TLR7-dependent eosinophil degranulation links psoriatic skin inflammation to small intestinal inflammatory changes in mice.

Recent evidence of gut microbiota dysbiosis in the context of psoriasis and the increased cooccurrence of inflammatory bowel disease and psoriasis suggest a close relationship between skin and gut immune responses. Using a mouse model of psoriasis induced by the Toll-like receptor (TLR) 7 ligand imiquimod, we found that psoriatic dermatitis was accompanied by inflammatory changes in the small intestine associated with eosinophil degranulation, which impaired intestinal barrier integrity. Inflammatory responses in the skin and small intestine were increased in mice prone to eosinophil degranulation. Caco-2 human intestinal epithelial cells were treated with media containing eosinophil granule proteins and exhibited signs of inflammation and damage. Imiquimod-induced skin and intestinal changes were attenuated in eosinophil-deficient mice, and this attenuation was counteracted by the transfer of eosinophils. Imiquimod levels and the distribution of eosinophils were positively correlated in the intestine. TLR7-deficient mice did not exhibit intestinal eosinophil degranulation but did exhibit attenuated inflammation in the skin and small intestine following imiquimod administration. These results suggest that TLR7-dependent bidirectional skin-to-gut communication occurs in psoriatic inflammation and that inflammatory changes in the intestine can accelerate psoriasis.

Analysis of Positive Patch Test Allergens in Allergic Contact Dermatitis Patients with Atopic Dermatitis.

BACKGROUND: There has been debate regarding whether patients with atopic dermatitis (AD) have an altered frequency of contact allergen sensitization. Increased exposure to topical medications and moisturizers as well as impaired skin barrier function increase the risk of contact sensitization, whereas the Th2-skewed inflammatory pathway of AD is associated with a reduced risk. OBJECTIVE: This retrospective study was performed to determine the characteristics of contact sensitization in allergic contact dermatitis (ACD) patients with a current or past history of AD. METHODS: A clinical record review was conducted for patients referred to Ewha Womans University Medical Center, for patch tests between March 2017 and March 2021. We compared the rates of contact sensitization between ACD patients with and without AD. RESULTS: In total, 515 patch test results were reviewed and divided into the AD group (n=53) and non-AD group (n=462). The AD group showed decreased any-allergen positivity (1+, 2+, or 3+) (56.6%) compared to the non-AD group (72.9%) (p=0.013). The positivity rate for budesonide was significantly higher in the AD group (p=0.011), while the prevalence of a positive result for balsam of Peru was higher in the non-AD group (p=0.036). Nickel sulfate, cobalt chloride, and potassium dichromate were the most common sensitized allergens in both groups. CONCLUSION: Our study shows a decreased prevalence of contact sensitization in AD patients compared to non-AD patients. Clinicians should be aware of the risk of corticosteroid allergies in ACD patients with history of AD.

Erratum: Assessment of Disease Severity and Quality of Life in Patients with Atopic Dermatitis from South Korea.

This corrects the article on p. 419 in vol. 34, PMID: 36478424.

Oncogenic signaling pathways and hallmarks of cancer in Korean patients with acral melanoma.

Acral melanoma (AM), a rare subtype of cutaneous melanoma, shows higher incidence in Asians, including Koreans, than in Caucasians. However, the genetic modification associated with AM in Koreans is not well known and has not been comprehensively investigated in terms of oncogenic signaling, and hallmarks of cancer. We performed whole-exome and RNA sequencing for Korean patients with AM and acquired the genetic alterations and gene expression profiles. KIT alterations (previously known to be recurrent alterations in AM) and CDK4/CCND1 copy number amplifications were identified in the patients. Genetic and transcriptomic alterations in patients with AM were functionally converge to the hallmarks of cancer and oncogenic pathways, including 'proliferative signal persistence', 'apoptotic resistance', and 'activation of invasion and metastasis', despite the heterogeneous somatic mutation profiles of Korean patients with AM. This study may provide a molecular understanding for therapeutic strategy for AM.

Assessment of Disease Severity and Quality of Life in Patients with Atopic Dermatitis from South Korea.

