Phase I/II trials of human bone marrow-derived clonal mesenchymal stem cells for treatment of adults with moderate-to-severe atopic dermatitis.

BACKGROUND: Mesenchymal stem cells (MSCs) play important roles in therapeutic applications by regulating immune responses. OBJECTIVE: To investigate the safety and efficacy of allogenic human bone marrow-derived clonal MSCs (hcMSCs) in subjects with moderate to severe atopic dermatitis (AD). METHODS: The study included a phase I open-label trial followed by a phase II randomized, double-blind, placebo-controlled trial that involved 72 subjects with moderate to severe AD. RESULTS: In phase I, intravenous (IV) administration of hcMSCs at two doses (1×106 and 5×105 cells/kg) was safe and well-tolerated in 20 subjects. Since there was no difference between the two dosage groups (P=0.9), it was decided to administer low-dose hcMSCs only for phase II. In phase II, subjects receiving three weekly IV infusions of hcMSCs at 5x105 cells/kg showed a higher proportion of an eczema area and severity index (EASI)-50 response at week 12 compared to the placebo group (P=0.038). The differences between groups in the dermatology life quality index and pruritus numerical-rating scale scores were not statistically significant. Most adverse events were mild or moderate and resolved by the end of the study period. CONCLUSIONS: Our findings demonstrate that hcMSCs treatment resulted in a significantly higher rate of achieving EASI-50 at 12 weeks compared to the control group in subjects with moderate to severe AD. The safety profile of hcMSCs treatment was acceptable. Further larger-scale studies are necessary to confirm these preliminary findings.

Lysophosphatidic Acid Mediates Imiquimod-Induced Psoriasis-like Symptoms by Promoting Keratinocyte Proliferation through LPAR1/ROCK2/PI3K/AKT Signaling Pathway.

Psoriasis is a chronic inflammatory skin disease. Recently, lysophosphatidic acid (LPA)/LPAR5 signaling has been reported to be involved in both NLRP3 inflammasome activation in macrophages and keratinocyte activation to produce inflammatory cytokines, contributing to psoriasis pathogenesis. However, the effect and molecular mechanisms of LPA/LPAR signaling in keratinocyte proliferation in psoriasis remain unclear. In this study, we investigated the effects of LPAR1/3 inhibition on imiquimod (IMQ)-induced psoriasis-like mice. Treatment with the LPAR1/3 antagonist, ki16425, alleviated skin symptoms in IMQ-induced psoriasis-like mouse models and decreased keratinocyte proliferation in the lesion. It also decreased LPA-induced cell proliferation and cell cycle progression via increased cyclin A2, cyclin D1, cyclin-dependent kinase (CDK)2, and CDK4 expression and decreased p27Kip1 expression in HaCaT cells. LPAR1 knockdown in HaCaT cells reduced LPA-induced proliferation, suppressed cyclin A2 and CDK2 expression, and restored p27Kip1 expression. LPA increased Rho-associated protein kinase 2 (ROCK2) expression and PI3K/AKT activation; moreover, the pharmacological inhibition of ROCK2 and PI3K/AKT signaling suppressed LPA-induced cell cycle progression. In conclusion, we demonstrated that LPAR1/3 antagonist alleviates IMQ-induced psoriasis-like symptoms in mice, and in particular, LPAR1 signaling is involved in cell cycle progression via ROCK2/PI3K/AKT pathways in keratinocytes.

Small intestinal immune-environmental changes induced by oral tolerance inhibit experimental atopic dermatitis.

