Efficacy and Safety of Topical Corticosteroid Treatment under Occlusion for Severe Alopecia Areata in Children. A single-center retrospective analysis.

BACKGROUND: Alopecia areata (AA) has a poor clinical course in children. There are no reliable therapeutic options for children with severe AA, including alopecia totalis (AT) and alopecia universalis (AU). AIM: We evaluated the efficacy and adverse effects of a potent topical corticosteroid (TCS) under occlusion in pediatric patients with severe AA. METHODS: We reviewed records of 23 patients under the age of 10 years with AT or AU treated with a potent TCS (0.05% clobetasol propionate or 0.3% diflucortolone valerate) for 8 hours under occlusion with a plastic film. We used the Severity of Alopecia Tool (SALT) to measure clinical improvement. The primary endpoint was a Severity of Alopecia Tool (SALT) score of 20 or less at six months. We analyzed the change in cortisol levels to identify the long-term safety of TCS therapy on the hypothalamus-pituitary-adrenal axis. RESULTS: Nineteen patients reached SALT 20 or less at the 6-month treatment. Six patients relapsed over the 6-month follow-up period. Four patients were suspected of adrenal insufficiency. However, the cortisol level of the patients recovered to normal at least 1-month after lowering TCS potency or changing to non-steroidal treatments. LIMITATIONS: Retrospective design and small sample size. CONCLUSION: This study shows that a potent TCS occlusion may be a safe treatment option in pediatric patients with severe AA. Further long-term studies are required to evaluate the safety and recurrence of TCS occlusion therapy for pediatric AA.

The crosstalk between PTEN-induced kinase 1-mediated mitophagy and the inflammasome in the pathogenesis of alopecia areata.

Alopecia areata (AA) is a T-cell-mediated autoimmune disease that causes chronic, relapsing hair loss; however, its precise pathogenesis remains to be elucidated. Recent studies have provided compelling evidence of crosstalk between inflammasomes and mitophagy-a process that contributes to the removal of damaged mitochondria. Our previous studies showed that the NLR family pyrin domain containing 3 (NLRP3) inflammasome is important for eliciting and progressing inflammation in AA. In this study, we detected mitochondrial DNA damage in AA-affected scalp tissues and IFNγ and poly(I:C) treated outer root sheath (ORS) cells. In addition, IFNγ and poly(I:C) treatment increased mitochondrial reactive oxygen species (ROS) levels in ORS cells. Moreover, we showed that mitophagy induction alleviates IFNγ and poly(I:C)-induced NLRP3 inflammasome activation in ORS cells. Lastly, PTEN-induced kinase 1 (PINK1) knockdown increased NLRP3 inflammasome activation, indicating that PINK1-mediated mitophagy plays a critical role in NLRP3 inflammasome activation in ORS cells. This study supports previous studies showing that oxidative stress disrupts immune privilege status and promotes autoimmunity in AA. The results emphasize the significance of crosstalk between mitophagy and inflammasomes in the pathogenesis of AA. Finally, mitophagy factors regulating mitochondrial dysfunction and inhibiting inflammasome activation could be novel therapeutic targets for AA.

Mechanistic Investigation of WWOX Function in NF-kB-Induced Skin Inflammation in Psoriasis.

Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperproliferation, aberrant differentiation of keratinocytes, and dysregulated immune responses. WW domain-containing oxidoreductase (WWOX) is a non-classical tumor suppressor gene that regulates multiple cellular processes, including proliferation, apoptosis, and migration. This study aimed to explore the possible role of WWOX in the pathogenesis of psoriasis. Immunohistochemical analysis showed that the expression of WWOX was increased in epidermal keratinocytes of both human psoriatic lesions and imiquimod-induced mice psoriatic model. Immortalized human epidermal keratinocytes were transduced with a recombinant adenovirus expressing microRNA specific for WWOX to downregulate its expression. Inflammatory responses were detected using Western blotting, real-time quantitative reverse transcription polymerase chain reaction (PCR), and enzyme-linked immunosorbent assay. In human epidermal keratinocytes, WWOX knockdown reduced nuclear factor-kappa B signaling and levels of proinflammatory cytokines induced by polyinosinic: polycytidylic acid [(poly(I:C)] in vitro. Furthermore, calcium chelator and protein kinase C (PKC) inhibitors significantly reduced poly(I:C)-induced inflammatory reactions. WWOX plays a role in the inflammatory reaction of epidermal keratinocytes by regulating calcium and PKC signaling. Targeting WWOX could be a novel therapeutic approach for psoriasis in the future.