BACKGROUND: Data illustrating the impact of atopic dermatitis (AD) on lives of adults with AD in South Korea are limited. OBJECTIVE: To assess the AD disease severity and its impact on quality of life (QoL) in patients with AD from South Korea. METHODS: Patients with AD utilizing the specialist dermatology services of major hospitals in South Korea were assessed for disease severity using Eczema Area and Severity Index (EASI) score, for QoL using Dermatology Life Quality Index (DLQI) (for QoL), and for comorbidities and treatment experience via retrospective review of 12-month medical records. Clinical and sociodemographic characteristics were also measured. RESULTS: Of the 1,163 patients, 695 (59.8%) were men (mean age [years]±standard deviation: 31.6±12.1). Overall, 52.9% (n=615) patients had moderate-to-severe disease (EASI>7). The QoL of 72.3% (n=840) patients was affected moderately-to-severely (DLQI score: 6~30). Systemic immunosuppressants were used ≥1 over past 12 months in 51.9% (n=603) patients, and the most commonly used were cyclosporines (45.7%, n=531) and systemic corticosteroids (40.5%, n=471). Approximately, 10.8% (n=126) patients consulted or received treatment for AD-related eye problem. Of these, 40% (n=50) patients reported poor, very poor, or completely blind status; approximately, 16.7% patients (n=192) reported having depression or anxiety; and 35.5% (n=410) reported suicidal ideation or suicidal attempt. CONCLUSION: A large proportion of patients had moderate-to-severe AD, a compromised QoL, and ocular or mental health comorbidities, indicating a high disease burden despite systemic treatment. These findings highlight the importance of a holistic approach for the evaluation and treatment of patients with AD.

Differences in Clinical Responses to Ustekinumab Treatment among Body Regions: Results from a Real-World Prospective, Observational, and Multi-Center Study in Korea.

BACKGROUND: In psoriasis treatment, not all body regions improve simultaneously after clinical interventions. OBJECTIVE: This study was aimed at evaluating clinical responses across body regions, which may differentially influence patient treatment plans. METHODS: This prospective, observational, and multi-center study was conducted in Koreans who adhered to ustekinumab treatment based on criteria per local label and reimbursement guidelines. A total of 581 were included in this analysis. RESULTS: The mean (±standard deviation) psoriasis area severity index (PASI) score at baseline, age, disease duration, and body surface area (%) were 18.9±9.69, 44.2±13.29 years, 11.3±9.65 years, and 27.8±17.83, respectively. Across the head and neck, upper extremities, trunk, and lower extremities, the correlation between the PASI sub-scores for the upper and lower extremities was the highest (r=0.680). The mean PASI sub-score for the lower extremities was the highest at baseline. PASI90 and PASI100 scores were the highest for the head and neck region, indicating the highest response rates, while those for the lower extremities were consistently low at all visits. CONCLUSION: We found differences in regional ustekinumab responses, with the lower extremities being the most difficult to treat. These findings should be considered in psoriasis treatment.

Efficacy and safety of guselkumab compared with placebo and adalimumab in Korean patients with moderate-to-severe psoriasis: post-hoc analysis from the phase III, double-blind, placebo- and active-comparator-controlled VOYAGE 1/2 trials.

BACKGROUND: The phase 3 studies, VOYAGE 1 and 2, were conducted to assess guselkumab in the treatment of patients with moderate-to-severe psoriasis. OBJECTIVES: To investigate the efficacy and safety of guselkumab in Korean patients. METHODS: The Korean sub-population of VOYAGE 1 and 2 study patients were included in this analysis. Efficacy and safety were evaluated through Weeks 24 and 28, respectively. RESULTS: Of 126 randomized Korean patients, 30, 63, and 33 received placebo, guselkumab, and adalimumab, respectively. At Week 16, guselkumab was superior to placebo in achieving an Investigator's Global Assessment (IGA) score of 0 or 1 (cleared or minimal; 90.5 vs. 20.0%, p<.001) and a Psoriasis Area and Severity Index (PASI) 90 response (71.4 vs. 3.3%, p<.001). At week 24, a significantly higher proportion of guselkumab-treated patients achieved PASI 75 and IGA 0 (clear skin) responses compared to adalimumab-treated patients (PASI 75: 93.7 vs. 66.7%, p<.001; IGA 0: 52.4 vs. 21.2%, p=.004). Through Week 28, guselkumab and adalimumab showed comparable safety profiles. CONCLUSION: The efficacy and safety of guselkumab in Korean psoriasis patients through 28 weeks were consistent with findings for the overall VOYAGE 1 and 2 study population.

Consensus Update for Systemic Treatment of Atopic Dermatitis.

