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.

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.

KLF4 suppresses the tumor activity of cutaneous squamous cell carcinoma (SCC) cells via the regulation of SMAD signaling and SOX2 expression.

Kruppel-like factor 4 (KLF4) is a zinc-finger transcription factor that plays a role in terminal differentiation of epidermal keratinocytes. There are conflicting reports regarding the role of KLF4 in tumor development, with both the tumor suppressive and/or oncogenic properties depending on different conditions and cell types. In this study, we investigated the functional importance of KLF4 in cutaneous squamous cell carcinoma (SCC). Immunohistochemistry showed that KLF4 expression was relatively low in SCC lesion compared to normal epidermis. To examine the effects of KFL4, we transduced SCC lines (SCC12 and SCC13 cells) with the KLF4-expressing recombinant adenovirus. Overexpression of KLF4 significantly decreased cell proliferation and colony forming activity. In addition, overexpression of KLF4 markedly reduced invasive potential, along with the downregulation of epithelial-mesenchymal transition (EMT)-related molecules. In a mechanistic study, KLF4 inhibited SOX2, of which expression is critical for tumor initiation and growth of SCC. Further investigations indicated that SOX2 expression is induced by TGF-ß/SMAD signaling, and that overexpression of KLF4 inhibited SMAD signaling via upregulation of SMAD7, an important inhibitory SMAD molecule. Based on these data, KLF4 plays a tumor suppressive role in cutaneous SCC cells.

Enhancement of lipid content and inflammatory cytokine secretion in SZ95 sebocytes by palmitic acid suggests a potential link between free fatty acids and acne aggravation.

A relationship between acne and free fatty acids (FFAs) has been suggested recently. However, the effects of FFAs on sebaceous glands are still largely unknown. At the same time, the role of FFAs during chronic inflammation is well established. Considering that FFAs are also a major component of sebum, it is likely that changes in FFA affect both the synthesis of sebum and the inflammatory response in sebaceous glands. In this study, we examined a hypothesis that FFAs increase the production of sebum and induce inflammation in the sebaceous glands. We found that treatment of SZ95 sebocytes with exogenously applied palmitic acid (PA), a major saturated FFA, induced a significant increase in intracellular lipid levels. Moreover, PA treatment also increased the expression and secretion of the proinflammatory cytokines in SZ95 sebocytes. We also found that Toll-like receptors were required for the inflammatory response triggered by PA. The results of our study strengthen the notion about the link between acne and FFAs and suggest the mechanism underlying this relationship. Our results serve as a foundation for future work that will explore the association between FFA and acne and pave way to the development of novel treatment options for acne.

Focal adhesion kinase and Src expression in premalignant and malignant skin lesions.

Focal adhesion kinase (FAK) and Src are non-receptor tyrosine kinases. FAK and Src play a critical role in inducing malignant transformation in tumor cells. We performed immunohistochemical staining for total and phosphorylated forms of FAK and Src, to evaluate the role of FAK and Src in the development of premalignant and malignant skin lesions. A total of 59 facial skin samples (30 actinic keratoses, 10 Bowen's diseases, 13 squamous cell carcinomas and six perilesional skins) were immunohistochemically stained for Ki-67, total (t) and phosphorylated (p) form of FAK and Src. Cells positive for t-Src, p-Src-y530, t-FAK and pFAK-s722 were detected in premalignant intra-epithelial lesions (PELs) and squamous cell carcinomas (SCCs), but not in the perilesional skin. There was a tendency towards high correlation between Ki-67 and t-FAK or pFAK-s722, suggestive of the active role of FAK in cell proliferation. However, our findings of higher t-Src and p-Src-y530 positive cells in PELs, as compared to SCCs (with higher Ki-67 level), are suggestive of the other role of Src in tumor formation and progression, which requires further investigation.

Beneficial effects of early treatment of nevus of Ota with low-fluence 1,064-nm Q-switched Nd:YAG laser.

