Erythematous reactions to two ultraviolet excimer therapy devices with different irradiance levels: Reconsidering the reciprocity law.

BACKGROUND: Few studies have examined the effectiveness of the reciprocity law in ultraviolet excimer therapy. This study aimed to examine the difference in erythematous reaction in human skin when the irradiance of ultraviolet excimer treatment devices differed while the irradiation dose was constant. MATERIALS AND METHODS: This study, conducted at the Department of Dermatology, Chiba University, included 15 healthy adults aged 20-65 years (mean age, 46.3 years; seven men). Using ultraviolet excimer treatment devices with different irradiances (50 or 150 mW/cm2 ), the upper abdomen of each participant was irradiated with ultraviolet light at set irradiation doses (80, 100, 120, 140, 160, 180, and 200 mJ/cm2 ). The erythema index of each irradiated site was measured using a melanin- and erythema-measuring device, and the difference in erythema index before and 24 h after irradiation was the primary endpoint. RESULTS: The change in erythema index was significantly higher for an irradiance of 150 mW/cm2 . Significant differences (p < 0.05) were observed between these irradiance levels at irradiation doses of 100-200 mJ/cm2 . CONCLUSIONS: Even for the same irradiation dose, stronger erythematous reactions occurred at higher irradiances in ultraviolet excimer treatment. This suggests that the reciprocity law may not always hold true in excimer therapy.

Simultaneous development of generalized pustular psoriasis and pemphigoid with multiple autoantibodies in a complete responder of pembrolizumab for lung cancer.

Patients with psoriasis vulgaris have a higher incidence of pemphigoid than the general population. However, there are only a few concise reports on the coexistence of generalized pustular psoriasis (GPP) and pemphigoid. The authors describe a rare case of the simultaneous development of GPP and pemphigoid with multiple autoantibodies (i.e., BP180-C-terminal, 200-kDa protein, and laminin 332 proteins) in a complete responder of immune checkpoint inhibitor (ICI) treatment for lung cancer. Anti-interleukin 17 inhibitors for the GPP and oral corticosteroids at 10 mg/day for the pemphigoid effectively achieved remission in both diseases. It may not be uncommon to detect multiple autoantibodies in patients with pemphigoid; however, the detection of autoantibodies to more than three antigens in a single patient is relatively rare. In the current patient, the severe inflammation of GPP might have generated multiple autoantibodies. In addition, although pembrolizumab achieved a complete response and was discontinued 9 months before the onset of GPP and pemphigoid, the ICI might have affected the development of the two diseases. This case report adds useful information to the limited knowledge regarding the coexistence of GPP and pemphigoid, and aids in a better understanding of the pathological mechanisms and treatment options for such patients. Furthermore, the possibility that more patients may develop multiple autoimmune and autoinflammatory diseases in the era of ICIs should be recognized.

Trends in mortality and morbidity in patients with bullous pemphigoid before and after approval of intravenous immunoglobulin in Japan: an interrupted time-series analysis.

BACKGROUND: Intravenous immunoglobulin (IVIg) has been reported to be an effective treatment for bullous pemphigoid. However, the impact of IVIg approval on real-world outcomes remains unclear. OBJECTIVES: To investigate the effect of IVIg approval on patients with bullous pemphigoid using a national inpatient database. METHODS: Using the Japanese Diagnosis Procedure Combination database, we identified 14 229 patients admitted to hospital for bullous pemphigoid and treated with systemic corticosteroids between July 2010 and March 2020. We conducted an interrupted time-series analysis to compare in-hospital mortality and morbidity between the patients admitted before and after the approval of reimbursement of IVIg for bullous pemphigoid in the Japanese universal health insurance system in November 2015. RESULTS: In-hospital mortality was 5.5% before and 4.5% after the approval of IVIg reimbursement. After the IVIg approval, 18% of the patients were treated with IVIg. Based on the interrupted time-series analysis, in-hospital mortality significantly decreased at the time of approval [-1.2%, 95% confidence interval (CI) -2.0 to -0.3, P = 0.009] and a downward trend was observed after the approval (-0.4% annual rate, 95% CI -0.7 to -0.1, P = 0.005). In-hospital morbidity also demonstrated a downward trend after the approval. CONCLUSIONS: IVIg approval is associated with lower in-hospital mortality and morbidity in inpatients with bullous pemphigoid.

