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.

Improvement of severe alopecia areata in an adolescent patient on upadacitinib.

Recently, alopecia areata (AA) treatment via the Janus kinase (JAK)-signal transducer and activator of transcription pathway has been reported. However, as baricitinib, a JAK1/2 inhibitor is only approved for adult patients, children, and adolescent patients still lack treatment options. We present a case that showed improvement of severe AA in an adolescent patient on upadacitinib, which has been approved by the Food and Drug Administration (FDA) for use in patients with rheumatoid disease or atopic dermatitis (AD) in children aged 12 years or older and weighing 40 kg or more. Herein, we suggest that upadacitinib can be a good alternative for adolescent patients with AA, particularly those who may also have AD.

Dermatophagoides farinae Extract Induces Interleukin 33-Mediated Atopic Skin Inflammation via Activation of RIP1.

Receptor-interacting protein kinase (RIP) family 1 signaling has complex effects on inflammatory processes and cell death, but little is known concerning allergic skin diseases. We examined the role of RIP1 in Dermatophagoides farinae extract (DFE)-induced atopic dermatitis (AD)-like skin inflammation. RIP1 phosphorylation was increased in HKCs treated with DFE. Nectostatin-1, a selective and potent allosteric inhibitor of RIP1, inhibited AD-like skin inflammation and the expression of histamine, total IgE, DFE-specific IgE, IL-4, IL-5, and IL-13 in an AD-like mouse model. The expression of RIP1 was increased in ear skin tissue from a DFE-induced mouse model with AD-like skin lesions and in the lesional skin of AD patients with high house dust mite sensitization. The expression of IL-33 was down-regulated after RIP1 inhibition, and the levels of IL-33 were increased by over-expression of RIP1 in keratinocytes stimulated with DFE. Nectostatin-1 reduced IL-33 expression in vitro and in the DFE-induced mouse model. These results suggest that RIP1 can be one of the mediators that regulate IL-33-mediated atopic skin inflammation by house dust mites.

Validation of Relationship between Patients' Descriptions of Pruritus and Patient-burden of Chronic Pruritus using Structural Equation Modelling.

Patients with chronic itch describe their pruritus in a wide variety of ways. However, these subjective descriptions are often not taken into consideration by physicians. This study aimed to validate patients' descriptions of pruritus, and to investigate the relationship between various descriptions of pruritus and the patient burden of chronic pruritus by examining the mediating effects of sleep disturbance and sexual dysfunction on patient's quality of life, as predicted by various descriptions of pruritus. Exploratory and confirmatory factor analyses were performed to identify the factor structure measured by 11 descriptions of pruritus. The study then analysed differences in the degree of sleep disturbance, sexual dysfunction, and quality of life deterioration factors using a structural equation modelling method. Using data from 419 patients with chronic pruritus, 11 descriptions of pruritus were classified into 2 groups: (i) sensory pruritus (i.e. stinging, stabbing, burning, painful, formication, throbbing, and cold) that are linked with descriptions of pruritus patterns; and (ii) affective pruritus (i.e. annoying, unbearable, worrisome, and warm) from patient reports of psychological or emotional distress. The study found that affective pruritus decreases patient's quality of life either directly or indirectly through sleep disturbance. In conclusion, clues about a patients' sleep disturbance or poor quality of life can be obtained through their descriptions of pruritus.

Cudraxanthone D Ameliorates Psoriasis-like Skin Inflammation in an Imiquimod-Induced Mouse Model via Inhibiting the Inflammatory Signaling Pathways.