Atopic dermatitis is a chronic skin inflammatory disease mediated by Th2-type immune responses. Although intestinal immune responses have been shown to play a critical role in the development or prevention of atopic dermatitis, the precise influence of intestinal immunity on atopic dermatitis is incompletely understood. We show here that orally tolerized mice are protected from experimental atopic dermatitis induced by sensitization and epicutaneous (EC) challenge to ovalbumin. Although the expression of Th2-type cytokines in the small intestine of orally tolerized and EC-challenged mice did not change significantly, these mice showed decreased inflammatory responses in the small intestine with restoration of microbial change elicited by the EC challenge. Interestingly, an increase in small intestinal eosinophils was observed with the EC challenge, which was also inhibited by oral tolerance. The role of small intestinal eosinophils and microbiota in the pathogenesis of experimental atopic dermatitis was further substantiated by decreased inflammatory mediators in the small intestine and attenuated Th2-type inflammation in the skin of eosinophil-deficient and microbiota-ablated mice with EC challenges. Based on these data, we propose that the bidirectional interaction between the skin and the intestine has a role in the pathogenesis of atopic dermatitis and that modulation of the intestinal microenvironments could be a therapeutic approach to atopic dermatitis.

Associations between ambient air pollution and medical care visits for atopic dermatitis.

BACKGROUND: Previous studies have reported numerous environmental factors for atopic dermatitis (AD), such as allergens and chemical stimulants. However, few studies have addressed the relationship between ambient air pollution and AD at a population level. OBJECTIVE: To evaluate the effect of air pollutants on medical care visits for AD and to identify susceptible populations. METHODS: In this time-series study conducted on 513,870 medical care visits for AD from 2012 to 2015 identified by reviewing national health insurance claim data in Incheon, Republic of Korea. Treating daily number of medical care visits for AD as a dependent variable, generalized additive models with Poisson distributions were constructed, which included air pollutant levels, ambient temperature, relative humidity, day of the week, national holiday, and season. Risks were expressed as relative risks (RR) with 95% confidence intervals (95% CIs) per interquartile range increase of each air pollutant. RESULTS: Higher levels of particulate matter of diameter ≤10 µm (PM10) (RR, 1.009; 95% CI, 1.007-1.012), ozone (1.028; 1.023-1.033), and sulfur dioxide (1.033; 1.030-1.037) were significantly associated with increased risk of medical care visits for AD on same days. In all age and sex groups, ozone was associated with a significantly higher risk of medical care visits, with the greatest risk among 13- to 18-year-old males (RR, 1.127; 95% CI, 1.095-1.159). CONCLUSION: This study suggests relationships of ambient PM10, ozone, and sulfur dioxide levels with medical care visits for AD.

High-fluence 1064-nm Q-Switched Nd:YAG laser: Safe and effective treatment of café-au-lait macules in Asian patients.

OBJECTIVES: Café-au-lait macules (CALMs) are benign cutaneous hyperpigmentary disorders. Usually, laser therapies for cosmetic concerns result in more severe side effects in the people of Asian descent than that of Caucasians. Unfortunately, there is no gold standard for the laser treatment of CALMs in skin of people of Asian descent. To investigate the efficacy and safety of a high-fluence 1064-nm Q-switched neodymium-doped yttrium aluminum garnet (Nd:YAG) laser treatment of CALMs in Asian patients. STUDY DESIGN: The medical records of 35 Korean patients (age range: 1 to 40 years old, mean age: 18.5 years) diagnosed with isolated CALMs were reviewed retrospectively. METHODS: The patients were treated with a 1064-nm Q-switched Nd:YAG laser. The parameters were a spot size of 7 mm, a fluence of 2.2-2.4 J/cm2 with a slow single sliding-stacking pass, and a pulse rate of 10 Hz with a 1-week interval for 20-50 sessions. RESULTS: At the week of the final treatment, all treated CALMs showed considerable pigmentation removal without any permanent side effects, such as scaring, mottled hypopigmentation and postinflammatory hyperpigmentation (PIH). All treated CALMs showed more than 50% clinical improvement. No recurrence was observed in any of the patients after 12 months of follow-up. CONCLUSION: A high-fluence 1064-nm Q-switched Nd:YAG laser treatment of CALMs in Asian patients is a safe and effective method without side effects and recurrence.

