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The present study compared trends in antimicrobial resistance patterns in pathogens isolated from skin and soft-tissue infections (SSTIs) in Japan with those of a nationwide survey conducted in 2013. Three organisms that caused most of the SSTIs were collected from 12 dermatology departments in medical centers and 12 dermatology clinics across Japan between April 2019 and August 2020. A total of 390 strains, including 267 Staphylococcus aureus, 109 coagulase-negative staphylococci (CNS), and 14 Streptococcus pyogenes strains were submitted to a central laboratory for antimicrobial susceptibility testing. Patient demographic and clinical information was collated. Methicillin-resistant S. aureus (MRSA) was detected in 25.8% (69/267) of the S. aureus strains. The prevalence of MRSA between the present study and the 2013 survey did not differ significantly. Furthermore, there were no significant differences in MIC values and susceptibility patterns of the MRSA strains to other agents, regardless of a history of hospitalization within 1 year or invasive medical procedures. Methicillin-resistant CNS (MRCNS) was detected in 48.6% (53/109) of CNS isolates, higher than the 35.4% prevalence in the 2013 survey. This difference could be attributed to the heterogeneity in the members of the MRCNS, which comprises multiple staphylococci species, between the 2013 and 2019 surveys. However, it was noted that the susceptibility profiles of the MRCNS to each antibiotic were not significantly different from those identified in the 2013 survey. Most strains of S. pyogenes were susceptible to each antibiotic, similar to the 2013 survey. Continuous monitoring of trends in pathogen and susceptibility profiles is important to advise local public health efforts regarding the appropriate treatment of SSTIs.

Epidermal stem cells adhere more efficiently to the extracellular matrix (ECM) than the less adhesive differentiating cells due to their high expression of cell adhesion molecules including β1-integrin. Podoplanin is majorly expressed in the markedly proliferative and differentiating basal cells of the wounded and psoriatic epidermis. This study was designed to reveal podoplanin's function in human epidermal keratinocytes (HEK) focusing on its interaction with β1-integrin. We analyzed the adhesion and differentiation of HEK in both podoplanin-overexpressing and -knock-down cells, considering their β1-integrin levels. The basal layer of IL-22-treated hyperproliferative reconstituted epidermis cells (simulating basal hyperproliferative psoriatic epidermal basal cells) expressed higher podoplanin levels than the untreated control cells. The adhesiveness of HaCaT cells, which do not express podoplanin, was reduced after the overexpression of podoplanin. HEK with podoplanin overexpression suppressed the cell adhesion to type I collagen (while downregulating β1-integrin functions) and podoplanin silencing augmented it (by increasing active ECM-bound β1-integrin). The increased cell adhesion to type I collagen induced by podoplanin silencing could be reversed by addition of P5D2, a neutralizing antibody against β1-integrin. In the psoriatic epidermis, podoplanin expression was especially upregulated on the rete ridges of the basal cell layer. This expression pattern was inversely correlated with the total/ECM-bound active β1-integrin-expression, which was stronger at the basal cell layer covering the dermal papillae. Our results indicate that podoplanin inhibits the cell ECM attachment by suppressing β1-integrin and initiating HEK differentiation. Podoplanin is presumably involved in the pathogenesis of psoriasis.

Background Psoriasis, a common inflammatory skin disorder characterized by scaly erythema and plaques, is induced by dysregulation of dendritic cell- and T cell-mediated immune reaction. Receptor-interacting protein kinase 1 (RIPK1) regulates inflammatory signaling in response to stimuli such as TNF-α, TRAIL, and TLRs, resulting in apoptosis, necroptosis and NF-κB activation. However, the physiological relevance in human epidermis remains elusive. Objective In this study, we examined whether RIPK1 is involved in the pathogenesis of psoriasis vulgaris. Methods Skin samples of eight patients with psoriasis vulgaris were investigated by western blotting and immunohistochemistry. The functions of RIPK1 in keratinocytes were examined by RT-PCR and ELISA in vitro. TRAIL-neutralization-experiment was employed in an imiquimod-induced murine psoriasis model. Results In lesional psoriatic epidermis, RIPK1-expression was decreased compared with that in normal epidermis. Cytokines involved in the pathomechanism of psoriasis, such as IL-1β, IL-17A, IL-22 and TRAIL, reduced RIPK1-expression in normal human epidermal keratinocytes (HEK) in vitro. In addition, RIPK1-knockdown enhanced TRAIL-mediated expression of psoriasis-relating cytokines, such as IL-1β, IL-6, IL-8, TNF-α, in HEK. Numerous TRAIL-positive cells were detected in the dermis of lesional psoriatic skin, and TRAIL receptors were expressed in psoriatic epidermis and HEK in conventional cultures. Moreover, TRAIL-neutralization in an imiquimod-induced murine psoriasis model remarkably improved skin phenotypes, such as ear thickness, and TNF-α expression in lesional skin. Conclusions These results lead us to conclude that RIPK1-downregulation in keratinocytes increases their susceptibility to TRAIL stimulation, and plays a role in the pathogenesis of psoriasis vulgaris.

