Clinical Signs of Kawasaki Disease from the Perspective of Epithelial-to-Mesenchymal Transition Recruiting Erythrocytes: A Literature Review.

Kawasaki disease (KD) is a systemic vasculitis affecting children younger than 5 years of age. Early period in life is marked by rapid somatic growth with cell proliferation and immaturity of the immunity with dominant innate immune system. Coronary complications in KD are the most common acquired heart disease in children, yet the diagnosis of KD still depends on the clinical diagnostic criteria. Glossy red lips and conjunctival injection are characteristic signs enabling pediatricians to make the initial diagnosis of KD; however, little is known why these are so characteristic. The diagnostic criteria of KD seem to be scattered in seemingly irrelevant body systems such as the eyes, lips, skin, and heart. KD is classified as a connective tissue disease. Recently, red blood cells (RBCs) have emerged as important modulators in innate immune response. RBCs are reported to participate in extracellular matrix remodeling and upregulating matrix metalloproteinase (MMP) expression in dermal fibroblasts. Also, fibroblast growth factors and microRNAs associated with fibrosis are drawing attention in KD. The cardinal signs of KD appear at the border of muco-cutaneous junction. Head and neck regions are abundant in tissues undergoing epithelial-to-mesenchymal transition (EMT). Interstitial carditis and valve insufficiency as well as coronary arterial lesions may complicate KD, and these lesions present in tissues that originated from epicardial progenitor cells by EMT. Having reviewed the recent research on KD, we presume that the signs of KD present at borders between keratinized and non-keratinized stratified squamous epithelium where the EMT is still ongoing for the rapid somatic growth where RBCs are recruited as an innate immune response and to prevent excessive fibrosis in mucosa. KD presents scarcely in adults with somatic growth and immune maturation completed. In this review, we attempted to explain the reasons for the clinical manifestations of KD and to search for a link among the diagnostic clues in the perspective of EMT during the somatic growth and immune system maturation in children with KD.

Risk of Skin Cancer and Actinic Keratosis in Patients with Rosacea: A Nationwide Population-based Cohort Study.

The association between rosacea and skin cancer remains inconclusive, with conflicting reports. The aim of this nationwide population-based cohort study was to determine the risk of skin cancer in patients with rosacea. A rosacea cohort (n = 11,420) was formulated and evaluated from 2010 to 2019. The incidence rate ratios of actinic keratosis, cutaneous melanoma, keratinocyte carcinoma and gastric, colorectal, and liver cancer were analysed in comparison with a matched control group, and multivariable stratified Cox proportional hazards model analysis was performed. The risk of actinic keratosis and keratinocyte carcinoma was increased in the rosacea group compared with the control group, with adjusted hazard ratios of 6.05 (95% confidence interval 3.63-10.09) and 2.66 (1.53-4.61), respectively. The risk of cutaneous melanoma and gastric, colorectal and liver cancer was not increased, with adjusted hazard ratios of 1.69 (0.25-11.37), 0.81 (0.59-1.10), 0.91 (0.69-1.18) and 1.32 (0.89-1.95), respectively. These results reveal an increased risk of actinic keratosis and keratinocyte carcinoma in patients with rosacea.

Guideline for the diagnosis, treatment and long-term management of cutaneous lupus erythematosus.