Effects of splenectomy on skin inflammation and psoriasis-like phenotype of imiquimod-treated mice.

Imiquimod (IMQ) is widely used as animal model of psoriasis, a chronic inflammatory skin disorder. Although topical application of IMQ to back skin causes splenomegaly in mice, how the spleen affects the psoriasis-like phenotype of IMQ-treated mice remains unclear. In this study, we analyzed the cellular composition of spleen and measured metabolites in blood of IMQ-treated mice. We also investigated whether splenectomy influences the degree of skin inflammation and pathology in IMQ-treated mice. Flow cytometry showed that the numbers of CD11b+Ly6c+ neutrophils, Ter119+ proerythroblasts, B220+ B cells, F4/80+ macrophages, and CD11c+ dendritic cells in the spleen were significantly higher in IMQ-treated mice compared to control mice. An untargeted metabolomics analysis of blood identified 14 metabolites, including taurine and 2,6-dihydroxybenzoic acid, whose levels distinguished the two groups. The composition of cells in the spleen and blood metabolites positively correlated with the weight of the spleen. However, splenectomy did not affect IMQ-induced psoriasis-like phenotypes compared with sham-operated mice, although splenectomy increased the expression of interleukin-17A mRNA in the skin of IMQ-treated mice. These data suggest that the spleen does not play a direct role in the development of psoriasis-like phenotype on skin of IMQ-treated mice, though IMQ causes splenomegaly.

Association between psoriasis and short-term outcomes of acute myocardial infarction: A matched-pair cohort study using a nationwide inpatient database in Japan.

Background: Psoriasis is a known risk factor for acute myocardial infarction (AMI). However, the associations between psoriasis and short-term outcomes of AMI remain controversial. Objective: To compare the short-term outcomes of AMI patients with and without psoriasis accounting for patient background characteristics and site-specific effects. Methods: We identified patients with AMI between July 2010 and March 2020, using a Japanese national inpatient database. We matched patients with and without psoriasis to generate a 1:10 matched-pair cohort matched for sex, hospital, and fiscal year at admission. Multivariable regression analyses with adjustment for background characteristics including age and Killip class at admission were conducted to compare short-term outcomes of AMI. Results: In this study of AMI patients with psoriasis (n = 455) and without psoriasis (n = 438,534), 30-day in-hospital mortality was 5.6%. Patients with psoriasis had higher proportions of comorbidities than patients without psoriasis. Multivariable regression analyses in the matched-pair cohort revealed that psoriasis was significantly associated with decreased 30-day in-hospital mortality (odds ratio [OR], 0.26; 95% confidence interval [CI], 0.08-0.85). Limitations: Retrospective study design without data on psoriasis severity. Conclusion: The matched-pair cohort analyses with adjustment for patient background characteristics and site-specific effects revealed decreased in-hospital mortality in AMI patients with psoriasis.

Epidermal clearance of Candida albicans is mediated by IL-17 but independent of fungal innate immune receptors.

