of BP, we retrospectively reviewed the clinical records of 78 BP patients at a single center. Of the 78 patients, 49 (62.8%) were treated with oral prednisolone (PSL) and 29 (37.2%) were treated without PSL. The patients with older age, lower Bullous Pemphigoid Disease Area Index (BPDAI), and/or lower anti‐BP180NC16a antibody titer at onset tended to be treated without oral PSL. Notably, only 9.1% patients without PSL experienced relapse, whereas 36.7% patients with oral PSL experienced relapse when the PSL was around 0.1 mg/kg. It suggests that the patients with mild disease severity could be well controlled without oral PSL. Receiver–operator curve analysis demonstrated that the cut‐off value for the use of oral PSL was 31 for total BPDAI and was 7 for BPDAI skin urticaria/erythema, with a high (>0.9) area under the curve. Notably, none of the patients who were negative for the anti‐BP180NC16a antibody at onset experienced relapse even though they were treated without PSL. In conclusion, in BP patients who were negative for anti‐BP180NC16a antibody at onset, with a total BPDAI score of less than 31 or with an urticaria/erythema score of less than 7 can be treated without PSL. When the PSL is tapered to around 0.1 mg/kg, we should carefully monitor the patients to detect relapse. [ABSTRACT FROM AUTHOR]

A long‐term immunosuppressive treatment can provoke latent infections. Autoimmune blistering diseases (AIBD) are mostly treated with systemic immunosuppressive agents. To prevent the reactivation or exacerbation of existing latent infections, patients must be screened for infectious diseases before immunosuppressive treatments are initiated. However, the prevalence of infectious diseases in AIBD remains to be elucidated. To evaluate the necessity of screening infectious diseases in AIBD, we retrospectively reviewed the clinical records of 215 patients at a single center with AIBD for hepatitis B virus (HBV), hepatitis C virus (HCV), Mycobacterium tuberculosis, Treponema pallidum, human T‐cell leukemia virus type 1 (HTLV‐1) and HIV infections. Approximately 40% of patients were infected with HBV. During systemic corticosteroid treatment, HBV DNA became positive in 3.4% of cases. Antibodies to HCV, interferon‐γ release assays for M. tuberculosis and the T. pallidum latex agglutination test were positive in 0.6%, 6.6% and 1.2% cases, respectively. Neither HTLV‐1 nor HIV infections were detected. In conclusion, checks for HBV and M. tuberculosis infections should be made before immunosuppressive treatments are started, because of the high prevalence of these potentially life‐threatening infections. Other infections should be tested for depending on the patient's risk factors. [ABSTRACT FROM AUTHOR]

The pemphigoid group is a category of autoimmune subepidermal blistering diseases in which autoantibodies deposit linearly at the epidermal basement membrane zone (BMZ). The main subtypes of pemphigoid mediated by immunoglobulin G autoantibodies are bullous pemphigoid (BP), mucous membrane pemphigoid (MMP) and epidermolysis bullosa acquisita (EBA). To establish the first guidelines approved by the Japanese Dermatological Association for the management of pemphigoid diseases, the Committee for Guidelines for the Management of Pemphigoid Diseases (Including EBA) was founded as part of the Study Group for Rare Intractable Skin Diseases under the Ministry of Health, Labor and Welfare Research Project on Overcoming Intractable Diseases. These guidelines aim to provide current information for the management of BP, MMP and EBA in Japan. Based on evidence, the guidelines summarize the clinical and immunological manifestations, pathophysiologies, diagnostic criteria, disease severity determination criteria, treatment algorithms and treatment recommendations. Because of the rarity of these diseases, there are few clinical studies with a high degree of evidence, so several parts of these guidelines were established based on the opinions of the Committee. To further optimize these guidelines, periodic revision in line with the new evidence is necessary. [ABSTRACT FROM AUTHOR]

Autoimmune blistering diseases (AIBDs), classified into pemphigus and pemphigoid, consist of relatively rare skin disorders caused by autoantibodies that target desmosomal and hemidesmosomal proteins, respectively. Although systemic corticosteroids are used as a first-line treatment for AIBDs, azathioprine is frequently co-administered as a steroid-sparing agent. Azathioprine is metabolized into thioguanine nucleotides (TGNs) which are its major active metabolites. The enzyme nudix hydrolase 15 (NUDT15) plays a key role in regulating TGNs. Serious side effects of azathioprine, including leukopenia and alopecia, are known to be particularly problematic in individuals with NUDT15 variants. The single-nucleotide polymorphism c.415C >T (p.Arg139Cys) is one of the most frequent NUDT15 variants associated with severe thiopurine toxicity. Recently, we treated a case of pemphigus vulgaris in a patient with NUDT15 variants in which the patient developed rapidly progressive diffuse hair loss and myelosuppression while receiving azathioprine. Previous reports on NUDT15 polymorphisms mainly focused on patients with inflammatory bowel disease or hematological malignancies, and the prevalence of NUDT15 polymorphisms remains unknown in AIBDs. This highlights the urgent need for research on NUDT15 polymorphisms in AIBDs to achieve a better understanding of the genetic factors influencing adverse reactions to azathioprine. To clarify the prevalence of NUDT15 variants in Japanese patients with AIBDs, we retrospectively reviewed the medical records of 78 patients with AIBDs (26 with bullous pemphigoid, 26 with pemphigus vulgaris, 17 with pemphigus foliaceus, and nine with other AIBDs) who had come to Hokkaido University Hospital between 2018 and 2023. The frequencies of NUDT15 variants of Arg/Arg, Arg/Cys, and Cys/Cys in these patients were approximately 72%, 23%, and 5%, respectively. Our findings indicate a prevalence of NUDT15 variants in AIBD patients that is similar to the prevalences of previous studies on patients with other diseases. These results emphasize the importance of screening for NUDT15 variants prior to initiating azathioprine treatment in Japanese patients with AIBDs., (© 2024 Japanese Dermatological Association.)