Cutaneous lupus erythematosus (CLE) is an inflammatory, autoimmune disease encompassing a broad spectrum of subtypes including acute, subacute, chronic and intermittent CLE. Among these, chronic CLE can be further classified into several subclasses of lupus erythematosus (LE) such as discoid LE, verrucous LE, LE profundus, chilblain LE and Blaschko linear LE. To provide all dermatologists and rheumatologists with a practical guideline for the diagnosis, treatment and long-term management of CLE, this evidence- and consensus-based guideline was developed following the checklist established by the international Reporting Items for Practice Guidelines in Healthcare (RIGHT) Working Group and was registered at the International Practice Guideline Registry Platform. With the joint efforts of the Asian Dermatological Association (ADA), the Asian Academy of Dermatology and Venereology (AADV) and the Lupus Erythematosus Research Center of Chinese Society of Dermatology (CSD), a total of 25 dermatologists, 7 rheumatologists, one research scientist on lupus and 2 methodologists, from 16 countries/regions in Asia, America and Europe, participated in the development of this guideline. All recommendations were agreed on by at least 80% of the 32 voting physicians. As a consensus, diagnosis of CLE is mainly based on the evaluation of clinical and histopathological manifestations, with an exclusion of SLE by assessment of systemic involvement. For localized CLE lesions, topical corticosteroids and topical calcineurin inhibitors are first-line treatment. For widespread or severe CLE lesions and (or) cases resistant to topical treatment, systemic treatment including antimalarials and (or) short-term corticosteroids can be added. Notably, antimalarials are the first-line systemic treatment for all types of CLE, and can also be used in pregnant patients and pediatric patients. Second-line choices include thalidomide, retinoids, dapsone and MTX, whereas MMF is third-line treatment. Finally, pulsed-dye laser or surgery can be added as fourth-line treatment for localized, refractory lesions of CCLE in cosmetically unacceptable areas, whereas belimumab may be used as fourth-line treatment for widespread CLE lesions in patients with active SLE, or recurrence of ACLE during tapering of corticosteroids. As for management of the disease, patient education and a long-term follow-up are necessary. Disease activity, damage of skin and other organs, quality of life, comorbidities and possible adverse events are suggested to be assessed in every follow-up visit, when appropriate.

Prevalence and Characteristics of Onychomycosis in Patients with Knee Osteoarthritis: A Single-centre Prospective Cross-sectional Study.

Knee disorders that compromise patients' lower leg movements and self-care may put these patients at greater risk of onychomycosis. However, little is known about the prevalence of onychomycosis in patients with knee diseases. This study evaluated the prevalence and characteristics of onychomycosis in patients with knee osteoarthritis. A total of 520 consecutive patients with symptomatic knee osteoarthritis who visited the Department of Orthopedics for a potential knee surgery were evaluated for onychomycosis by PCR-based reverse blot hybridization assay. Of the 520 patients, 308 (59.2%) were diagnosed with onychomycosis. Age (p = 0.004), male sex (p = 0.015), and being barefooted (p = 0.031) were statistically significant risk factors for onychomycosis. Knee disease severity, based on Kellgren-Lawrence grade, was associated with severity of onychomycosis. The impairment of physical function and self-care caused by knee disorders may increase the prevalence of onychomycosis in these patients.

IGF-1 Upregulates Biglycan and Decorin by Increasing Translation and Reducing ADAMTS5 Expression.

Proteoglycan (PG) is a glycosaminoglycan (GAG)-conjugated protein essential for maintaining tissue strength and elasticity. The most abundant skin PGs, biglycan and decorin, have been reported to decrease as skin ages. Insulin-like growth factor-1 (IGF-1) is important in various physiological functions such as cell survival, growth, and apoptosis. It is well known that the serum level of IGF-1 decreases with age. Therefore, we investigated whether and how IGF-1 affects biglycan and decorin. When primary cultured normal human dermal fibroblasts (NHDFs) were treated with IGF-1, protein levels of biglycan and decorin increased, despite no difference in mRNA expression. This increase was not inhibited by transcription blockade using actinomycin D, suggesting that it is mediated by IGF-1-induced enhanced translation. Additionally, both mRNA and protein expression of ADAMTS5, a PG-degrading enzyme, were decreased in IGF-1-treated NHDFs. Knockdown of ADAMTS5 via RNA interference increased protein expression of biglycan and decorin. Moreover, mRNA and protein expression of ADAMTS5 increased in aged human skin tissues compared to young tissue. Overall, IGF-1 increases biglycan and decorin, which is achieved by improving protein translation to increase synthesis and preventing ADAMTS5-mediated degradation. This suggests a new role of IGF-1 as a regulator for biglycan and decorin in skin aging process.

Comparison of the Treatment Outcome of Oral Tofacitinib with Other Conventional Therapies in Refractory Alopecia Totalis and Universalis: A Retrospective Study.

