Oroxylin A suppress LL-37 generated rosacea-like skin inflammation through the modulation of SIRT3-SOD2-NF-κB signaling pathway.

Rosacea is a long-term inflammatory skin disease associated with the dysfunction of vascular and immunological systems. Treatment options for rosacea are difficult to implement. Oroxylin A(OA), a traditional Chinese medicine, has anti-inflammation effects in a variety of inflammatory diseases. However, it is not known that whether OA exerts protective effects against LL-37-induced rosacea. In this study, bioinformatics analyses showed that the mechanisms of rosacea and the pharmacological targets of OA were highly overlapped. Subsequently, it was shown that the administration of OA resulted in a notable amelioration of rosacea-like skin lesions, as evidenced by a reduction in immune cell infiltration, modulation of cytokine production, and inhibition of angiogenesis. Plus, it was shown that OA effectively suppressed the generation of ROS generated by LL-37, as well as the subsequent activation of NF-κB signaling pathway. To explore further, we found that OA inhibited LL-37-induced ROS production via SIRT3-SOD2 signaling pathway in keratinocytes. Based on the aforementioned evidence, it can be inferred that OA exhibits a mitigating effect on the inflammatory response in rosacea by modulating the SIRT3-SOD2-NF-κB signaling pathway.

Association Between Acid-Suppressive Drugs and Risk of Rosacea: Retrospective Study Using the Korean National Health Insurance Service-National Sample Cohort.

BACKGROUND: Rosacea is a common inflammatory skin disease with multiple etiologies. Proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RA) are acid suppressive drugs widely used for gastrointestinal (GI) diseases, and long-term use has been reported to be associated with dysbiosis which is a potential risk for development of rosacea. This study aimed to study the association between rosacea and acid suppressants in the Korean national cohort. METHODS: We used Korean National Health Insurance Service-National Sample Cohort data of 749,166 patients with upper GI diseases between 2001 and 2013. Duration of acid suppressants was compared between patients with and without rosacea together with other sociodemographic characteristics and hazard ratios were estimated. RESULTS: Longer use of acid suppressants was significantly associated with increased risk of rosacea. After adjustment for possible confounders, increased cumulative defined daily dose was significantly associated with risk of rosacea (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.20-2.00; P = 0.001). Other factors significantly associated with risk of rosacea include residing in the rural area (OR, 2.58; 95% CI, 2.18-3.06; P < 0.001), greater Charlson Comorbidity Index score (OR, 1.45; 95% CI, 1.15-1.83; P = 0.002), and comorbidities (malignancy, thyroid disease, and depression). CONCLUSION: Results from our study indicate that H2RA or PPI is associated with the occurrence of rosacea among patients with GI diseases in the Korean population. The risk was increased in dose-dependent manner, even after adjusting for confounding variables. Clinicians should be aware of risks associated with prolonged use of acid suppressive drugs.

Narrow-Band Intense Pulsed Light as Treatment for Erythematotelangiectatic Rosacea: A Retrospective Study.

BACKGROUND: Erythematotelangiectatic rosacea can be successfully treated using various laser and light-based devices. However, the use of narrow-band intense pulsed light for the treatment of erythematotelangiectatic rosacea has not been investigated in detail. This retrospective study aimed to analyze the clinical efficacy of narrow-band intense pulsed light (500-600 nm) for the treatment of erythematotelangiectatic rosacea among Chinese individuals.  Methods: Patients with erythematotelangiectatic rosacea who had completed 3 sessions of treatment with narrow-band intense pulsed light and follow-up from July 2016 to December 2018 were retrospectively evaluated. Clinical improvement was assessed by 2 blinded dermatologists based on photographs obtained at each follow-up visit using the clinician erythema assessment scale and 5-grade scale. RESULTS: Forty-five patients with erythematotelangiectatic rosacea treated with narrow-band intense pulsed light were included in this study. The effectiveness and excellent rates after 3 treatment sessions were 68.9% and 35.6%, respectively. An average of 2 treatment sessions was required among patients who achieved good or excellent clearance of erythema and telangiectasia. Except for transient erythema and edema, no severe adverse effects were observed. CONCLUSIONS: Narrow-band intense pulsed light is a safe and effective treatment for erythematotelangiectatic rosacea. Even with a small number of treatment sessions, narrow-band intense pulsed light can deliver a significant therapeutic effect, which may be applicable in clinical practice. J Drugs Dermatol. 2023;22(11):1095-1098     doi:10.36849/JDD.4920.

Vitamin D Status, Vitamin D Receptor Polymorphisms, and the Risk of Incident Rosacea: Insights from Mendelian Randomization and Cohort Study in the UK Biobank.