BACKGROUND: In 2015, the Korean Atopic Dermatitis Association (KADA) working group published consensus guidelines for treating atopic dermatitis (AD). OBJECTIVE: We aimed to provide updated consensus recommendations for systemic treatment of AD in South Korea based on recent evidence and experience. METHODS: We compiled a database of references from relevant systematic reviews and guidelines on the systemic management of AD. Evidence for each statement was graded and classified based on thestrength of the recommendation. Forty-two council members from the KADA participated in three rounds of voting to establish a consensus on expert recommendations. RESULTS: We do not recommend long-term treatment with systemic steroids forpatients with moderate-to-severe AD due to the risk of adverse effects. We recommend treatment with cyclosporine or dupilumab and selective treatment with methotrexate or azathioprine for patients with moderate-to-severe AD. We suggest treatment with antihistamines as an option for alleviating clinical symptoms of AD. We recommend selective treatment with narrowband ultraviolet B for patients with chronic moderate-to-severe AD. We do not recommend treatment with oral antibiotics for patients with moderate-to-severe AD but who have no signs of infection. We did not reach a consensus on recommendations for treatment with allergen-specific immunotherapy, probiotics, evening primrose oil, orvitamin D for patients with moderate-to-severe AD. We also recommend educational interventions and counselling for patients with AD and caregivers to improve the treatment success rate. CONCLUSION: We look forward to implementing a new and updated consensus of systemic therapy in controlling patients with moderate-to-severe AD.

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.

Expression pattern of tissue-resident memory T cells in cutaneous lupus erythematosus.

BACKGROUND: Tissue resident memory T cells (TRMs) persist long-term in peripheral tissues without recirculation, triggering an immediate protective inflammatory state upon the re-recognition of the antigen. Despite evidence incriminating the dysregulation of TRMs in autoimmune diseases, few studies have examined their expression in cutaneous lupus erythematosus (CLE). OBJECTIVES: We aimed to examine whether there are differences among TRM populations in CLE depending on different clinical conditions, such as the CLE subtype or association with systemic lupus erythematosus, and to determine the effect of type I interferon (IFN) on the development of TRMs in CLE. METHODS: CLE disease activity was evaluated using the Cutaneous Lupus Erythematosus Disease Area and Severity Index. The expression of the TRM markers CD69 and CD103 in CLE lesions was evaluated by immunofluorescence. Flow cytometry was performed on peripheral blood mononuclear cells after IFNα treatment. RESULTS: The number of TRMs expressing either CD69 or CD103 was significantly higher in CLE lesions than in control skin; however, it was not significantly different between discoid lupus erythematosus and subacute CLE, or dependent on the presence of concomitant systemic lupus. Lesional severity was not correlated with an increase in TRMs in CLE. IFNα treatment induced a conspicuous increase in CD69 expression in skin-homing T cells, more profoundly in CD4+ T cells than in CD8+ T cells. CONCLUSIONS: Skin TRMs, either CD69 or CD103-positive cells, showed increased levels in the lesional skin of CLE, and IFNα increased the expression of CD69 in T cells.

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.

The KAAACI/KDA Evidence-Based Practice Guidelines for Chronic Spontaneous Urticaria in Korean Adults and Children: Part 2. Management of H1-Antihistamine-Refractory Chronic Urticaria.

Quite a few patients with chronic spontaneous urticaria (CSU) are refractory to H1-antihistamines, even though the dose of H1-antihistamines is increased up to 4-fold. CSU that is not controlled with H1-antihistamines results in increased disease burden. Several immunomodulators have been used to manage these patients. The guidelines reported herein are connected to Part 1 of the KAAACI/KDA Evidence-Based Practice Guidelines for Chronic Spontaneous Urticaria in Korean Adults and Children, and aimed to provide evidence-based recommendations for the management of H1-antihistamine-refractory CSU. Part 2 focuses on the more commonly used additional treatment options for refractory CSU, including omalizumab, cyclosporine, leukotriene receptor antagonist, dapsone, methotrexate, and phototherapy. The evidence to support their efficacy, dosing, safety, and selection of these agents is systematically reviewed. To date, for patients with refractory CSU, the methodologically sound data to evaluate the use of omalizumab has been growing; however, the evidence of other immunomodulators and phototherapy is still insufficient. Therefore, an individualized stepwise approach with a goal of achieving complete symptom control and minimizing side effects can be recommended. Larger controlled studies are needed to elevate the level of evidence to select a rational therapeutic agent for patients with refractory CSU.

The KAAACI/KDA Evidence-Based Practice Guidelines for Chronic Spontaneous Urticaria in Korean Adults and Children: Part 1. Definition, Methodology and First-line Management.