IL-17 plays important roles in host defense against Candida albicans at barrier surfaces and during invasive infection. However, the role of IL-17 in host defense after colonization of the epidermis, a main site of C. albicans infection, remains poorly understood. Using a murine model of epicutaneous candidiasis without skin abrasion, we found that skin inflammation triggered by epidermal C. albicans colonization was self-limiting with fungal clearance completed by day 7 after inoculation in wild-type mice or animals deficient in IL-17A or IL-17F. In contrast, marked neutrophilic inflammation in the epidermis and impaired fungal clearance were observed in mice lacking both IL-17A and IL-17F. Clearance of C. albicans was independent of Dectin-1, Dectin-2, CARD9 (caspase-recruitment domain family, member 9), TLR2 (Toll-like receptor 2) and MyD88 in the epidermal colonization model. We found that group 3 innate lymphoid cells (ILC3s) and γδT cells were the major IL-17 producers in the epicutaneous candidiasis model. Analyses of Rag2-/- mice and Rag2-/-Il2rg-/- mice revealed that production of IL-17A and IL-17F by ILC3s was sufficient for C. albicans clearance. Finally, we found that depletion of neutrophils impaired C. albicans clearance in the epidermal colonization model. Taken together, these findings indicate a critical and redundant function of IL-17A and IL-17F produced by ILC3s in host defense against C. albicans in the epidermis. The results also suggest that epidermal C. albicans clearance is independent of innate immune receptors or that these receptors act redundantly in fungal recognition and clearance.

Secondary Adrenal Insufficiency in a Patient with Metastatic Melanoma Treated with Nivolumab.

We report a case of secondary adrenal insufficiency due to nivolumab. An 83-year-old man with acral lentiginous types of melanoma on the right sole visited our department in March 2017. He received primary surgery at referred hospital in June 2017, and pathological stage was IIIC (pT3bN3M0) according to AJCC (American Joint Committee on Cancer) 7th edition criteria. During the follow-up period, a lot of in-transit metastases appeared on the right leg. While we were resecting in-transit metastases, we concurrently started nivolumab in September 2018. After 17 cycles of nivolumab treatment, he developed severe nausea and anorexia. At baseline, his cortisol and adrenocorticotropic hormone levels were both at normal range, but corticotropin-releasing hormone loading test revealed secondary adrenal insufficiency. We diagnosed isolated adrenal insufficiency due to nivolumab. Treatment by hydrocortisone immediately relieved nausea and anorexia, and we could have continued treatment of nivolumab.

Assessment of malignant melanoma lesions using violet-light dermoscopy: A case report.

Malignant melanomas often present with irregular shapes and in multiple shades of brown under white light. Dermoscopy is used to diagnose malignant melanomas; nevertheless, it is often difficult to differentiate malignant melanoma from healthy pigmented skin. The DZ-D100 dermoscope (Casio Computer) is a digital camera equipped with a white light-emitting diode (LED) and a violet LED, which can capture non-polarized/polarized conventional dermoscopy images (CDS) as well as violet-light dermoscopy (VLD) images. Since the absorption wavelength of melanin approaches that of ultraviolet rays, VLD with a wavelength of 405 nm can be used to visualize it. This camera allows three images with the same composition to be captured simultaneously. In this case, we performed dermoscopy with DZ-D100 to determine the surgical resection margins of a melanoma of the heel in a 76-year-old woman. The pale-colored lesions that were difficult to demarcate by CDS were clearly visible by VLD, presenting as dark areas in the grayscale images. Preoperatively determined lesion boundaries with CDS in combination with VLD were histologically more accurate than those with conventional CDS alone. Therefore, the combination of CDS and VLD may reveal the distribution of subtle pigmentation of fine melanin in the skin, making it easier to distinguish between lesions and healthy skin. As one of the limitations, parts of the heel with thick stratum corneum were also observed to be dark gray in the VLD images. Therefore, the evaluation of pigment lesion should be performed by comparing both CDS and VLD.

Ungual seborrheic keratosis with longitudinal melanonychia: A case report.

In this paper, we report the case of a 71-year-old man with an 8-year history of melanonychia on the right little finger, who referred to our hospital because the color of pigmented area had gradually darkened and the width had expanded. Physical examination revealed longitudinal melanonychia with brown color (4 mm in width). Dermoscopic examination revealed multiple white round clods and splinter hemorrhages. No micro-Hutchinson sign was observed. We performed a punch biopsy (diameter 3 mm) of the nail matrix for diagnosis. Histopathological examination revealed irregular acanthosis of epithelium of the nail bed and distal matrix, which consisted of basaloid cells without nuclear atypia. Several zones exhibited cell whorls reminiscent of squamous eddies. The whorls were composed of large pink cells arranged in an onion peel-like fashion. The basaloid cells tested negative for human papillomavirus in situ hybridization and p16 staining. The morphology of white round clods (milia-like cysts in metaphoric term) observed in dermoscopic analysis corresponded to squamous eddies in histopathology. Considering these features, ungual seborrheic keratosis (SK) with longitudinal melanonychia was diagnosed, which is an atypical site for SK. We suggest that the dermoscopic finding of milia-like cysts may be useful for the diagnosis of ungual SK.