Biologics show great efficacy in treating psoriasis, a chronic inflammatory skin disease. The high cost and side-effects of biologics, dose-reduction, elongation of administration interval and suspension are possible options. However, there has been no reliable biomarker we can use when we consider these moderations in therapy. This study was conducted to test the possibility of using serum thymus and activation-regulated chemokine (TARC) level as an indicator for step down of biologic therapy. Serum TARC level was measured in 70 psoriatic patients at Asahikawa Medical University, and a correlation of TARC and severity of skin lesions was analyzed. Referring to serum TARC level, psoriatic patients can be divided into two groups. One is a population in which serum TARC level is positively correlated with severity of skin lesions, and the other is a population with low psoriatic severity and high TARC level. Serum TARC level was higher in the group that achieved PASI-clear with biologics than in the group which did not achieve PASI-clear. Among biologics, the group treated with secukinumab, an anti-interleukin (IL)-17A agent, showed significantly higher TARC level compared with the group treated with anti-tumor necrosis factor agents. In certain populations achieving PASI-clear, serum TARC level may be a potent marker reflecting better response to IL-17A inhibitors, and in this case step down of treatment for psoriasis is possible.

Psoriasis is a multifactorial inflammatory disorder, in which the inflammation affects not only the skin but also the other internal organs, and can induce cardiovascular and cerebrovascular involvements. However, few predictive factors of cardiovascular diseases have been clarified in patients with psoriasis. This study was performed to verify whether diagonal earlobe creases (ELC) can reflect the hidden comorbidities in Japanese psoriatic patients. Prevalence and subtypes of ELC were analyzed in patients with psoriatic and with non-psoriatic skin diseases, and the correlation with coronary artery calcification (CAC) or fatty liver (FL) detected by computed tomography. Prevalence of CAC was approximately twice higher than data of a Japanese resident-based study previously reported. Generally, prevalence of ELC in a psoriatic group and mean age of psoriatic groups accompanied by ELC were higher and younger than those of a non-psoriatic skin disease group, respectively. Statistically significant differences were detected in the mean age of total or male subjects accompanied by bilateral ELC with complete and incomplete length. Bilateralism of ELC was closely correlated with prevalence of CAC and CAC on multiple branches in psoriatic patients (P = 6.6e-6 and odds ratio [OR] = 14.1, P = 0.00884 and OR = 10.7, respectively), but not with that of FL. On the contrary, body mass index of more than 25 was closely correlated with prevalence of FL, but not that of CAC. Comorbidities of psoriatic patients are frequently unnoticed. ELC, an apparatus-related feature, can be a useful predictive factor for hidden coronary artery involvements in psoriatic patients.

Azathioprine (AZA)-metabolizing enzyme gene polymorphism is strongly related to thiopurine-induced leukocytopenia, which has not been well recognized in dermatological practice. We tried to see whether NUDT15 gene polymorphism can be the most susceptible genetic factor for AZA toxicity and the gene screening is beneficial to avoid the adverse events of AZA for the treatment of skin diseases. A retrospective study was carried out on 15 adult Japanese patients who were treated with AZA. Gene polymorphism of thiopurine-metabolizing enzymes NUDT15 R139C, ITPA 94C>A, TPMT*2, TPMT*3B and TPMT*3C was analyzed. The single nucleotide polymorphisms were prospectively investigated in eight patients who were considered to have received AZA treatments. Two NUDT15 R139C homozygous patients developed agranulocytosis, severe thrombocytopenia and massive hair loss. The gene screening prior to AZA treatment identified one heterozygote of NUDT15 R139C and ITPA 94C>A, and three heterozygotes of ITPA 94C>A or TMPT*3C. Although this study was a retrospective single-center case-control observational study that enrolled a small number of patients, NUDT15 R139C homozygosity is a genetic risk of thiopurine-induced potentially fetal hematological abnormalities. To avoid serious adverse events, gene screening of thiopurine-metabolizing enzymes, at least NUDT15 R139C, should be considered prior to administration in genetically predisposed populations, such as Japanese. We highlight that massive hair loss in the early period of the initiation of AZA would be a sign of impending severe myelotoxicity.

