Genome-wide Association Study of Susceptibility Loci for Self-Reported Atopic Dermatitis and Allergic Rhinitis in the Korean Population.

BACKGROUND: Allergic diseases include atopic dermatitis (AD) and allergic rhinitis (AR), which are chronic, relapsing inflammatory disorders of the skin or mucosa that usually accompany immunoglobulin E-mediated immune responses. They are complex, multifactorial diseases with an etiology involving interactions between genetic and environmental factors. OBJECTIVE: We performed a genome-wide association study (GWAS) to identify single nucleotide polymorphisms (SNPs) associated with allergic diseases in the Korean population. METHODS: A total of 8,840 samples were obtained from the Korean Association Resource Consortium dataset of the Korean Genome and Epidemiology Study Ansan-Anseong cohort. The allergic disease phenotype was determined based on self-reported physician diagnoses. After quality control, 8,823 subjects with 877,242 variants remained for the final analysis. The GWAS was performed using logistic regression analysis in an additive model adjusted for age and sex. RESULTS: A total of 636 patients with allergic disease and 8,176 controls were analyzed. Three SNPs were associated with allergic disease at a level of genome-wide suggestive significance (p<1.0×10-5) in the Korean population: rs7275360, located in neural cell adhesion molecule 2; rs698195; and rs3750552, located in family with sequence similarity 189, member A2. These polymorphisms were on chromosomes 21q21.1, 7q31.1, and 9q21.12, respectively. CONCLUSION: We identified 3 novel SNPs significantly associated with allergic diseases in the Korean population. Further research is required to confirm the association between these novel SNPs and allergic disease in the Korean population and in other ethnicities.

Automated mass screening and association rules analysis for comorbidities of psoriasis: A population-based case-control study.

Patients with psoriasis frequently have comorbidities, which are linked to higher mortality rates. An in-depth investigation of comorbidities and their effects on health can help improve the management of patients with psoriasis. We conducted a comprehensive and unbiased investigation of comorbidities in patients with psoriasis and explored the pattern of association between comorbidities. A nationwide population-based study included 384 914 patients with psoriasis and 384 914 matched controls between 2011 and 2021. We used automated mass screening of all diagnostic codes to identify psoriasis-associated comorbidities and applied association rule analysis to explore the patterns of comorbidity associations in patients with psoriasis. Patients with psoriasis had an increased risk of autoimmunity-related diseases such as inflammatory arthritis, Crohn's disease, type 1 diabetes, and acute myocardial infarction. The comorbidities of patients with psoriasis with a history of cardiovascular events demonstrated strong interrelationships with other cardiovascular risk factors including type 2 diabetes mellitus, essential hypertension, and dyslipidemia. We also found comorbidities, such as malignant skin tumors and kidney and liver diseases, which could have adverse effects of anti-psoriasis therapy. In contrast, patients with psoriasis showed a decreased association with upper respiratory tract infection. Our results imply that comorbidities in patients with psoriasis are associated with the systemic inflammation of psoriasis and the detrimental effects of its treatment. Furthermore, we found patterns of associations between the cardiovascular risk factors and psoriasis. Mass screening and association analyses using large-scale databases can be used to investigate impartially the comorbidities of psoriasis and other diseases.

Association between cardio-cerebrovascular disease and systemic antipsoriatic therapy in psoriasis patients using population-based data: A nested case-control study.

The effect of antipsoriatic therapy on cardio-cerebrovascular disease (CCVD) is not well described. Thus, we performed a population-based nested case-control study to investigate the effect of systemic antipsoriatic therapy on CCVD in psoriasis patients. Using nationwide cohort data from the Korean National Health Insurance Claims database, newly diagnosed psoriasis patients were identified. Among the enrolled participants, postenrollment development of CCVD events (ischemic heart disease, myocardial infarction, cerebral infarction, and cerebral hemorrhage) was investigated. To evaluate the effect of systemic antipsoriatic therapy on CCVD risk, we calculated the proportion of the treatment period with systemic antipsoriatic therapy during the study period (PTP [%]: the sum of all systemic antipsoriatic therapy durations divided by total observation period). Among 251 813 participants, 6262 experienced CCVD events during the study period (CCVD group). Controls included 245 551 patients without CCVD history during the study period (non-CCVD group). The non-CCVD group had greater PTP than the CCVD group (CCVD 2.12 ± 7.92, non-CCVD 2.64 ± 9.64; P < 0.001). In multiple logistic regression analysis, PTP was inversely associated with the CCVD risk after adjusting for age, sex, diabetes, hypertension, and dyslipidemia. A 10% increase in PTP reduced CCVD risk by 0.96 (95% confidence interval 0.93 to 0.99). Reduced CCVD risk was robust for both conventional antipsoriatic therapy and biologics. Our study found that systemic antipsoriatic therapy use was inversely associated with CCVD risk in psoriasis patients. These findings suggested that systemic antipsoriatic therapy could reduce CCVD development in patients with psoriasis.