PD-1 blockade therapy promotes infiltration of tumor-attacking exhausted T cell clonotypes.

PD-1 blockade exerts clinical efficacy against various types of cancer by reinvigorating T cells that directly attack tumor cells (tumor-specific T cells) in the tumor microenvironment (TME), and tumor-infiltrating lymphocytes (TILs) also comprise nonspecific bystander T cells. Here, using single-cell sequencing, we show that TILs include skewed T cell clonotypes, which are characterized by exhaustion (Tex) or nonexhaustion signatures (Tnon-ex). Among skewed clonotypes, those in the Tex, but not those in the Tnon-ex, cluster respond to autologous tumor cell lines. After PD-1 blockade, non-preexisting tumor-specific clonotypes in the Tex cluster appear in the TME. Tumor-draining lymph nodes (TDLNs) without metastasis harbor a considerable number of such clonotypes, whereas these clonotypes are rarely detected in peripheral blood. We propose that tumor-infiltrating skewed T cell clonotypes with an exhausted phenotype directly attack tumor cells and that PD-1 blockade can promote infiltration of such Tex clonotypes, mainly from TDLNs.

Treatments and outcomes of generalized pustular psoriasis: A cohort of 1516 patients in a nationwide inpatient database in Japan.

BACKGROUND: Because generalized pustular psoriasis (GPP) is rare, there are few studies reporting treatments and outcomes for large numbers of patients. OBJECTIVE: To report treatments and outcomes in a large cohort of patients hospitalized with GPP. METHODS: Using a Japanese national inpatient database, we identified 1516 patients with GPP who required hospitalization between July 2010 and March 2019. We categorized patients into 3 medication groups: biologics (294 patients), oral agents without biologics (948 patients), and systemic corticosteroids only (274 patients). We investigated their characteristics, treatments, and outcomes. RESULTS: Mean age was 66 years (interquartile range: 52-77 years). Fifty patients (3.3%) were admitted to the intensive care unit, 125 (8.2%) required blood pressure support, and 63 (4.2%) died. Patients who received biologics were younger and had fewer comorbidities. In-hospital mortality was lower in the biologics group (1.0% [biologics group] vs 3.7% [oral-agents group] vs 9.1% [corticosteroids-only group]; P < .001) as was morbidity (5.4% vs 8.2% vs 12%, respectively; P = .02). Among those who received biologics, IL-17 inhibitor use increased over time, with in-hospital mortality and morbidity comparable to those of tumor necrosis factor inhibitors. LIMITATIONS: Retrospective study design. Some patients received multiple medications. CONCLUSION: Biologic treatments showed favorable outcomes compared with other treatments.

TIGIT/CD155 axis mediates resistance to immunotherapy in patients with melanoma with the inflamed tumor microenvironment.