Psoriasis is a chronic inflammatory skin disease accompanied by excessive keratinocyte proliferation. Corticosteroids, vitamin D3 analogs, and calcineurin inhibitors, which are used to treat psoriasis, have diverse adverse effects, whereas natural products are popular due to their high efficiency and relatively low toxicity. The roots of the Cudrania tricuspidata (C. tricuspidata) are known to have diverse pharmacological effects, among which the anti-inflammatory effect is reported as a potential therapeutic agent in skin cells. Nevertheless, its effectiveness against skin diseases, especially psoriasis, is not fully elucidated. Here, we investigated the effect of cudraxanthone D (CD), extracted from the roots the C. tricuspidata Bureau, on psoriasis using an imiquimod (IMQ)-induced mouse model and the tumor necrosis factor (TNF)-α/interferon (IFN)-γ-activated keratinocytes. IMQ was topically applied to the back skin of C57BL/6 mice for seven consecutive days, and the mice were orally administered with CD. This resulted in reduced psoriatic characteristics, such as the skin thickness and Psoriasis Area Severity Index score, and the infiltration of neutrophils in IMQ-induced skin. CD inhibited the serum levels of TNF-α, immunoglobulin G2a, and myeloperoxidase, and the expression of Th1/Th17 cells in splenocytes. In TNF-α/IFN-γ-activated keratinocytes, CD reduced the expressions of CCL17, IL-1ß, IL-6, and IL-8 by inhibiting the phosphorylation of STAT1 and the nuclear translocation of NF-kB. Taken together, these results suggest that CD could be a potential drug candidate for the treatment of psoriasis.

Validity and reliability of itch assessment scales for chronic pruritus in adults: A prospective multicenter study.

BACKGROUND: Several tools can provide a reliable and accurate evaluation of pruritus, including the visual analog scale (VAS), numeric rating scale (NRS), verbal rating scale (VRS), and multidimensional questionnaires such as the Itch Severity Scale (ISS). However, no single method is considered a gold standard. OBJECTIVE: We evaluated the validity and reliability of VAS, NRS, VRS, and ISS and their correlation with a pruritus-specific quality of life instrument, ItchyQoL. METHODS: A total of 419 patients (215 men and 204 women) with chronic pruritus (mean age, 46.58 years) recorded their pruritus intensity on VAS, NRS, VRS, and ISS. Retest reliability was analyzed in a second assessment 3 hours after the initial assessment. All participants answered ItchyQoL. RESULTS: A strong correlation between VAS, NRS, and VRS was found. ISS showed a low intercorrelation validity with these tools. However, ISS was more strongly correlated with ItchyQoL. The retest reliability scores were similar for VAS, NRS, and VRS but lower than the scores obtained for ISS. LIMITATIONS: Limitations include patient heterogeneity and recall bias. CONCLUSION: The assessment of pruritus is challenging because of the subjective symptoms and the multifactorial nature. Therefore, more studies are needed to determine the best strategy to assess itch intensity.

Long-Term Prognosis of Alopecia Totalis and Alopecia Universalis: A Longitudinal Study with More than 10 Years of Follow-Up: Better than Reported.

BACKGROUND: In alopecia totalis (AT) and alopecia universalis (AU), the chance of full hair regrowth is known to be less than 10%. However, this information is based on a few older studies conducted in the 1950s and 1960s. OBJECTIVE: We investigated the current long-term prognosis of individuals with AT/AU. METHODS: A retrospective chart review was performed in patients with AT/AU between 1994 and 2005. Outcome data were collected by reviewing outpatient clinical files or by phone interviews. Finally, the long-term assessment of 70 patients with valid outcome data was performed. RESULTS: Twelve out of 70 patients with AT/AU (17.1%) had complete hair regrowth. Five out of 24 patients with AT (20.8%) showed complete hair regrowth, and 7 of 46 patients with AU (15.2%) achieved complete regrowth. Seventeen out of 70 patients with AT/AU (24.2%) reported hair regrowth greater than or equal to 90%. Thirty patients with AU (65.2%) remained in an alopecic state without improvement, while 5 patients with AT (20.8%) showed no hair regrowth. CONCLUSION: Our results suggest that the long-term prognosis of AT/AU is more favorable than previously thought. However, the clinical burden of AT/AU is still substantial.

1,2,4,5-Tetramethoxybenzene Suppresses House Dust Mite-Induced Allergic Inflammation in BALB/c Mice.