Automated Mass Screening for Comorbidities of Vitiligo Using the National Health Insurance Database.

Although the study design for identifying specific disease associations using a health insurance database has been well-established, few studies explore unknown comorbidities. We conducted a series of automated case-control studies for all International Classification of Disease, Tenth Revision, Clinical Modification diagnostic codes (A01-Z99) using the Korean National Health Insurance database from 2007 to 2017 to reveal undiscovered disease associations of vitiligo. A total of 90,297 patients with vitiligo and 90,297 age- and sex-matched controls without vitiligo were included, and disease associations for 1,265 relevant diagnostic codes were screened. A meta-analysis of the individual ORs for each International Classification of Disease, Tenth Revision code was performed to identify the possibility of selection bias. Finally, the association with vitiligo was significantly increased in 45 diseases and decreased in 6 diseases. We not only reaffirmed the positive correlation between vitiligo and other autoimmune diseases but also observed associations with obsessive-compulsive disorder and melanoma. In contrast, femur fracture showed a negative correlation. In this study, we attempted an automated mass screening and suggested a possible selection bias. In the era of large-scale databases, a systematic and comprehensive approach might be needed.

Risk of uveitis in patients with psoriasis in Korea: A nationwide population-based cohort study.

BACKGROUND: Evidence for the association between psoriasis and uveitis according to the severity of psoriasis including psoriatic arthritis (PsA) and type of uveitis is lacking, and there are no data on the frequency or timing of recurrence of uveitis in patients with psoriasis. OBJECTIVES: We aimed to evaluate the risk of first occurrence and recurrence of uveitis in patients with psoriasis in the Korean population. We further evaluated the risk of uveitis according to the severity of psoriasis, comorbidity of PsA and location of uveitis. METHODS: In a nationwide retrospective cohort study, we compared 317,940 adult patients who had psoriasis with 635,880 matched controls. Incidence rates (IRs) and estimated IR ratios of the first occurrence and recurrence of uveitis were calculated using survival analysis and Poisson regression, respectively. RESULTS: The rate of uveitis incidence and uveitis recurrence in patients with psoriasis was 1.18 and 2.31 per 1000 person-years, respectively. Compared to the controls, the IR ratios of development and recurrence of uveitis in patients with psoriasis were 1.14 (95% CI 1.08, 1.2) and 1.16 (95% CI 1.12, 1.21), respectively. The recurrence rate of uveitis was highest within 3 years after the onset of psoriasis. The corresponding IR ratios for uveitis recurrence in patients with mild psoriasis, severe psoriasis and PsA were 1.11 (1.06, 1.16), 1.24 (1.16, 1.33) and 1.49 (1.31, 1.7), respectively. Patients with psoriasis had an increased risk of recurrence of anterior uveitis, and patients with both psoriasis and PsA had an increased risk of recurrence of both anterior-uveitis and panuveitis. CONCLUSIONS: Patients with psoriasis had a higher risk of both development and recurrence of uveitis, especially with severe psoriasis and PsA. The timing of uveitis recurrence was related to the onset of psoriasis, and patients who had psoriasis with PsA had an increased risk of vision-threatening panuveitis.

Association between the cumulative dose of cyclosporine and liver enzyme abnormalities in dermatology patients managed with a low-dose regimen.

