Clinical Efficacy of 5-Fluorouracil and Bleomycin in Dermatology.

Bleomycin and 5-fluorouracil (5-FU) are widely used in various dermatological disorders. Both drugs are well-recognized as antineoplastic drugs and exert their effect by blocking the cell cycle. Topical and intralesional formulations are available and have been studied in both non-neoplastic and cancerous lesions. However, data comparing the effect of bleomycin and 5-FU in the dermatological disorders are limited. This review outlines the action mechanisms of both drugs and compares their clinical efficacies in a wide range of dermatologic diseases including hypertrophic scar, wart, skin cancer, vascular malformation, hemangioma, and vitiligo, and discusses the overall safety of the drugs. Intralesional bleomycin treatment is effective in hypertrophic scars and warts, but intralesional 5-FU may also be considered since it is cheaper and less painful. Moreover, intralesional 5-FU and bleomycin injection is a viable option for premalignant lesions (i.e., actinic keratosis) and inoperable skin cancers. Both bleomycin and 5-FU have been applied as treatment adjuncts for vitiligo, with 5-FU showing a slightly better outcome. Both agents have a good safety profile, and no serious side effects have been reported following their use in the field of dermatology.

Metformin: A Potential Treatment for Acne, Hidradenitis Suppurativa and Rosacea.

Metformin is a widely used drug for treatment of diabetes mellitus, due to its safety and efficacy. In addition to its role as an antidiabetic drug, numerous beneficial effects of metformin have enabled its use in various diseases. Considering the anti-androgenic, anti-angiogenic, anti-fibrotic and antioxidant properties of metformin, it may have the potential to improve chronic inflammatory skin diseases. However, further evidence is needed to confirm the efficacy of metformin in dermatological conditions, This review focuses on exploring the therapeutic targets of metformin in acne vulgaris, hidradenitis suppurativa and rosacea, by studying their pathogeneses.

Itch and Janus Kinase Inhibitors.

Itch is a common skin symptom, with complex aetiology and pathogenesis. It is mediated by 2 pathways, the histaminergic and non-histaminergic pathways. Chronic itch is understood to be processed by the latter and is difficult to treat with traditional pruritus therapies. The Janus kinase and signal transducer and activator of transcription pathway is a signalling mechanism that regulates gene expression through various cytokines. Janus kinase inhibitors, which have been tested and used for several autoimmune diseases, have also been shown to be effective for itch through clinical trials and case reports. Janus kinase inhibitors could be a good choice for pruritus in atopic dermatitis, psoriasis, and other diseases, such as prurigo nodularis and lichen planus, with rapid itch relief compared with conventional treatments. The most common adverse effects reported include nasopharyngitis, acne, and elevated blood creatine phosphokinase levels. Janus kinase inhibitors are currently prescribed with warnings about a potential increase in malignancies and cardiovascular diseases and usage in people of older ages. This review aims to provide knowledge about itch and the Janus kinase and signal transducer and activator of transcription pathway and to analyse the current evidence for itch relief by Janus kinase inhibitors.

Allergic Sensitization Pattern in the Korean Dermatologic Patients.

BACKGROUND: Avoiding causative allergens is important for controlling the clinical course of allergic diseases. Allergen sensitization is influenced by many factors including the environment and lifestyle. The socioeconomic development, climate, and lifestyle changes have increased the prevalence of allergic diseases worldwide. However, there is little information about changes in the trend of the common allergens over time. OBJECTIVE: This study was aimed at identifying the trends of the common allergens in Korea over a 10-year period based on the results of the multiple allergosorbent test chemiluminescent assay (MAST-CLA). METHODS: We retrospectively reviewed the medical records of 5,760 patients aged ≥18 years who visited the Dermatology Department at a tertiary hospital over a period of 10 years. The serum total immunoglobulin (Ig) E and specific IgE levels to 41 allergens were determined using MAST-CLA, along with the clinical diagnosis, duration of illness, white blood cell count and eosinophil percentage. RESULTS: Dermatophagoides farinae, Dermatophagoides pteronyssinus, and house dust were the most prevalent allergens during the 10 years period, but the percentage of higher class responses has decreased in recent years. The number of patients sensitized to house dust (p<0.001), dogs (p=0.005), and cats (p<0.001) increased while that of patients sensitized to cockroaches (p<0.001) and storage mites (p<0.001) decreased over time. There were no significant changes in the total number of sensitizing allergens over time. CONCLUSION: The common allergens have changed over time. Based on the findings of this study, physicians and patients should consider changing their strategies for disease prevention and management.

Characterization of Distinct Microbiota Associated with Scalp Dermatitis in Patients with Atopic Dermatitis.