BACKGROUND: Childhood nevus of Ota is likely to be more superficial than the adult nevus, therefore early laser treatment of nevus of Ota might have some beneficial effects in children. OBJECTIVE: To evaluate the beneficial effects of early treatment of nevus of Ota with a low-fluence 1,064-nm Q-switched neodymium-doped yttrium aluminum garnet (Nd:YAG) laser. MATERIALS AND METHODS: The authors performed a retrospective study of 31 Korean patients (Fitzpatrick skin Type IV) with nevus of Ota. The patients received a series of 6 to 32 treatment sessions at 2- to 3-week intervals with a Q-switched Nd:YAG laser at settings of 7- or 8-mm spot, 1.9 to 5.0 J/cm2 mean fluence. RESULTS: The mean fluence was less in patients younger than 10 years (2.2 ± 0.3 J/cm2) than in those older than 10 years (2.8 ± 0.8 J/cm2) (p = .006). Patients who started their first treatment earlier required fewer treatment sessions to reach moderate, marked, and near total improvement (p < .05). By starting treatment early, low mean fluence was required to reach the end point in each session (p < .001). Post-treatment hyperpigmentation was observed in 1 patient. CONCLUSION: This treatment was clinically effective and safe for early nevus of Ota using a low-fluence Q-switched Nd:YAG laser.

Novel facial cosmetic area 'O zone' shows unique characteristics in sebum excretion and acne lesion distribution.

BACKGROUND: We usually divided cosmetic facial zone into the T zone and U zone by the level of sebum secretion. Our recent studies suggested that the perioral area showed different characteristics in the aspect of acne development. OBJECTIVE: To investigate the unique characteristics of the O zone (perioral area) among the three facial areas. METHODS: A total of 102 patients clinically diagnosed as acne vulgaris were included. The acne lesions were counted from the clinical digital photographs by facial areas. The sebum level was measured using Sebumeter(®) . Area-weighted (AW) sebum and AW density of three areas of face were calculated. Statistical analysis was performed according to age and gender. RESULTS: There were no differences in the mean AW sebum level between the gender and age groups. Male has higher AW density of acne lesions than female at the O zone. The mean AW density of acne lesions on the NT zone, U zone, and whole face showed decrease by age, but at the O zone, 21-30 years group showed the highest mean AW density of acne. LIMITATIONS: Age- and gender-matched patients do not represent the whole acne patients. CONCLUSION: We suggested that the O zone is an independent facial zone, which showed a moderate-to-high sebum secreting area, maintained the acne lesions development by age, and predominated acne lesions in the male acne patients than female acne patients. Therefore, the O zone should be separated from the usual cosmetic T zone, and NT zone should replace the old T zone.

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.

Surgical corner. Evaluation of the wound healing response after deep dermal heating by fractional micro-needle radiofrequency device.

BACKGROUND: Fractional Radiofrequency Microneedles (FRM) are minimally invasive devices that use inserting bipolar radiofrequency for deep dermal heating, has been introduced. We investigated the tissue response after FRM according to different energy levels in porcine skin. METHODS: Porcine back skin was used in the study. A FRM device was composed of 49 insulated needles. Needles were vertically inserted with 1.5mm depth and four different energy levels were used to examine wound healing response chronologically. Histologic evaluation was done by hematoxylin & eosin (H&E) and heat shock proteins (HSP) 47 staining for immediately after, 2 days after, 14 days after, 28 days after and 10 weeks after the procedure. RT-PCR was done for various cytokines including HSP47, HSP72, metalloproteinase (MMP), and extracellular matrix (ECM) proteins. RESULTS: FRM treatment generated a thermally coagulated zone localized in the reticular dermis, without damaging the epidermis. The coagulation necrosis zone in H&E staining was replaced by new collagen tissue over 10 weeks. RT-PCR studies revealed an increase in HSP, MMPs, and ECM proteins. In the high energy level procedure, an increased number of fibroblasts were found. CONCLUSION: FRM treatment induced a dermal remodeling process including neocollagenesis in the deep dermis. From this result, FRM is expected to provide a good and positive efficacy for skin rejuvenation.

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.

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.

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.

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.

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.