Treatment of alopecia totalis and alopecia universalis is often challenging and unsatisfactory. Recently, Janus kinase inhibitor has shown promising results. The aim of this study is to compare the efficacy and tolerability of oral tofacitinib and conventional modalities for treating refractory alopecia totalis/universalis. A total of 74 patients (18 treated with tofacitinib, 26 treated with conventional oral treatment (steroid ± cyclosporine), and 30 treated with diphenylcyclopropenone) were included in the study. The patients' medical records were reviewed retrospectively. After 6 months, 44.4% of patients in the tofacitinib group, 37.5% in the conventional oral treatment group, and 11.1% in the diphenylcyclopropenone group achieved 50% improvements in the Severity of Alopecia Tool score. During treatment, 10% of patients in the tofacitinib group, 73.1% in the conventional oral treatment group, and 10% in the diphenylcyclopropenone group experienced adverse drug reactions. In conclusion, oral tofacitinib was more effective than diphenylcyclopropenone immunotherapy and more tolerable than conventional oral treatment after 6 months of treatment.

Imiquimod-applied Interleukin-10 deficient mice better reflects severe and persistent psoriasis with systemic inflammatory state.

Previous studies have shown that imiquimod-induced psoriasis-like skin inflammation in mice resembles phenotypic changes and cytokine profiles of human psoriasis. However, a psoriasis animal model reflecting the chronic inflammatory course and comorbidities has not yet been established. We aimed to evaluate the imiquimod-applied interleukin (IL)-10 deficient mouse model in comparison with previous models. IL-10 deficient and wild-type (WT) mice received either imiquimod or vehicle cream for 12 days and were sacrificed on day 15. For earlier time point data, either imiquimod or vehicle cream was applied for 2 days, and the mice were sacrificed on day 3. Imiquimod-applied IL-10 deficient mice showed more persistent psoriasis-like inflammation and higher severity index than did WT between day 8 and 15. Histopathologically, they demonstrated significantly thicker epidermis and larger number of CD45+, myeloperoxidase+ and IL-17+ cell counts on day 15. Quantitative reverse transcription-polymerase chain reaction with skin tissue revealed significantly higher imiquimod-induced IL-23p19 expression in imiquimod-applied IL-10 deficient mice on day 15. IL-10 deficient mice also showed significantly higher serum levels of imiquimod-induced IL-17A and tumor necrosis factor-α by enzyme-linked immunosorbent assay on day 15. Furthermore, IL-10 deficient mice showed more prominent increase of spleen weight and decrease of body weight in response to imiquimod application on day 3 and 15. In conclusion, IL-10 deficient mice model with imiquimod application may better reflect severe and persistent psoriasis with systemic inflammatory state.

Misclassification of study designs in the dermatology literature.

BACKGROUND: The appropriate classification of study designs is important for review and assessment of the relevant scientific literature as a basis for decision making; however, little is known about whether study designs have been appropriately reported in the dermatology literature. OBJECTIVE: We aimed to validate the study designs in the dermatology literature and investigate discrepancies between author-reported and actual study designs. METHODS: We reviewed all issues of 3 major dermatology journals from January to December 2016. A total of 295 original articles investigating associations between exposures and health outcomes were included for analysis. We used a validated algorithm to classify the study designs. RESULTS: Among the 295 articles, 174 (59.0%) clearly mentioned the study design in the text. All interventional studies were correctly classified on the basis of study design (n = 42); however, 35 of 132 observational studies (26.5%) showed discrepancies between the author-reported and actual study design. When the author-reported design was a prospective cohort, retrospective cohort, or case-control study (n = 61), approximately half of the studies were misclassified by the authors (n = 30). LIMITATIONS: We analyzed only 3 journals in the dermatology field. CONCLUSIONS: Our findings revealed substantial discrepancies between author-reported and actual study designs in the dermatologic literature, particularly among observational studies.

Dermatofibrosarcoma protuberans: A retrospective study of clinicopathologic features and related Akt/mTOR, STAT3, ERK, cyclin D1, and PD-L1 expression.