Recessive dystrophic epidermolysis bullosa (RDEB) is an intractable genetic blistering skin disease in which the epithelial structure easily separates from the underlying dermis because of genetic loss of functional type VII collagen (Col7) in the cutaneous basement membrane zone. Recent studies have demonstrated that allogeneic bone marrow transplantation (BMT) ameliorates the skin blistering phenotype of RDEB patients by restoring Col7. However, the exact therapeutic mechanism of BMT in RDEB remains unclear. In this study, we investigated the roles of transplanted bone marrow–derived circulating mesenchymal cells in RDEB (Col7-null) mice. In wild-type mice with prior GFP-BMT after lethal irradiation, lineage-negative/GFP-positive (Lin−/GFP+) cells, including platelet-derived growth factor receptor α-positive (PDGFRα+) mesenchymal cells, specifically migrated to skin grafts from RDEB mice and expressed Col7. Vascular endothelial cells and follicular keratinocytes in the deep dermis of the skin grafts expressed SDF-1α, and the bone marrow–derived PDGFRα+ cells expressed CXCR4 on their surface. Systemic administration of the CXCR4 antagonist AMD3100 markedly decreased the migration of bone marrow–derived PDGFRα+ cells into the skin graft, resulting in persistent epidermal detachment with massive necrosis and inflammation in the skin graft of RDEB mice; without AMD3100 administration, Col7 was significantly supplemented to ameliorate the pathogenic blistering phenotype. Collectively, these data suggest that the SDF1α/CXCR4 signaling axis induces transplanted bone marrow–derived circulating PDGFRα+ mesenchymal cells to migrate and supply functional Col7 to regenerate RDEB skin.

Although mental health is hampered in various skin disorders, few studies regarding anxiety in psoriasis patients are available, and specifically, no evaluation exists between mental health and psoriasis severity or the patients' quality of life. To examine the relation between mental health, psoriasis severity and patient's quality of life, 119 psoriasis vulgaris patients were assessed for anxiety using the General Health Questionnaire (GHQ)-30. Psoriasis area and severity index (PASI) and Dermatological Life Quality Index (DLQI) scores were also measured. The average total GHQ-30 score was significantly decreased from 4.41 to 2.11 (52.2% decrease) in biologics-treated patients. That of patients treated with other systemic agents decreased from 4.36 to 3.32 (23.9% decrease) and that of those treated with topical agents from 4.21 to 3.48 (17.3% decrease). In the biologics-treated group five of the six categories of GHQ-30, i.e., general illness, somatic symptoms, sleep disturbance, social dysfunction, and anxiety and dysphoria, were significantly decreased after the treatment. In contrast, in the other systemic treatment and topical treatment groups, three of the six categories, general illness, somatic symptoms, and sleep disturbance were significantly decreased. There was a significant correlation between GHQ-30 and DLQI, but not with PASI. The psoriasis patients show impaired mental health and among various treatment modalities biologics are superior to other systemic or topical treatments for improving the defective mental state.

Pemphigus vulgaris (PV) is an autoimmune bullous disease characterized by autoantibodies against desmogleins. We report a case of recalcitrant PV, which progressed from the mucosal to the mucocutaneous type, with a corresponding increase in anti-desmoglein (Dsg)1 and decrease in anti-Dsg3 antibody titres. Thus, the clinical features seemed to correlate with the ratio of anti-Dsg1 and 3. The patient also had anti-Dsg4 antibodies, which might be related to the nonscarring diffuse hair loss and marked facial involvement she also had. The patient did not respond to treatment with systemic steroid, ciclosporin, azathioprine, cyclophosphamide or double filtration plasmapheresis, and eventually died from fulminant thrombotic thrombocytopenic purpura of unknown cause.