BACKGROUND: Atopic dermatitis (AD) is the most common allergic inflammatory skin disease. The activation of innate immunity by house dust mite (Dermatophagoides farinae extract, DFE) allergen plays an important role in the pathogenesis of AD. We previously showed the inhibitory effect of an extract of Amomum xanthioides on allergic diseases, and isolated 1,2,4,5-tetramethoxybenzene (TMB) as a major active component. In this study, we investigated whether TMB relieves DFE-induced allergic inflammation symptoms. METHODS: We established a DFE-induced allergic inflammation model in BALB/c mice by repeated skin exposure to DFE. To define the underlying mechanisms of action, we used a tumor necrosis factor-α and interferon-x03B3;-activated human keratinocytes (HaCaT cell line) and mouse keratinocytes (3PC cell line) cell line model. RESULTS: Oral administration of TMB suppressed allergic inflammation symptoms, such as histopathological analysis and ear thickness, in addition to serum IgE, DFE-specific IgE and IgG2a levels. TMB decreased the serum histamine levels and tissue infiltration of inflammatory cells, including mast cells and eosinophils. TMB also inhibited CD4+IFN-x03B3;+, CD4+IL-4+, and CD4+IL-17A+ lymphocyte expansion in the draining lymph nodes and expression of the Th2 cytokines in the ear tissue. TMB significantly inhibited the expression of cytokines and chemokines by the downregulation of the mitogen-activated protein kinases and nuclear factor of activated cytoplasmic T cells in HaCaT cells. CONCLUSIONS: TMB improved DFE-induced allergic inflammation by suppressing the production of proinflammatory cytokines and chemokines. Our results suggest that TMB might be a potential therapeutic agent for AD.

Alopecia Areata Progression Index, a Scoring System for Evaluating Overall Hair Loss Activity in Alopecia Areata Patients with Pigmented Hair: A Development and Reliability Assessment.

BACKGROUND: No scoring systems to evaluate overall hair loss activity in alopecia areata (AA) have been established. OBJECTIVE: We sought to develop a measurement tool (Alopecia Areata Progression Index, AAPI) for the evaluation of overall hair loss activity in AA patients with pigmented hair. METHODS: The scalp surface area was divided into 4 quadrants. In each quadrant, hair loss activity was scored on the basis of the percentage of alopecic area, clinical findings associated with hair loss. The AAPI was measured in 17 patients with different severities of AA. RESULTS: Interobserver and intraobserver reliabilities were assessed by 4 investigators. A significant correlation of the total AAPI was found among the 4 investigators. In addition, intraobserver reliability was excellent, and interobserver reliability was statistically reliable. CONCLUSION: The AAPI seems to represent a system capable of truly quantifying overall hair loss activity in AA patients with different severity, demonstrating trustworthy interobserver and intraobserver reliability.

Skin Infection due to Trichophyton tonsurans Still Occurs in People in Korea but not as Outbreaks.

Since 1995, Trichophyton tonsurans has been one of the causative agents of dermatophytosis in Korea. Herein we evaluate 77 patients infected with T. tonsurans who visited an outpatient clinic between 2004 and 2014. Infections due to T. tonsurans were diagnosed by mycological examination, which included direct microscopic examination using 15% KOH and culture in potato dextrose agar complemented with 0.5% chloramphenicol. The annual prevalence of infection due to T. tonsurans was the highest in 2014 (15 cases) but remained constant in non-gladiators between 2004 and 2014. The ratio of male to female patients was 1:0.3. The spring season presented the highest incidence compared with other seasons, with 27 cases. The incidence of infections due to T. tonsurans among gladiators was highest in spring compared with the other seasons whereas the incidence in non-gladiators was the highest in the winter. The body site most commonly affected was the face. Tinea corporis was the most common subtype of dermatophytosis caused by T. tonsurans. Herein, we demonstrate that the prevalence of infection with T. tonsurans remain constant throughout the study period in Korea.

Fractional carbon dioxide laser-assisted photodynamic therapy for patients with actinic keratosis.