Role of Substance P in Regulating Micro-Milieu of Inflammation in Alopecia Areata.

BACKGROUND: Alopecia areata (AA) is an autoimmune disease characterized by chronic inflammation, the pathogenesis of which is unknown. Stress is believed to play a role; however, evidence remains insufficient. A recent study showed that substance P (SP) damaged hair follicles by causing neurogenic inflammation, activating perifollicular mast cells, and inducing keratinocyte apoptosis. OBJECTIVE: We aimed at studying the role of SP in AA pathogenesis. We investigated the SP levels in the lesional scalp tissues and serum. We also studied the effect of SP on the inflammatory response and hair growth in the outer root sheath (ORS) cells. METHODS: We compared the serum levels of SP in 58 AA patients and 28 healthy subjects. Then, we checked the expression of SP and SP receptor, neurokinin-1 receptor (NK-1R) in the scalps of AA patients and healthy controls using immunohistochemical staining. Finally, we analyzed the mRNA expression of inflammatory cytokines and hair growth-related factors in ORS cells. RESULTS: SP and NK-1R expression were markedly higher in the hair follicles and interfollicular epidermis of the scalp lesions of AA patients. However, there was no statistically significant difference in serum SP levels between controls and patients, regardless of the type of alopecia. SP significantly increased the mRNA expression of inflammatory cytokines and decreased hair growth-related growth factors in ORS cells, but the results were not dramatic. CONCLUSION: SP triggered a localized micro-inflammation in lesional hair follicles, provoked an inflammatory response, and inhibited hair growth, thereby confirming the pathogenic role of SP in AA.

Primary cutaneous malignant melanoma with rhabdomyosarcomatous differentiation originating from a melanocytic nevus in a patient with myelodysplastic syndrome.

Malignant melanoma (MM) may rarely exhibit divergent differentiation, in which melanocytic markers may be lost, leading to difficulty in diagnosis. A 64-year-old man recently diagnosed with myelodysplastic syndrome complained of development of a nodule in a melanocytic nevus on his scalp. On histopathologic examination, junctional nevus nests and diffuse cellular infiltrations with a sheet-like growth pattern of pleomorphic epithelioid cells were observed in the upper dermis. Junctional nevus cells were S-100 positive, and pleomorphic epithelioid cells extending from the junctional nests were weakly positive for S-100. Large polygonal cells with eccentric nuclei and intracytoplasmic hyaline inclusions were observed in the mid to deep dermis. These rhabdomyoblast-like polygonal cells diffusely expressed desmin and were focally positive for MyoD1. Some clusters of polygonal cells in the deep dermis expressed SOX10. Collectively, these clinical and histopathologic features suggested MM with rhabdomyosarcomatous differentiation. Desmin- and skeletal-muscle-specific markers should be applied to melanocytic tumors with atypical epithelioid cells resembling rhabdomyoblasts, especially if these cells are negative for melanocytic markers.

The potential role of fibroblast-derived multi-peptide factors in activation of growth factors and ß-Catenin in hair follicle cells.

BACKGROUND: Dermal fibroblasts play a pivotal role in hair follicle regeneration during wound repair. Recently, dermal fibroblast-conditioned medium (DFCM), which contains multi-peptide factors (MPFs), has been used to promote wound repair. AIM: This study aimed to investigate the stimulatory effects of MPF-containing DFCM on hair growth. METHODS: MPF-containing DFCM was prepared using human neonatal dermal fibroblasts. Outer root sheath (ORS) and dermal papilla (DP) cells were cultured in MPF-containing DFCM. We examined the expression and secretion of growth factors and cytokines using quantitative polymerase chain reaction and a growth factor array. In addition, the effect of MPFs on ß-catenin activity was determined using the TOPflash assay. All experiments were repeated at least three times with separate batches of cells. RESULTS: MPF-containing DFCM increased keratinocyte growth factor (KGF), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF) mRNA expression in ORS cells and KGF and VEGF mRNA expression in DP cells. When ORS cells were treated with MPF-containing DFCM, the secretion of several growth factors, including EGF, VEGF, insulin-like growth factor-binding protein (IGFBP)-4, IGFBP-6, and fibroblast growth factor-7, was increased in the cell-cultured medium compared with that in control. Additionally, MPF-containing DFCM increased the transcriptional activation of ß-catenin in DP cells. CONCLUSIONS: These results suggest that MPF-containing DFCM might stimulate hair growth by inducing growth factors in ORS and DP cells and regulating ß-catenin in DP cells.