A Possible Case of Statin-Induced Ichthyosis in an Elderly Woman.

Ichthyosis is a heterogeneous group of hereditary or acquired skin disorders, characterized by increased stratum corneum production. Several systemic diseases and many drugs can occasionally cause acquired ichthyosis. We report a case of statin-induced ichthyosis in which the causality between statin and ichthyosis was found possible by using the Naranjo scale. A 79-year-old woman presented with pruritic skin lesions on both legs that appeared erythematous, scaly, and cracked. A clinical diagnosis of acquired ichthyosis was made and the statin was suspected as the cause. The skin lesions improved after 6 weeks of dose reduction of the statin.

Efficacy of a bleomycin microneedle patch for the treatment of warts.

Warts are a common skin disease caused by infection of the human papilloma virus. Most treatments involving physical destruction of the infected cells, such as cryotherapy and electrocautery, are limited by intense pain, failure, or recurrences. Our aim was to compare the therapeutic effects of a newly developed bleomycin microneedle patch with cryotherapy in the treatment of warts. Forty-two patients with more than two wart lesions were included in the study. The two treatment modalities were randomly applied to different warts on each patient. Treatment efficacy was assessed using the Physician's Global Assessment (PGA) and the Patient's Global Assessment (PaGA). Mean PGA and PaGA scores were not significantly different between cryotherapy and bleomycin microneedle patch treatment. It was also determined that the mean size of all the warts treated with either modality shrank about equally at weeks 8 and 16 after initial treatment. Thus, treatment efficacy of the bleomycin microneedle patch was comparable to that of conventional cryotherapy. According to a visual analogue scale of pain, bleomycin microneedle patch treatment was significantly less painful than cryotherapy (p < .0001). In addition, use of the bleomycin microneedle patch was more tolerable for patients who were reluctant to receive the painful treatment. Thus, the bleomycin microneedle patch can be an effective, convenient, and innovative treatment modality for warts.

Demodex Mite Density Determinations by Standardized Skin Surface Biopsy and Direct Microscopic Examination and Their Relations with Clinical Types and Distribution Patterns.

BACKGROUND: Demodicosis is a parasitic skin disease caused by Demodex mites, and the determination of mite density per square centimeter is important to diagnose demodicosis. Standardized skin surface biopsy (SSSB) and direct microscopic examination (DME) are commonly used to determine Demodex mites density (Dd). However, no study has previously compared these two methods with respect to clinical types and distribution patterns of demodicosis. OBJECTIVE: The aim of this study was to compare the value of SSSB and DME findings in reference to the clinical types and distribution patterns of demodicosis. METHODS: The medical records of 35 patients diagnosed with demodicosis between December 2011 and June 2015 were retrospectively reviewed. Demodicosis was classified according to four clinical types (pityriasis folliculorum, rosacea type, acne type, and perioral type) and three distribution patterns (diffuse pattern, U-zone pattern, and T-zone pattern). Two samples, one for SSSB and one for DME, were obtained from a lesion of each patient. RESULTS: In all patients, mean Dd and the proportion with a high Dd (>5D/cm2) by DME (14.5±3.3, 80.0%, respectively) were higher than by SSSB (5.5±1.3, 37.1%, respectively; p<0.01, p=0.02, respectively). In terms of clinical types, for rosacea type, mean Dd and proportion with a high Dd by DME (12.4±3.5, 84.6%, respectively) were significantly greater than those determined by SSSB (3.6±1.2, 23.1%; p=0.04, p=0.04, respectively). In terms of distribution pattern, for the diffuse pattern, mean Dd and the proportion with a high Dd by DME (17.5±3.7, 100%, respectively) were significantly higher than those determined by SSSB (6.0±2.7, 26.7%; p<0.01, p<0.01, respectively). CONCLUSION: The results of our study revealed that DME is a more sensitive method for detecting Demodex than SSSB, especially in patients with diffuse pattern and suspected rosacea type. Further research is needed to confirm this finding.