BACKGROUND: Little is known regarding oncoproteins other than platelet-derived growth factor subunit B in dermatofibrosarcoma protuberans (DFSP). Moreover, the risk factors for worse prognosis are controversial. OBJECTIVE: We sought to determine the clinicopathologic features and key factors for adverse outcome in DFSP, including the implication of expression of protein kinase B (Akt)/mammalian target of rapamycin (mTOR), signal transducer and activator of transcription 3 (STAT3), extracellular signal regulated kinase (ERK), cyclin D1, and programmed death ligand 1 (PD-L1). METHODS: Clinicopathologic and immunohistochemical analyses were performed for 44 DFSPs having wide local excision and 92 dermatofibromas as controls. RESULTS: Compared with the 35 nonrecurrent DFSPs, the 9 recurrent DFSPs exhibited larger tumor size, deeper invasion beyond the subcutis, and more diverse histologic subtype. The fibrosarcomatous subtype revealed frequent mitotic figures and a high cyclin D1-positive index. The 2 metastatic DFSPs (1 each of the fibrosarcomatous and myxoid subtypes) demonstrated 4 and 11 instances of local recurrence, respectively, as well as larger tumor size, deeper invasion beyond the subcutis, and high expression of cyclin D1. Expression of Akt/mTOR, STAT3, ERK, and PD-L1 ranged from none or low in the primary skin lesions to high in the corresponding metastatic sites. Akt/mTOR and ERK were expressed more frequently in DFSP than in dermatofibroma. LIMITATIONS: Lack of information on patients before hospital evaluation. CONCLUSION: Complex factors beyond fibrosarcomatous subtype may portend local recurrence or metastasis. Akt/mTOR, STAT3, ERK, and PD-L1 may be associated with development and/or progression of DFSP.

Pulsed intravenous immunoglobulin therapy in refractory ulcerated livedoid vasculopathy: seven cases and a literature review.

Livedoid vasculopathy (LV) is a thrombotic vasculopathy of the skin of unknown origin. No treatment has been validated in this indication, but case reports demonstrated successful use of intravenous immunoglobulins (IVIg) in LV. We assessed the efficacy and tolerability of 2 g/kg IVIg therapy every month for 2∼3 cycles in patients with refractory LV. We analyzed the efficacy, side effects and recurrence after long-term follow-up (51.9 ± 14.0 months) in seven patients with LV treated with 2 g/kg of IVIg. Mean clinical score of sum of erythema, ulceration and pain index (each: 0-3) was 5.7 ± 0.9 before the therapy and significantly lower after therapy (1.1 ± 0.5) (p = 0.001). Even after just one cycle of IVIg, the score decreased significantly from 5.7 ± 0.9 to 3.7 ± 0.9 (p = 0.002), especially the pain score. In one patient, LV has not recurred for over 7 years; six patients experienced recurrence after a mean of 12.7 ± 2.8 months. Out of the six patients, two patients were re-administered IVIg whereas the others were well controlled by conventional therapy. We propose that IVIg is a rapid, effective, and safe therapeutic option in LV refractory to other treatment modalities.

Maternal and Perinatal Factors of Importance for Occurrence and Severity of Infantile Haemangioma.

To determine which patient and maternal factors are associated with the occurrence and the severity of infantile haemangioma (IH), a single-centre retrospective observational study was conducted with 96 haemangioma patients and 143 age-matched control babies, born in the same hospital between March 2012 and March 2013. The IH patients were selected according to diagnosis from dermatologists, either consulted from the department of paediatrics or in outpatient setting. Unplanned female children whose mothers smoked and/or consumed alcohol when pregnant was more likely to have IH (p < 0.0.05). The higher the birth weight, the more superficial the haemangioma (p = 0.023), and localised lesions were more common in singleton babies (p = 0.023) and babies conceived by normal fertilisation (p = 0.002). The occurrence and severity of IH is not only influenced by patient factors but also by maternal factors especially care during pregnancy period. By controlling these factors, the incidence and severity of IH may be lowered.

Pulse in pulse intense pulsed light for melasma treatment: a pilot study.