BACKGROUND/PURPOSE: A relatively long incubation time is needed for photosensitizer absorption in conventional photodynamic therapy (PDT) for actinic keratosis (AK). The use of ablative CO2 fractional lasers (AFXLs) to increase drug delivery could shorten the incubation time. Here, we aimed to compare the efficacy between AFXL-assisted PDT with a short incubation time and conventional PDT for AK. METHODS: Patients with histopathologically confirmed facial AK were randomly divided into two groups. The lesions were histopathologically classified into grades I-III. In the AFXL-assisted PDT group, an ablative fractional laser was used for pretreatment, prior to the application of methyl aminolevulinate, with an incubation time of 90 min. Irradiation was performed with a 630-nm light-emitting diode. In the conventional PDT group, the incubation time was 180 min. All the patients received two rounds of PDT at 2-week intervals and underwent clinical or histological evaluation at 10 weeks after the first PDT course. RESULTS: Twenty-two patients underwent conventional PDT and 24 patients underwent AFXL-assisted PDT. Thirty-four AKs were included in the conventional PDT group, and 35 AKs were included in the AFXL-assisted PDT group. The clearance rate was 64.7% in the conventional PDT and 71.4% in the AFXL-assisted PDT group; no significant differences in the clearance rate were noted between the groups (P = 0.55). The clearance rates for each grade also did not significantly differ between the two groups. CONCLUSIONS: The use of AFXL before PDT reduced the incubation time, but yielded similar treatment efficacy as compared to conventional PDT.

Increasing Prevalence of Trichophyton rubrum Identified through an Analysis of 115,846 Cases over the Last 37 Years.

Trichophyton rubrum is the most common dermatophyte in the world with the highest prevalence in Korea. There are few reports about epidemiological and mycological characteristics of T. rubrum based on long-term, large-scale studies. The purpose of this study was to investigate the clinical and epidemiological characteristics of T. rubrum infections in Korea. We retrospectively investigated with patients' records about the epidemiological and mycological status of 115,846 cases with T. rubrum infection that was mycologically diagnosed at Catholic Skin Disease Clinic from 1979 to 2013. Direct microscopy in 15% KOH solution and culture was done in each case. The annual incidence of patients with T. rubrum infection had been increasing during the period; and of 131,122 patients with dermatophytosis, 115,846 patients (88.35%) had T. rubrum infection. Disease was most prevalent among patients in their twenties in the 1970s and 1980s; in their thirties in the 1990s; in their forties in the 2000s; and in their fifties in the 2010s. The sex ratio was 1.5:1. T. rubrum infection was most commonly seen in summer and was found predominantly in patients living in urban areas. Toe webs were most frequently involved, followed by toenails and groin. This epidemiologic findings provide useful information for prevention of T. rubrum infection and future dermatophytosis prospects.

Ethanol Extract of Ampelopsis brevipedunculata Rhizomes Suppresses IgE-Mediated Mast Cell Activation and Anaphylaxis.

More than 20% of the world's population suffers from allergic diseases, including allergic asthma, rhinitis, and atopic dermatitis that severely reduce the patient's quality of life. The treatment of allergy has been developed, but there are still unmet needs. Ampelopsis brevipedunculata (Maxim.) Trautv. is a traditional medicinal herb with beneficial bioactivities, such as antioxidant, anti-hypertension, anti-viral, anti-mutagenic, and skin and liver (anti-hepatotoxic) protective actions. However, its anti-allergic effect has not been addressed. This study designed to investigate the pharmacological effect of an ethanol extract of A. brevipedunculata rhizomes (ABE) on mast cell and anaphylaxis models. For in vivo studies, we used ovalbumin-induced active systemic anaphylaxis (ASA) and immunoglobulin (Ig) E-mediated passive cutaneous anaphylaxis (PCA) models. In ASA model, oral administration of ABE (1, 10, and 100 mg/kg) attenuated the anaphylactic responses, such as hypothermia, serum histamine, and IgE productions. In PCA model, ABE also suppressed the plasma extravasation and swelling. The underlying mechanisms of action were identified in various mast cell types. In vitro, ABE (10, 30, and 60 µg/mL) inhibited the release of essential allergic mediators, such as histamine and ß-hexosaminidase, in a concentration-dependent manner. ABE prevented the rapid increase in intracellular calcium levels induced by the DNP-HSA challenge. In addition, ABE downregulated the tumor necrosis factor-α and interleukin-4 by suppressing the activation of nuclear factor-κB. Collectively, this study is the first to identify the anti-allergic effect of ABE, suggesting that ABE is a promising candidate for treating allergic diseases.