Chronic spontaneous urticaria (CSU) is defined as the occurrence of spontaneous wheals, angioedema, or both for >6 weeks in the absence of specific causes. It is a common condition associated with substantial disease burden both for affected individuals and societies in many countries, including Korea. CSU frequently persists for several years and requires high-intensity treatment; therefore, patients experience deteriorations in quality of life and medication-associated complications. During the last decade, there have been major advances in the pharmacological treatment of CSU and there is an outstanding need for evidence-based guidelines that reflect clinical practice in Korea. The guidelines reported here represent a joint initiative of the Korean Academy of Asthma, Allergy and Clinical Immunology and the Korean Dermatological Association, and aim to provide evidence-based guidance for the management of CSU in Korean adults and children. In Part 1, disease definition, guideline scope and development methodology as well as evidence-based recommendations on the use of antihistamines and corticosteroids are summarized.

Development and clinical study of the use of infrared radiation to accelerate the dissolution rate of a microneedle array patch (MAP).

The dissolution rate of a microneedle array patch (MAP) determines how long a MAP must remain attached to the skin (often called "wear time"). In this study, the dissolution rate of a MAP was increased, not by changing the drug formulation but by employing an infrared (IR) device that is widely used for hospital treatment and in-home therapy. A MAP with microneedles 480 µm in height was prepared using hyaluronic acid (HA). Changes in transepidermal water loss (TEWL), the surface temperature of the skin, and the dissolution rate of the MAP tips with IR irradiation were evaluated on human skin in vivo. Time for recovery from erythema that occurred after MAP attachment and IR irradiation was also evaluated. TEWL increased more than fourfold with IR irradiation. Water that evaporated as a result of IR irradiation was trapped in the skin layer by the patch, resulting in the increased dissolution rate of the MAP tips. After 10 min of IR irradiation, the height of the dissolving tips compared with their initial height increased from 41 to 56%, and the dissolved volume of the tips compared with their initial volume increased from 7 to 18%. During the 10 min of irradiation, the skin surface temperature rose from 32 to 40 °C. Erythema occurred in the early stage of treatment with IR irradiation and MAP attachment, but it abated within 2 h after removal of the MAP and cessation of IR irradiation. Through this study, it was possible to shorten the administration time of MAPs by using an IR device that could be easily accessed. This method can be applied to various types of MAPs in order to reduce the time that the MAPs must remain attached to the skin without changing the drug formulation. Graphical abstract The increase in dissolution rate of dissolving microneedle array patch (MAP) as a result of infrared radiation. a Water-soluble tips of MAP dissolved in water in skin without infrared irradiation. Dotted line indicates the initial dissolving microneedles. b Water in skin and subcutaneous layer evaporated actively with infrared irradiation and was stored under patch of MAP. Increased amount of water in skin induced faster dissolution of MAP tips.

Cutaneous lupus erythematosus and its association with systemic lupus erythematosus: A nationwide population-based cohort study in Korea.

Although lupus erythematosus is known to be more common among women of color, the study populations in previous reports were predominantly Caucasian and there is scarce information on Asian patients. Therefore, we performed a retrospective study using a nationwide population-based cohort in South Korea. The average annual incidence of cutaneous lupus was 4.36/100 000. Among 634 patients with cutaneous lupus, 20.8% had systemic disease: cutaneous lupus was diagnosed before systemic lupus in 4.26% and after systemic lupus in 8.52%. More female patients than male patients developed systemic lupus erythematosus. The average time to progression to systemic lupus was 1.53 ± 1.46 years.

Reducing Radiation Dermatitis Using a Film-forming Silicone Gel During Breast Radiotherapy: A Pilot Randomized-controlled Trial.

BACKGROUND/AIM: To evaluate whether topical use of a film-forming silicone gel (StrataXRT®) could reduce radiation dermatitis compared to a moisturizing cream (X-derm®) in patients receiving whole breast radiotherapy. PATIENTS AND METHODS: A total of 56 patients with breast cancer were randomized to use StrataXRT or X-derm. The severity of radiation dermatitis was graded using physiological skin parameters, clinician-assessed visual rating scales and patient-reported symptoms. Changes in these parameters from baseline to 4 weeks post-radiotherapy were evaluated every two weeks. RESULTS: Two-way repeated-measures ANOVA revealed different patterns of changes in the erythema index (F=3.609, p=0.008) and melanin index (F=3.475, p=0.015). The post hoc analysis demonstrated a significantly lower erythema index and melanin index in the patients allocated to the StrataXRT group. CONCLUSION: The use of StrataXRT can reduce radiation dermatitis with respect to objectively measured physiological skin parameters. The results of the present study will support the feasibility of conducting a larger randomized controlled trial.