BACKGROUND: Patients with cancer benefit from treatment with immune checkpoint inhibitors (ICIs), and those with an inflamed tumor microenvironment (TME) and/or high tumor mutation burden (TMB), particularly, tend to respond to ICIs; however, some patients fail, whereas others acquire resistance after initial response despite the inflamed TME and/or high TMB. We assessed the detailed biological mechanisms of resistance to ICIs such as programmed death 1 and/or cytotoxic T-lymphocyte-associated protein 4 blockade therapies using clinical samples. METHODS: We established four pairs of autologous tumor cell lines and tumor-infiltrating lymphocytes (TILs) from patients with melanoma treated with ICIs. These tumor cell lines and TILs were subjected to comprehensive analyses and in vitro functional assays. We assessed tumor volume and TILs in vivo mouse models to validate identified mechanism. Furthermore, we analyzed additional clinical samples from another large melanoma cohort. RESULTS: Two patients were super-responders, and the others acquired resistance: the first patient had a non-inflamed TME and acquired resistance due to the loss of the beta-2 microglobulin gene, and the other acquired resistance despite having inflamed TME and extremely high TMB which are reportedly predictive biomarkers. Tumor cell line and paired TIL analyses showed high CD155, TIGIT ligand, and TIGIT expression in the tumor cell line and tumor-infiltrating T cells, respectively. TIGIT blockade or CD155-deletion activated T cells in a functional assay using an autologous cell line and paired TILs from this patient. CD155 expression increased in surviving tumor cells after coculturing with TILs from a responder, which suppressed TIGIT+ T-cell activation. Consistently, TIGIT blockade or CD155-deletion could aid in overcoming resistance to ICIs in vivo mouse models. In clinical samples, CD155 was related to resistance to ICIs in patients with melanoma with an inflamed TME, including both primary and acquired resistance. CONCLUSIONS: The TIGIT/CD155 axis mediates resistance to ICIs in patients with melanoma with an inflamed TME, promoting the development of TIGIT blockade therapies in such patients with cancer.

Abnormal composition of microbiota in the gut and skin of imiquimod-treated mice.

Psoriasis is a chronic, inflammatory skin disease. Although the precise etiology of psoriasis remains unclear, gut-microbiota axis might play a role in the pathogenesis of the disease. Here we investigated whether the composition of microbiota in the intestine and skin is altered in the imiquimod (IMQ)-treated mouse model of psoriasis. Topical application of IMQ to back skin caused significant changes in the composition of microbiota in the intestine and skin of IMQ-treated mice compared to control mice. The LEfSe algorithm identified the species Staphylococcus lentus as potential skin microbial marker for IMQ group. Furthermore, there were correlations for several microbes between the intestine and skin, suggesting a role of skin-gut-microbiota in IMQ-treated mice. Levels of succinic acid and lactic acid in feces from IMQ-treated mice were significantly higher than control mice. Moreover, the predictive functional analysis of the microbiota in the intestine and skin showed that IMQ caused alterations in several KEGG pathways. In conclusion, the current data indicated that topical application with IMQ to skin alters the composition of the microbiota in the gut and skin of host. It is likely that skin-gut microbiota axis plays a role in pathogenesis of psoriasis.

Keratinocyte IL-36 Receptor/MyD88 Signaling Mediates Malassezia-Induced IL-17-Dependent Skin Inflammation.

BACKGROUND: Among skin commensal fungi, lipophilic Malassezia species exist on nearly all human skin surfaces. The pathophysiology of Malassezia-associated skin diseases remains poorly understood due in part to the lack of appropriate animal models. Our objective was to investigate the mechanisms underlying Malassezia-induced skin inflammation using a novel murine model that physiologically recapitulates Malassezia skin infection. METHODS: Mice were inoculated epicutaneously with Malassezia yeasts without barrier disruption and in the absence of external lipid supplementation. Skin inflammation, lesional fungal loads, and expression of cytokines and antimicrobial peptides were evaluated in wild-type and mutant mouse strains. RESULTS: Malassezia-induced skin inflammation and epidermal thickening were observed on day 4 after inoculation in wild-type mice. High fungal burdens were detected in the cornified layer on day 2 and decreased thereafter with near complete clearance by day 7 after inoculation. Malassezia-induced skin inflammation and fungal clearance by the host were interleukin-17 (IL-17) dependent with contribution of group 3 innate lymphoid cells. Moreover, IL-17-dependent skin inflammation was mediated through IL-36 receptor and keratinocyte MyD88 signaling. CONCLUSION: Using a new skin infection model, it is shown that Malassezia-induced IL-17- dependent skin inflammation and control of fungal infection are mediated via keratinocyte IL-36 receptor/MyD88 signaling.

Post-vaccination subcutaneous aluminum granuloma.