Cyclosporine (CsA) is an immunosuppressive agent that specifically inhibits T cell-related immune responses. There is little evidence regarding the association between low-dose CsA administration and abnormal hepatic function in dermatology patients. This study aimed to examine the association between the cumulative dose of CsA and liver enzyme abnormalities obtained from peripheral blood tests in patients with skin diseases. A retrospective single-center study of 697 patients who were prescribed CsA for skin disease in the outpatient dermatology clinic between 2015 and 2019 were performed. Multiple logistic regression with confounder adjustment was performed to assess the association between the cumulative dose of CsA and liver enzyme abnormalities. Compared to patients with the lowest cumulative dose of CsA (˂7.0 g), patients with the highest cumulative dose of CsA (≥30.6 g) were significantly associated with an increased likelihood of developing liver enzyme abnormalities (odds ratio [OR] = 1.96; 95% confidence interval [CI] = 1.02-3.79). In the stratified analysis, patients with the highest cumulative dose of CsA (≥30.6 g) were significantly associated with a 1.5-or higher alanine aminotransferase elevation from baseline (OR = 2.26, CI = 1.08-4.73). Patients prescribed long-term, low-dose CsA up to a high cumulative dose (≥30.6 g) may be associated with an increased risk of developing liver enzyme abnormalities. However, these liver enzyme elevations were not severe in magnitude and were reversible.

Azidothymidine Downregulates Insulin-Like Growth Factor-1 Induced Lipogenesis by Suppressing Mitochondrial Biogenesis and Mitophagy in Immortalized Human Sebocytes.

BACKGROUND: Increased sebum secretion is considered the main causative factor in the pathogenesis of acne. There is an unmet pharmacological need for a novel drug that can control sebum production with a favorable adverse effect profile. OBJECTIVE: To investigate the effect of azidothymidine on lipid synthesis in sebocytes and to identify the underlying mechanism of the inhibitory effect of azidothymidine on insulinlike growth factor (IGF)-1-induced lipid synthesis in sebocytes. METHODS: Immortalized human sebocytes were used for the analysis. Thin-layer chromatography (TLC) and Oil Red O staining were performed to evaluate lipid synthesis in the sebocytes. The differentiation, lipid synthesis, mitochondrial biogenesis, and mitophagy in sebocytes were investigated. RESULTS: TLC and Oil Red O staining revealed that azidothymidine reduced IGF-1 induced lipid synthesis in the immortalized human sebocytes. Azidothymidine also reduced IGF-1-induced expression of transcriptional factors and enzymes involved in sebocyte differentiation and lipid synthesis, respectively. Moreover, we found that IGF-1 upregulated the levels of peroxisome proliferator-activated receptorgamma coactivator-1α, LC-3B, p62, and Parkin, major regulators of mitochondrial biogenesis and mitophagy in immortalized human sebocytes. In contrast, azidothymidine inhibited IGF-1 induced mitochondrial biogenesis and mitophagy in the sebocytes. CONCLUSION: These results suggest that azidothymidine downregulates IGF-1-induced lipogenesis by dysregulating the quality of mitochondria through suppression of mitochondrial biogenesis and mitophagy in immortalized human sebocytes. Our study provides early evidence that azidothymidine may be an effective candidate for a new pharmacological agent for controlling lipogenesis in sebocytes.

Predictor of Subungual Melanoma against Benign Longitudinal Melanonychia: A Retrospective Cohort Study from Korea.

BACKGROUND: Longitudinal melanonychia (LM) is a common clinical finding. Most cases of LM are benign, and a wait-and-see approach is preferred in the management of this condition. Nevertheless, it is important for clinicians to distinguish subungual melanoma (SUM) from other benign LMs. OBJECTIVE: To evaluate the demographic and clinicopathologic characteristics of LM in the Korean population and to identify the predictor of SUM against other benign conditions. METHODS: This was a single-center retrospective cohort study including patients who underwent nail biopsy for LM from January 2000 to May 2019. To identify the predictor of SUM, receiver operating characteristic (ROC) analyses was performed. RESULTS: A total of 68 cases of biopsy-proven LM were included in the analysis. Among the 68 cases, 8 were SUM. In univariable analysis, patients diagnosed with SUM were older (p=0.035) and had a longer disease duration (p=0.004). They also showed multicolor pigmentation of LM (p=0.022), a larger width of LM (p<0.001), and associated nail plate dystrophy (p=0.010) than patients diagnosed with benign conditions. In multivariable logistic regression, width of LM showed statistical significance (odds ratio, 1.083; 95% confidence interval, 1.018~1.153). ROC analysis suggested that an LM width >28% of the whole nail was the predictor of SUM (area under the curve=0.883; p<0.001). CONCLUSION: SUM has distinct demographic and clinical features. The width of LM can predict SUM against other benign LMs.