Treatment of erythematotelangiectatic rosacea with the fractionation of high-fluence, long-pulsed 595-nm pulsed dye laser.

Various lasers have been used for the treatment of erythematotelangiectatic rosacea (ETR) that does not respond to systemic or topical therapy. The pulsed dye lasers (PDLs) are an effective option for ETR, and the purpuragenic fluence proved to be superior until now. Given that purpura and subsequent possible postinflammatory hyperpigmentation (PIH) are occasionally unbearable in some patients, and several studies using the low nonpurpuragenic fluence were reported. To deliver the sufficient high fluence of a PDL without generating purpura, we designed the fractionation of high fluence using five passes and longer pulse duration (6 milliseconds) of a PDL in succession. A total of eight patients with ETR were enrolled in this study; all patients were treated with PDL 10 times at 2-week intervals. Erythema and telangiectasia scores, as well as improvement, were assessed by two physicians using the digital photographs. Moderate-to-marked improvement was achieved in most of the patients, and erythema and telangiectasia scores were significantly decreased. Purpura and PIH were not reported in all patients. The fractionation of high-fluence, long-pulsed 595 nm PDL is a very safe and effective treatment for ETR.

Treatment of patients with refractory atopic dermatitis sensitized to house dust mites by using sublingual allergen immunotherapy.

Even though atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases, its treatment remains a challenge in clinical practice, with most approaches limited to symptomatic, unspecific anti-inflammatory, or immunosuppressive treatments. Many studies have shown AD to have multiple causes that activate complex immunological and inflammatory pathways. However, aeroallergens, and especially the house dust mite (HDM), play a relevant role in the elicitation or exacerbation of eczematous lesions in many AD patients. Accordingly, allergen-specific immunotherapy has been used in AD patients with the aim of redirecting inappropriate immune responses. Here, we report three cases of refractory AD sensitized to HDM who were treated with sublingual immunotherapy.

Analysis of the prevalence of and risk factors for atopic dermatitis using an ISAAC questionnaire in 8,750 Korean children.

BACKGROUND: Since 1995, epidemiologic studies of atopic disorders using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire have been performed in many countries, including the Republic of Korea. The prevalence, burden and risk factors of atopic dermatitis were surveyed in these studies, which helped to enhance their comparability among different areas and age groups, as well as to clarify the nature of atopic dermatitis and other atopic disorders. METHODS: From 21 facilities, 8,750 children were enrolled in this cross-sectional study. The data were collected via the Internet using a questionnaire based on the Korean-language version of the ISAAC study format. RESULTS: The prevalence of atopic dermatitis over the previous 12 months was 14.4%. The prevalence in preschool children was significantly higher than in elementary school children. Family history of atopic diseases, diagnosis of allergic conjunctivitis and diagnosis of food allergy were positively associated with atopic dermatitis in both preschool and elementary school children. In addition, raising pets was positively associated with atopic dermatitis in preschool children. In elementary school children, female gender, secondhand smoking, breastfeeding, changing the parents' house to a newly built one during the first year of life, diagnosis of asthma and diagnosis of allergic rhinitis were positively associated with atopic dermatitis. CONCLUSION: The prevalence of atopic dermatitis in preschool and elementary school children in Korea is similar to that of children in other developing countries. The risk factors for atopic dermatitis are different in preschool and elementary school children. More detailed strategies will be necessary to reduce atopic dermatitis in both age groups.

Atypical hydroa vacciniforme-like epstein-barr virus associated T/NK-cell lymphoproliferative disorder.