Vaccination is a successful and cost-effective public health intervention. Aluminum-containing adjuvants are used worldwide to improve the immune response of vaccines. Side effects of aluminum-containing adjuvants in skin and subcutis are usually accompanied by persistent itch, and it may be challenging to diagnose asymptomatic cases. Here we present a case of a 1-year-old girl with asymptomatic subcutaneous nodules. Magnetic resonance imaging (MRI) revealed subcutaneous lesions: 16 mm on the upper right and 4 mm on the upper left arms. Histological examination revealed a granulomatous reaction with lymphoid follicle-like structures in the subcutis, accompanied by a considerable number of macrophages with PAS-positive granular cytoplasm. Moreover, the granules stained positive with aluminon staining, which revealed the existence of aluminum. These findings indicate post-vaccination aluminum granuloma. Due to the benign nature of aluminum granuloma and the benefit of routine vaccination, we decided to recommend that the patient continue taking the routine vaccination.

Usefulness of 2-D shear wave elastography for the diagnosis of inguinal lymph node metastasis of malignant melanoma and squamous cell carcinoma.

We used 2-D shear wave elastography to quantify lymph node hardness, from the shear wave velocity, to determine the presence or absence of metastatic lymphadenopathy in the inguinal lymph nodes of five patients with malignant melanoma and squamous cell carcinoma. The shear wave velocity accurately identified all cases of metastasis confirmed by histology, compared with two false-positive and one false-negative finding with positron emission tomography/computed tomography. 2-D shear wave elastography would be useful to evaluate inguinal lymph node metastasis.

Staphylococcus Agr virulence is critical for epidermal colonization and associates with atopic dermatitis development.

Atopic dermatitis (AD) is commonly associated with colonization by Staphylococcus aureus in the affected skin. To understand the role of S. aureus in the development of AD, we performed whole-genome sequencing of S. aureus strains isolated from the cheek skin of 268 Japanese infants 1 and 6 months after birth. About 45% of infants were colonized with S. aureus at 1 month regardless of AD outcome. In contrast, skin colonization by S. aureus at 6 months of age increased the risk of developing AD. Acquisition of dysfunctional mutations in the S. aureus Agr quorum-sensing (QS) system was primarily observed in strains from 6-month-old infants who did not develop AD. Expression of a functional Agr system in S. aureus was required for epidermal colonization and the induction of AD-like inflammation in mice. Thus, retention of functional S. aureus agr virulence during infancy is associated with pathogen skin colonization and the development of AD.

Higher methylation subtype of malignant melanoma and its correlation with thicker progression and worse prognosis.

Malignant melanoma (MM) is the most life-threatening disease among all skin malignancies, and recent genome-wide studies reported BRAF, RAS, and NF1 as the most frequently mutated driver genes. While epigenetic aberrations are known to contribute to the oncogenic activity seen in various cancers, their role in MM has not been fully investigated. To investigate the role of epigenetic aberrations in MM, we performed genome-wide DNA methylation analysis of 51 clinical MM samples using Infinium 450k beadarray. Hierarchical clustering analysis stratified MM into two DNA methylation epigenotypes: high- and low-methylation subgroups. Tumor thickness was significantly greater in case of high-methylation tumors than low-methylation tumors (8.3 ± 5.3 mm vs 4.5 ± 2.9 mm, P = .003). Moreover, prognosis was significantly worse in high-methylation cases (P = .03). Twenty-seven genes were found to undergo significant and frequent hypermethylation in high-methylation subgroup, where TFPI2 was identified as the most frequently hypermethylated gene. MM cases with lower expression levels of TFPI2 showed significantly worse prognosis (P = .001). Knockdown of TFPI2 in two MM cell lines, CHL-1 and G361, resulted in significant increases of cell proliferation and invasion. These indicate that MM can be stratified into at least two different epigenetic subgroups, that the MM subgroup with higher DNA methylation shows a more progressive phenotype, and that methylation of TFPI2 may contribute to the tumor progression of MM.