Recent studies have focused on the role of skin microbiota in the pathogenesis of atopic dermatitis (AD). Among the various clinical phenotypes of AD, scalp dermatitis is a commonly observed clinical feature of AD. However, little is known about the pathogenesis of scalp dermatitis in AD. Hence, the aim of this study was to identify the distinct microbiota associated with scalp dermatitis in patients with AD. Using scalp swab samples from 10 patients with AD and 10 healthy controls, this study characterized the scalp microbiota in patients with AD via V3-V4 regions of the 16S rRNA gene sequencing for bacterial identification, and ITS2 gene sequencing for fungal identification. Among bacterial genera, Staphylococcus was the most abundant in AD than in healthy controls, whereas Cutibacterium was the most abundant species in the healthy controls. The most predominant scalp fungal microbiota was Malassezia both in AD and healthy controls, while a higher diversity of non-Malassezia fungi was observed in AD than in healthy controls. The study findings indicate the dysbiosis of scalp microbiota in AD and highlight the potential biomarker role of specific microbiota in AD on the scalp dermatitis.

The Human Microbiota and Skin Cancer.

Skin cancer is the most common type of cancer in the US with an increasing prevalence worldwide. While ultraviolet (UV) radiation is a well-known risk factor, there is emerging evidence that the microbiota may also contribute. In recent years, the human microbiota has become a topic of great interest, and its association with inflammatory skin diseases (i.e., atopic dermatitis, acne, rosacea) has been explored. Little is known of the role of microbiota in skin cancer, but with the recognized link between microbial dysbiosis and inflammation, and knowledge that microbiota modulates the effect of UV-induced immunosuppression, theories connecting the two have surfaced. In this paper, we provide a comprehensive review of the key literature on human microbiota, especially the skin microbiota, and skin cancer (i.e., non-melanoma skin cancer, melanoma, cutaneous T cell lymphoma). Also, mechanistic perspectives as to how our microbiota influence skin cancer development and treatment are offered.

Ocular Comorbidities in Rosacea: A Case-Control Study Based on Seven Institutions.

Rosacea is a facial inflammatory dermatosis that is linked with various systemic illnesses. With regards to the eye, rosacea patients have been described to manifest ocular surface changes, such as blepharitis and conjunctivitis. However, studies that examine the association of rosacea with a wider array of ocular diseases are limited. Thus, our aim was to identify the range of ocular comorbidities in the Korean patient population and create a reference data set. A multi-institutional, case-control study was conducted, where 12,936 rosacea patients and an equal number of sex- and age-matched control subjects were extracted over a 12-year period. We were able to discover a notable association between rosacea and blepharitis (adjusted odds ratio (aOR) 3.44; 95% confidence interval, 2.71-4.36, p < 0.001), conjunctivitis (aOR 1.65; 95% CI, 1.50-1.82, p < 0.001), glaucoma (aOR 1.93; 95% CI, 1.70-2.20, p < 0.001), dry eye syndrome (aOR 1.89; 95% CI, 1.70-2.09, p < 0.001), and chalazion (aOR 3.26; 95% CI, 1.41-7.57, p = 0.006) from logistic regression analysis. Female subjects and individuals younger than 50 exclusively showed higher odds for chalazion. Our study suggests that ocular comorbidities (i.e., glaucoma, dry eye syndrome, and chalazion as well as blepharitis and conjunctivitis) are more prevalent among Koreans with rosacea. Clinicians should proactively check ocular symptoms in rosacea and employ joint care with an ophthalmologist in cases of need.

Updates on the Risk of Neuropsychiatric and Gastrointestinal Comorbidities in Rosacea and Its Possible Relationship with the Gut-Brain-Skin Axis.

Rosacea is a common chronic cutaneous inflammatory disorder. Recently, patients with rosacea were identified as having a higher risk of developing various comorbidities such as cardiovascular disease, psychiatric disorders, neurologic disorders, and gastrointestinal disorders. However, the risks of some comorbidities in patients with rosacea are somewhat contradictory, depending upon the study design. Moreover, pathomechanisms associated with the comorbidities of patients with rosacea remain poorly elucidated. The purpose of this review was to provide the most up-to-date evidence on the risks of neuropsychiatric and gastrointestinal comorbidities in patients with rosacea. Moreover, the molecular pathomechanisms associated with neuropsychiatric and gastrointestinal comorbidities in patients with rosacea were evaluated based on recent studies. This review was also intended to focus more on the role of the gut-brain-skin axis in the association of neuropsychiatric and gastrointestinal comorbidities in rosacea.