Persistent expression of interleukin-17 and downstream effector cytokines in recalcitrant psoriatic lesions after ustekinumab treatment.

The interleukin (IL)-23/T-helper (Th)17 axis is considered central to the pathogenesis of psoriasis, with IL-36γ considered a marker for histological differential diagnosis. However, expression data regarding key cytokines in the pathogenesis of psoriasis, as well as data on the effects of IL-23 inhibition on downstream cytokines in human psoriatic skin, are limited. We investigated the expression profile of key cytokines and the effect of ustekinumab (UST) on cytokine expression in human psoriatic tissue. Tumor necrosis factor (TNF)-α, IL-23, IL-17A, and IL-22 were highly expressed in the epidermis, dermal papillae, and upper dermis in patients with psoriasis compared with controls; IL-36γ was strongly expressed in the upper epidermis. Compared with the untreated group, expression intensity and area of IL-23 were significantly decreased in the UST group; expression areas of TNF-α, IL-17A, IL-22, and IL-36γ did not differ. This study identified the distribution and quantitative expression levels of key cytokines in psoriatic lesions and demonstrated that only IL-23 was downregulated without blocking downstream effector cytokines in recalcitrant psoriatic lesions during UST treatment. Our results suggest that, although IL-23 is inhibited, the persistent expression of IL-17 through an alternative pathway maintains the vicious cycle of the TNF-α/IL-23/IL-17 axis with IL-36γ, inducing refractory psoriatic lesions in patients with well-controlled psoriasis.

The long-term risk of lymphoma and skin cancer did not increase after topical calcineurin inhibitor use and phototherapy in a cohort of 25,694 patients with vitiligo.

BACKGROUND: Topical calcineurin inhibitors have been used to treat vitiligo, either alone or in combination with phototherapy; however, the long-term safety of these agents remains controversial. OBJECTIVE: To investigate the risk of lymphoma and skin cancer in vitiligo patients who received topical calcineurin inhibitors or phototherapy. METHODS: A multicenter retrospective cohort study of 25,694 vitiligo patients who received topical calcineurin inhibitors or phototherapy for 6 weeks or more between 2001 and 2019 was performed. Cumulative doses of topical calcineurin inhibitors and total phototherapy sessions were determined. Outcomes were the development of lymphoma or skin cancer after enrollment, confirmed through chart review and pathology reports. RESULTS: During 95,203 person-years, 13 cases of lymphoma, 22 of actinic keratosis, 15 of nonmelanoma skin cancer, and 5 of melanoma were observed. The risk of lymphoma and skin cancer was not significantly increased by topical calcineurin inhibitor dose or phototherapy sessions. The interaction between the topical calcineurin inhibitors and phototherapy was not associated with an increased risk of skin cancer. LIMITATIONS: Retrospective study, individual follow-up duration less than 4 years, and no adjustment for comorbidities and medication history. Not generalizable to other races. CONCLUSION: The long-term risk of skin cancer or lymphoma was not associated with the use of topical calcineurin inhibitors, phototherapy, and both treatments in combination in patients with vitiligo.

Development of evidence-based consensus on critical issues in the management of patients with vitiligo: A modified Delphi study.