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.

Potential Role of Cytosolic RNA Sensor MDA5 as an Inhibitor for Keratinocyte Differentiation in the Pathogenesis of Psoriasis.

BACKGROUND: Psoriasis is a chronic inflammatory skin disease. The etiology of psoriasis is not fully understood, but the genetic background is considered to be the most important factor. To date, many psoriasis-related genes have been discovered, but the role of many important genes has not been well understood. OBJECTIVE: The purpose of this study is to uncover possible roles of MDA5 in psoriasis. METHODS: Expression of MDA5 was investigated using immunohistochemistry. Then, MDA5 was overexpressed in keratinocytes using a recombinant adenovirus. RESULTS: As a result of immunohistochemical staining, the expression of MDA5 was significantly increased in the epidermis of psoriasis compared to normal skin. Similarly, the expression of MDA5 was increased in imiquimod-induced psoriasiform dermatitis model. In cultured keratinocytes, toll-like receptor 3 agonist poly(I:C) induced expression of MDA5 at both mRNA and protein levels. When MDA5 was overexpressed using a recombinant adenovirus, poly(I:C)-induced cytokine expression was significantly increased. Finally, MDA5 overexpression significantly inhibited calcium-induced differentiation of keratinocytes. CONCLUSION: These results suggest that MDA5 increases in psoriasis and negatively regulates keratinocyte differentiation.

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.

Eosinophilic Panniculitis Following the Subcutaneous Injection of Exenatide Extended-Release.

Exenatide extended-release was recently developed as an antidiabetic drug; it acts as a glucagon-like peptide-1 receptor agonist. A 54-year-old male visited our clinic complaining of a subcutaneous tender nodule on his left thigh that had developed over the course of 1 week. The patient had received exenatide extended-release injections for 5 months to treat diabetes. A histopathologic examination showed septal and lobular panniculitis with lymphohistiocyte and eosinophil infiltration. The patient was diagnosed with eosinophilic panniculitis (EP) due to exenatide extended-release injection. EP is a rare type of panniculitis characterized by a prominent infiltrate of eosinophils in the subcutaneous fat layer. It is a histologic reaction pattern that is associated with various clinical conditions. Among the injection-site reactions reported in exenatide extended-release users, injection-site nodules occur infrequently. Clinicians who treat diabetics who use exenatide extended-release should be aware of the possible occurrence of injection-site nodules.

Possible Role of Lysine Demethylase 2A in the Pathophysiology of Psoriasis.

BACKGROUND: Psoriasis is a common chronic inflammatory skin disease. The development of psoriasis is dependent on many intercellular events such as innate immunity and T cell-mediated inflammation. Furthermore, genetic factors are strongly implicated in the pathophysiology of psoriasis. Although a variety of susceptible genes are identified, it is likely that many important genes remain undisclosed. OBJECTIVE: The aim of this study is to investigate the possible role of lysine demethylase 2A (KDM2A) in the pathophysiology of psoriasis. METHODS: We examined the expression of KDM2A using a well established imiquimod-induced psoriasiform dermatitis model. RESULTS: Immunohistochemistry analysis showed that expression of KDM2A was increased in imiquimod-induced psoriasiform dermatitis. Consistent with this result, KDM2A level was markedly increased in the epidermis of psoriatic patient. When keratinocytes were stimulated with TLR3 agonist poly(I:C), KDM2A was increased at both the mRNA and protein levels. Poly(I:C) increased the expression of psoriasis-related cytokines including tumor necrosis factor-α, interleukin-8, and CCL20, and KDM2A inhibitor daminozide enhanced the poly(I:C)-induced cytokine expression. Finally, topical co-application of imiquimod and daminozide exacerbated the imiquimod-induced psoriasiform dermatitis. CONCLUSION: Together, these results suggest that KDM2A is increased to negatively regulate the inflammatory reaction of epidermal keratinocytes in psoriasis.