Systemic Comorbidities in Korean Patients with Rosacea: Results from a Multi-Institutional Case-Control Study.

Recent evidence links rosacea to systemic disease, but there are not enough methodologic studies addressing this association in Asians. Our aim was to identify rosacea comorbidities in Koreans and establish a reference database. A multi-center, case-control study was performed where a total of 12,936 rosacea patients and 12,936 age- and sex-matched control subjects were identified from 2007 to 2018. Logistic regression was performed to find significant association between rosacea and Sjögren syndrome (odds ratio [OR] 2.05; 95% confidence interval, 1.40-3.00), systemic sclerosis (OR 6.56; 95% CI, 1.50-28.7), rheumatoid arthritis (OR 1.72; 95% CI, 1.50-1.98), ankylosing spondylitis (OR 2.32; 95% CI, 1.42-3.84), autoimmune thyroiditis (OR 1.96; 95% CI, 1.40-2.73), alopecia areata (OR 1.77; 95% CI, 1.27-2.45), vitiligo (OR 1.90; 95% CI, 1.30-2.77), lung cancer (OR 1.54; 95% CI, 1.06-2.21), hepatobiliary cancer (OR 1.38; 95% CI, 1.06-1.77), alcohol abuse (OR 1.59; 95% CI, 1.05-2.39), diabetes mellitus (OR 1.11; 95% 1.02-1.19), obesity (OR 1.72; 95% CI, 1.22-2.41), allergic rhinitis (OR 1.65; 95% CI, 1.54-1.76), allergic conjunctivitis (OR 1.57; 95% CI, 1.27-1.94), chronic rhinosinusitis (OR 1.28; 95% CI, 1.14-1.42), herpes infection (OR 1.69; 95% CI, 1.53-1.86), and human papillomavirus infection (OR 2.50; 95% CI, 2.06-3.02). Higher odds for Sjogren syndrome, systemic sclerosis, ankylosing spondylitis, thyroiditis, vitiligo, hepatobiliary cancer, and obesity was exclusive in female subjects with rosacea, whereas increased prevalence of alopecia areata and alcohol abuse was confined to men. Only those who were 50 years and older exhibited higher odds for vitiligo, lung cancer, and gastroesophageal reflux disease while individuals younger than 50 were exclusively associated with hepatobiliary cancer, allergic conjunctivitis, and irritable bowel syndrome. Our study suggests that Koreans with rosacea are more likely to experience systemic comorbidity. Clinicians should acknowledge these interrelations and employ comprehensive care with an individual-based approach.

Characterization and Analysis of the Skin Microbiota in Rosacea: Impact of Systemic Antibiotics.

Systemic antibiotics are extensively used to control the papules and pustules of rosacea. Hence, it is crucial to understand their impact on the rosacea skin microbiota which is thought to be perturbed. The purpose of this study was to compare the makeup and diversity of the skin microbiota in rosacea before and after taking oral antibiotics. We also compared the skin microbiota at baseline according to age and rosacea severity. A longitudinal cohort study was performed on 12 rosacea patients with papules/pustules and no recent use of oral and topical antimicrobials/retinoids. Patients were prescribed oral doxycycline, 100 mg, twice daily for six weeks. Skin areas on the cheek and nose were sampled for 16S ribosomal RNA gene sequencing at baseline, and after six weeks of doxycycline treatment. Eleven females and one male aged 20-79 (median 51) with a median Investigator's Global Assessment score of 3 (moderate) were enrolled. At baseline, Staphylococcus epidermidis was the most dominant species followed by Cutibacterium acnes (formerly Propionibacterium acnes). In the 60 Over-age group, the prevalence of Cutibacterium acnes was lower than that of the 60 & Under-age group. Rosacea severity increased with age and was associated with a decrease in the relative abundance of Cutibacterium acnes and an increase of Snodgrassella alvi. Across all subjects, antibiotic treatment reduced clinical rosacea grades and was associated with an increase in the relative abundance of Weissella confusa (P = 0.008, 95% CI 0.13% to 0.61%). Bacterial diversity (alpha diversity) was not significantly altered by antibiotics treatment. Principal coordinates analysis showed mild clustering of samples by patient (ANOSIM, Analysis of Similarity, R = 0.119, P = 0.16) and scant clustering with treatment (ANOSIM, R = 0.002; P = 0.5). In conclusion, we believe that rosacea has a unique age-dependent characteristic (i.e., severity). Although we were not able to pinpoint a causative microbiota, our study provides a glimpse into the skin microbiota in rosacea and its modulation by systemic antibiotics.

Air Pollution, Autophagy, and Skin Aging: Impact of Particulate Matter (PM10) on Human Dermal Fibroblasts.