BACKGROUND/PURPOSE: Vitiligo remains a major challenge in dermatology. However, much of the treatment remains unclear, because little evidence is available. We sought to answer some critical questions pertaining to management of vitiligo patients. METHODS: A modified Delphi process among 31 vitiligo experts was conducted. A total of 12 clinical vitiligo treatment questions without clear answers were collected via a vote. To address each question, two members performed systematic literature reviews and prepared draft statements along with the levels of evidence and strength of recommendation. After reviewing the draft, all expressed their extent of agreement from 1 (strong disagreement) to 9 (strong agreement) for each item. The drafts were revised to reflect suggested comments. Discussion continued until all members agreed with the ultimate decision. RESULTS: The consensus process was completed after five rounds. We identified the best answers to 12 key questions, including issues on long-term phototherapy, systemic and topical corticosteroids, topical calcineurin inhibitors, immunosuppressants, excimer laser treatment, and surgical interventions. CONCLUSION: This consensus would complement current guidelines and aid both physician and patient decision-making in the treatment of vitiligo.

Infection, antibiotic exposure and development of atopic dermatitis: A nationwide case-control study.

Previous studies suggest an association between atopic dermatitis (AD) and exposure to microorganisms and antibiotics. However, these studies have limitations, and the sole influence on the development of AD was elusive. We performed a nationwide population-based case-control study in a Korean population to investigate the association between AD and early-life infection or antibiotic exposure. A total of 244 805 children with AD from the 2 283 601 children born between January 2010 and December 2014 and an equal number of sex- and age-matched healthy children were enrolled. A conditional logistic regression analysis showed that the episode of infection and antibiotic exposure were associated with an increased risk of AD (odds ratio [OR], 1.60; 95% confidence interval [CI], 1.58-1.63 for infection; and OR, 1.11; 95% CI, 1.09-1.13 for antibiotic exposure). A dose-dependent relationship was observed between risk for AD, the number of infection episodes and antibiotic cycles and the duration of antibiotic exposure. On further analysis using a conditional logistic model, the risk of AD was less when the antibiotics were used during the infection episode than that without the use of antibiotics, especially if the duration of the infection was short. Although our study could not consider the effect of cause or severity of infection, class of antibiotics and genetic or environmental factors of enrolled subjects, our results suggested that infection and antibiotic exposure were associated with an increased risk of AD. In addition, the results also implied that the use of antibiotics during an infection episode can decrease the risk of AD induced by the infection and that appropriate management of infections can minimize the risk of AD induced by infection or antibiotics.

Deficiency of Crif1 in hair follicle stem cells retards hair growth cycle in adult mice.

Hair growth is the cyclically regulated process that is characterized by growing phase (anagen), regression phase (catagen) and resting phase (telogen). Hair follicle stem cells (HFSCs) play pivotal role in the control of hair growth cycle. It has been notified that stem cells have the distinguished metabolic signature compared to differentiated cells, such as the preference to glycolysis rather than mitochondrial respiration. Crif1 is a mitochondrial protein that regulates the synthesis and insertion of oxidative phosphorylation (OXPHOS) polypeptides to inner membrane of mitochondria. Several studies demonstrate that tissue-specific knockout of Crif1 leads to mitochondrial dysfunction. In this study, we investigated the effect of mitochondrial dysfunction in terms of Crif1 deficiency on the hair growth cycle of adult mice. We created two kinds of inducible conditional knockout (icKO) mice. In epidermal specific icKO mice (Crif1 K14icKO), hair growth cycle was significantly retarded compared to wild type mice. Similarly, HFSC specific icKO mice (Crif1 K15icKO) showed significant retardation of hair growth cycle in depilation-induced anagen model. Interestingly, flow cytometry revealed that HFSC populations were maintained in Crif1 K15icKO mice. These results suggest that mitochondrial function in HFSCs is important for the progression of hair growth cycle, but not for maintenance of HFSCs.

Evaluation for Skin Cancer and Precancer in Patients With Vitiligo Treated With Long-term Narrowband UV-B Phototherapy.