Epstein-Barr virus (EBV)-associated T-cell/natural killer (NK)-cell lymphoproliferative disorders (EBV-T/NK-LPDs) accompany severe chronic active EBV infection (CAEBV) or comprise the CAEBV disease entity. The CAEBV disease entity has the common feature of lymphoproliferation of T or NK cells (primarily), and B cells (rarely), with chronic activation of EBV infection. The disease is rare and seems to be more prevalent in East Asian countries. The CAEBV disease entity encompasses heterogenous disorders, including hydroa vacciniforme (HV), hypersensitivity to mosquito bites, EBV-associated hemophagocytic syndrome, NK/T-cell lymphoma, and NK-cell leukemia. Atypical HV-like eruptions are present on sun-exposed and nonexposed areas with facial edema, fever, and hepatosplenomegaly, unlike classic HV. Recently, it has been suggested that classic HV and atypical HV-like eruptions are variants within the same disease spectrum of EBV-T/NK-LPD. We report a Korean boy with an atypical HV-like eruption and various systemic manifestations, including fever, sore throat, abdominal pain, headaches, seizures, and hematologic abnormalities for 2 years. After the initial mild eruption, which resembled a viral exanthem, ulceronecrotic skin lesions gradually developed and were associated with a high-grade fever and constitutional symptoms. He had a CAEBV infection, which showed a predominant proliferation of NK cells with high EBV DNA levels in the peripheral blood. However, in the skin lesions, there were nonneoplastic CD4 T-cell infiltrations predominantly showing a monoclonal T-cell receptor-γ gene rearrangement and positive EBV in situ hybridization.

Assessment of an imiquimod-induced psoriatic mouse model in relation to oxidative stress.

Psoriasis is a chronic inflammatory skin disease that is thought to be related to oxidative stress. Much progress has been made in understanding the pathophysiology of psoriasis in relation to the immunologic and antioxidant systems. However, this progress has been hindered by the lack of an appropriate animal model for psoriasis. Recently, imiquimod (IQM)-induced psoriasis-like cutaneous inflammation has been reported in mice and humans. We verified the usefulness of an IQM-induced mouse model in relation to the antioxidant system. BALB/C female mice at 8-10 weeks of age were treated with IQM cream in this study. We analyzed clinical and histopathological changes. Increased reactive oxygen species production was measured by glutathione assay. Levels of myeloperoxidase (MPO) and superoxide dismutase-1 (SOD1) were determined by western blotting and immunohistochemical analyses. The activity of SOD was measured by a SOD activity assay kit. Application of IQM-induced skin inflammation similar to psoriasis in clinical and histopathological aspects. Accumulation of immune cells was confirmed. Oxidative stress was increased, the antioxidant enzyme MPO levels were increased, and both SOD levels and activity were decreased. In conclusion, the IQM-induced mouse model showed an aberrant antioxidant system. Levels of MPO and oxidative stress were increased, and the level and activity of SOD were decreased. Since this model seemed to be an appropriate model for psoriasis, it can be used to further study the pathogenic role of redox imbalance in psoriasis.

Chromoblastomycosis Caused by Phialophora richardsiae.

Chromoblastomycosis is a chronic fungal disease of the skin and subcutaneous tissues caused by a group of dematiaceous (black) fungi. The most common etiologic agents are Fonsecaea pedrosoi and Cladophialophora carrionii, both of which can be isolated from plant debris. The infection usually follows traumatic inoculation by a penetrating thorn or splinter wound. Several months after the injury, painless papules or nodules appear on the affected area; these papules then progress to scaly and verrucose plaques. We report a case of chromoblastomycosis caused by Phialophora richardsiae, which has been rarely associated with chromoblastomycosis. The case involved a 43-year-old male, who for the past 2 months had noted an erythematous, pustulous plaque that was somewhat dark brown in color on his right shin; the plaque also had intermittent purulent discharge and crust formation. On histopathological examination, chronic granulomatous inflammation and sclerotic cells were seen. The tissue fungus culture grew out the typical black fungi of P. richardsiae, which was confirmed by polymerase chain reaction. The patient has been treated with a combination of terbinafine and itraconazole for 3 months with a good clinical response.