A World Health Organization (WHO) report from 2016 states that over 3 million people die annually from air pollution, which places air pollution as the world's largest single environmental health risk factor. Particulate matter (PM) is one of the main components of air pollution, and there is increasing evidence that PM exposure exerts negative effects on the human skin. To see the impact of air pollution on skin aging, we analyzed the effect of PM exposure on human dermal fibroblasts (HDFs) with Western blot, enzyme-linked immunosorbent assay (ELISA), and gene analysis. Cultured HDFs were exposed to PM10 at a concentration of 30 µg/cm² for 24 h, and their gene/protein expression of inflammatory cytokines, fibroblast chemical mediators, and autophagy were assessed. A total of 1977 genes were found to be differentially expressed following PM exposure. We observed a significantly increased expression of pro-inflammatory genes interleukin (IL)-1ß, IL-6, IL-8 and IL-33 in dermal fibroblasts exposed to PM10. Protein expression of IL-6 and IL-8 also significantly increased, which complemented our gene analysis results. In addition, there was a significant increase in cytochrome P450 (CYP1A1, CYP1B1), matrix metalloproteinase (MMP-1, MMP-3) mRNA expression, and significant decrease in transforming growth factor (TGF)-ß, collagen type I alpha chain (COL1A1, COL1A2), and elastin (ELN) mRNA expression in PM-exposed dermal fibroblasts. Protein expression of MMP-1 was significantly increased and that of TGF-ß and procollagen profoundly decreased, similar to the gene analysis results. Autophagy, an integrated cellular stress response, was also increased while transmission electron microscopy (TEM) analysis provided evidence of PM internalization in the autolysosomes. Taken together, our results demonstrate that PM10 contributes to skin inflammation and skin aging via impaired collagen synthesis. Increased autophagy in our study suggests a reparative role of autophagy in HDFs stressed with PM, but its biological significance requires further research.

Autophagy in Human Skin Fibroblasts: Impact of Age.

Autophagy is an intracellular stress response that is enhanced under starvation conditions, and also when the cellular components are damaged. Aging accompanies an increase in intracellular stress and has significant impact on the skin. Since dermal fibroblasts are a powerful indicator of skin aging, we compared the autophagic activity of human skin fibroblasts between the young and old. According to TEM analyses, the number of autophagosomes per 1 µm² cytoplasmic area was similar between young and aged fibroblasts. The amount of LC3 (microtubule-associated protein 1 light chain 3)-II, a form associated with autophagic vacuolar membranes, was also similar between the groups from Western blot analysis. Although residual bodies were more common in aged dermal fibroblasts, LC3 turnover and p62 assay showed little difference in the rate of lysosomal proteolysis between the young and old. RNA-seq analysis revealed that the major autophagy-modulating genes (BECN1, MAP1LC3B, ATG5, ATG7, ULK1, PIK3C3, mTOR) were not differentially expressed with age. Our results suggest that the basal autophagic flux in aged dermal fibroblasts is largely comparable to that of young fibroblasts. However, with a higher speed and amount of waste production in aged cells, we postulate that such autophagic flux may not be sufficient in keeping the old cells "clean", resulting in skin aging. Aging is a complex process and, as such, the relationship between autophagy and aging is not straightforward. That is to say, autophagy does not simply decline with age. Regardless of the controversies on autophagic activity with age, autophagy plays a crucial role in counteracting aging, and strategies aimed at its modulation should hold promise for the prevention of skin aging.

Fractional Carbon Dioxide Laser as an "Add-on" Treatment for Vitiligo: A Meta-analysis with Systematic Review.

Treatment of vitiligo is challenging and requires a multidisciplinary approach. Fractional carbon dioxide (CO2) laser as an add-on to conventional treatment has been reported to be effective, but there is no consensus on its use. A systematic review was performed by searching major databases for relevant publications to February 2017. Six studies with 85 participants were included. For those with refractory vitiligo, the addition of fractional CO2 laser to routine treatment modalities was superior to conventional treatment alone in terms of > 50% re-pigmentation (risk ratio (RR) 4.90, 95% confidence interval (95% CI), 1.15-20.93; p = 0.03), physician improvement score (mean difference (MD) 0.81, 95% CI 0.33-1.29; p < 0.001), < 25% re-pigmentation (RR 0.64, 95% CI, 0.49-0.85; p=0.002) and patient satisfaction (MD 1.61, 95% CI 0.73-2.49; p< 0.001). Side-effects were minor. These results provide evidence supporting that fractional CO2 laser is a valuable treatment modality for patients with vitiligo, especially for those with refractory vitiligo.