Importance: Narrowband UV-B (NBUVB) phototherapy has been the mainstay in the treatment of vitiligo, but its long-term safety in terms of photocarcinogenesis has not been established. Objectives: To investigate the risks of skin cancer and precancerous lesions among patients with vitiligo undergoing NBUVB phototherapy, based on the number of NBUVB phototherapy sessions. Design, Setting, and Participants: This nationwide population-based retrospective cohort study enrolled 60 321 patients with vitiligo 20 years or older between January 1, 2007, and December 31, 2017. Patients and outcomes were identified through nationwide cohort data from the Korean national health insurance claims database, and frequency matching by age and sex was performed. Exposures: The number of phototherapy sessions each patient received between 2008 and 2017. Patients were classified into 5 groups according to the number of phototherapy sessions (0 sessions, 20 105 patients; 1-49 sessions, 20 106 patients; 50-99 sessions, 9702 patients; 100-199 sessions, 6226 patients; and ≥200 sessions, 4182 patients). We also identifed patients who underwent at least 500 phototherapy sessions (717 patients). Main Outcomes and Measures: Primary outcomes were the development of actinic keratosis, Bowen disease, nonmelanoma skin cancer, or melanoma after enrollment. Results: Among the 60 321 patients with vitiligo in this study (33 617 women; mean [SD] age, 50.2 [14.9] years), the risks of Bowen disease (<50 sessions of phototherapy: hazard ratio [HR], 0.289 [95% CI, 0.060-1.392]; 50-99 sessions: HR, 0.603 [95% CI, 0.125-2.904]; 100-199 sessions: HR, 1.273 [95% CI, 0.329-4.924]; ≥200 sessions: HR, 1.021 [95% CI, 0.212-4.919]), nonmelanoma skin cancer (<50 sessions: HR, 0.914 [95% CI, 0.533-1.567]; 50-99 sessions: HR, 0.765 [95% CI, 0.372-1.576]; 100-199 sessions: HR, 0.960 [95% CI, 0.453-2.034]; ≥200 sessions: HR, 0.905 [95% CI, 0.395-2.073]), and melanoma (<50 sessions: HR, 0.660 [95% CI, 0.286-1.526]; 50-99 sessions: HR, 0.907 [95% CI, 0.348-2.362]; 100-199 sessions: HR, 0.648 [95% CI, 0.186-2.255]; ≥200 sessions: HR, 0.539 [95% CI, 0.122-2.374]) did not increase after phototherapy. The risk of actinic keratosis increased significantly for those who had undergone 200 or more NBUVB phototherapy sessions (HR, 2.269 [95% CI, 1.530-3.365]). A total of 717 patients with vitiligo underwent at least 500 sessions of NBUVB phototherapy; their risks of nonmelanoma skin cancer and melanoma were no greater than those of the patients who did not undergo NBUVB phototherapy (nonmelanoma skin cancer: HR, 0.563 [95% CI, 0.076-4.142]; melanoma: HR, not applicable). Conclusions and Relevance: Our results suggest that long-term NBUVB phototherapy is not associated with an increased risk of skin cancer in patients with vitiligo and that NBUVB phototherapy may be considered a safe treatment.

Predictive Model for Differential Diagnosis of Inflammatory Papular Dermatoses of the Face.

BACKGROUND: The clinical features of inflammatory papular dermatoses of the face are very similar. Their clinical manifestations have been described on the basis of a small number of case reports and are not specific. OBJECTIVE: This study aimed to use computer-aided image analysis (CAIA) to compare the clinical features and parameters of inflammatory papular dermatoses of the face and to develop a formalized diagnostic algorithm based on the significant findings. METHODS: The study included clinicopathologically confirmed inflammatory papular dermatoses of the face: 8 cases of eosinophilic pustular folliculitis (EPF), 13 of granulomatous periorificial dermatitis-lupus miliaris disseminatus faciei (GPD-LMDF) complex, 41 of granulomatous rosacea-papulopustular rosacea complex (GR-PPR) complex, and 4 of folliculitis. Clinical features were evaluated, and area density of papular lesions was quantitatively measured with CAIA. Based on these variables, we developed a predictive model for differential diagnosis using classification and regression tree analysis. RESULTS: The EPF group showed lesion asymmetry and annular clusters of papules in all cases. The GPD-LMDF complex group had significantly higher periocular density. The GR-PPR complex group showed a higher area density of unilateral cheek papules and the highest total area density. According to the predictive model, 3 variables were used for differential diagnosis of the 4 disease groups, and each group was diagnosed with a predicted probability of 67%~100%. CONCLUSION: We statistically confirmed the distinct clinical features of inflammatory papular dermatoses of the face and proposed a diagnostic algorithm for clinical diagnosis.