BACKGROUND: A new type of intense pulsed light IPL with pulse-in-pulse (PIP) mode (multiple fractionated subpulses in one pulse width) has recently been developed. OBJECTIVE: To evaluate the clinical efficacy and safety of PIP IPL in patients with melasma. MATERIALS AND METHODS: Half of each patient's face was treated with IPL and six treatment sessions with a low-fluence quality-switched neodymium-doped yttrium aluminum garnet laser (IPL/T) every 2 weeks. The other half was treated with PIP IPL. Outcome assessments included photography, modified Melasma Area and Severity Index (MASI) score, and patient satisfaction. The melanin and erythema indices were used for objective evaluation. Patients were followed up for 6 months after the last treatment. RESULTS: All patients completed the study successfully. On both treated sides, the melanin index decreased significantly after treatment. The modified MASI score also fell 54.4% on the PIP IPL side and 50.0% on the IPL/T side. No patients reported serious aggravation of melasma for 6 months after the last treatment. Patients favored PIP IPL due to less discomfort during and after treatments. CONCLUSION: PIP IPL may be a safe and promising treatment for melasma.

Pregnane X receptor reduces particulate matter-induced type 17 inflammation in atopic dermatitis.

Background: Epidemiological evidence suggests that particulate matter (PM) exposure can trigger or worsen atopic dermatitis (AD); however, the underlying mechanisms remain unclear. Recently, pregnane X receptor (PXR), a xenobiotic receptor, was reported to be related to skin inflammation in AD. Objectives: This study aimed to explore the effects of PM on AD and investigate the role of PXR in PM-exposed AD. Methods: In vivo and in vitro AD-like models were employed, using BALB/c mice, immortalized human keratinocytes (HaCaT), and mouse CD4 + T cells. Results: Topical application of PM significantly increased dermatitis score and skin thickness in AD-like mice. PM treatment increased the mRNA and protein levels of type 17 inflammatory mediators, including interleukin (IL)-17A, IL-23A, IL-1ß, and IL-6, in AD-like mice and human keratinocytes. PM also activated PXR signaling, and PXR knockdown exacerbated PM-induced type 17 inflammation in human keratinocytes and mouse CD4 + T cells. In contrast, PXR activation by rifampicin (a human PXR agonist) reduced PM-induced type 17 inflammation. Mechanistically, PXR activation led to a pronounced inhibition of the nuclear factor kappa B (NF-κB) pathway. Conclusion: In summary, PM exposure induces type 17 inflammation and PXR activation in AD. PXR activation reduces PM-induced type 17 inflammation by suppressing the NF-κB signaling pathway. Thus, PXR represents a promising therapeutic target for controlling the PM-induced AD aggravation.

Adiponectin Prevents Skin Inflammation in Rosacea by Suppressing S6 Phosphorylation in Keratinocytes.

Numerous recent evidence highlights epidemiological connections between rosacea and metabolic disorders. However, the precise path through which metabolic factors impact rosacea risk is still unclear. Therefore, this study aims to investigate the role of adiponectin, a crucial adipokine that regulates metabolic homeostasis, in the pathogenesis of rosacea. We elucidated a detrimental feedback loop between rosacea-like skin inflammation and decreased levels of skin adiponectin. To elaborate, rosacea lesional skin exhibits diminished adiponectin expression compared with nonlesional areas in the same patients. Induction of rosacea-like inflammation reduced adiponectin levels in the skin by generating inflammatory cytokines that suppress adiponectin production from subcutaneous adipocytes. Conversely, complete depletion of adiponectin exacerbated rosacea-like features in the mouse model. Mechanistically, adiponectin deficiency led to heightened S6 phosphorylation, a marker of the mTORC1 signaling pathway, in the epidermis. Adiponectin significantly inhibited S6 phosphorylation in cultured keratinocytes. Notably, replenishing adiponectin whole protein or topically applying an agonist for adiponectin receptor 1 successfully improved rosacea-like features in mice. This study contributes to understanding the role of adiponectin in skin inflammation associated with rosacea pathophysiology, suggesting that restoring adiponectin function in the skin could be a potential therapeutic strategy.