BACKGROUND: Previous cross-sectional studies have failed to definitively establish a causal relationship between serum 25-hydroxyvitamin D (25OHD) concentrations and the onset of rosacea. OBJECTIVE: To investigate the potential association between serum 25OHD levels, vitamin D receptor (VDR) polymorphisms, and the risk of developing incident rosacea. METHODS: This cross-sectional population-based cohort study utilizing 370,209 individuals from the UK Biobank. Cox proportional hazard regression models and two-sample Mendelian randomization (MR) analyses were applied to explore the causative relationship between 25OHD and incident rosacea. RESULTS: Our findings revealed that elevated levels of serum 25OHD were inversely correlated with the risk of incident rosacea. Specifically, compared to participants with 25OHD levels below 25 nmol/L, the multivariate-adjusted HR for incident rosacea was 0.81 (95% CI: 0.70, 0.94) in those with 25OHD levels exceeding 50 nmol/L. Further, in comparison to individuals with serum 25OHD less than 25 nmol/L and the rs731236 (TaqI) AA allele, those with serum 25OHD higher than 75 nmol/L and the TaqI GG allele had a multivariate-adjusted HR of 0.51 (95% CI 0.32 to 0.81) for developing rosacea. Results from the MR study supported a significant association, with each standard deviation increase in serum 25OHD concentrations correlating to a 23% reduced risk of rosacea (HR = 0.77, 95% CI: 0.63, 0.93). CONCLUSIONS: The findings of this cohort study indicate an inverse association between increased concentrations of serum 25OHD and the risk of developing incident rosacea. While our results highlight the potential protective role of vitamin D, the definitive efficacy of vitamin D supplementation as a preventive strategy against rosacea requires further investigation.

Treatment of ocular rosacea: A practical review from an interdisciplinary approach.

Rosacea is a chronic and inflammatory disease that primarily affects the skin, although more than half of cases also present with ocular symptoms ranging from blepharitis to conjunctivitis and keratitis. It represents a frequent reason for consultation with a psychosocial impact, affecting quality of life, and requires management involving ophthalmologists, dermatologists, and primary care physicians. For this paper, a search was conducted in several databases, including Medline, Embase, Cochrane, and Google Scholar, using the MeSH term "rosacea" in conjunction with other relevant keywords such as "ocular rosacea", "management", "treatment", and "guidelines". Available articles were reviewed. International and local guidelines recommend initiating the management of rosacea with lifestyle changes, including ocular hygiene and avoidance of triggers. Topical or oral treatment is recommended as the next step, with topical cyclosporine, topical azithromycin, topical tacrolimus, and oral doxycycline being the treatments most supported by evidence. Combination treatments are also recommended. Current management guidelines mainly focus on cutaneous manifestations, generating few guidelines on ophthalmologic treatment, and most recommendations are issued by experts. This work compares local and international treatment guidelines for rosacea, as well as other available medical literature, and suggests a practical and interdisciplinary treatment scheme for ocular involvement based on the reviewed bibliography.

A new 532 nm, variable-pulse-structure, dual-wavelength, KTP laser incorporating cryogen spray cooling, effectively treats rosacea.

BACKGROUND: A new dual-wavelength, high-energy, solid-state laser incorporating both 532 and 1064 nm wavelengths was developed with cryogen spray cooling and the unique ability to deliver three types of pulse structures including single pulses of a specific pulse-duration or pulses composed of a train of subpulses in the millisecond or microsecond domain with an intervening delay over the selected pulse-duration. We investigate the efficacy of this laser using all three pulse structures and the 532 nm wavelength for treating rosacea. METHODS: Twenty-one subjects were enrolled in this IRB-approved study. A total of up to three treatments were administered at monthly intervals. Each treatment consisted of a first pass tracing linear vessels with a 40 ms pulse-duration immediately followed by a second pass using a 5 ms pulse, using all three available pulse structures. Assessment of cross-polarized digital images by blinded physician observers compared baseline and 3-month follow-up images. RESULTS: Blinded observers correctly identified the posttreatment images 89% of the time, in 17 of 19 subjects completing the study, with an average overall improvement rating of 39% after only three treatments. Side effects were limited to short-term erythema and edema. CONCLUSION: This study demonstrates that this new, variable-pulse-structure, dual wavelength, solid state, KTP laser with dynamic cooling is a safe and effective for treating rosacea.

Clinical and histological features and treatment outcomes of patients with Morbihan disease: a systematic review.

Morbihan disease (MD) is considered a rare complication of rosacea, which is difficult to diagnose and challenging to treat. Here, we performed a systematic review of available case reports and case series to summarize key clinical and pathologic features of and successful treatment regimens for MD. We conducted a search of the PubMed/MEDLINE, EMBASE, and Cochrane electronic databases from their inception to the date of search on March 6, 2023. We found that MD affects patients in the fifth decade of life on average, more commonly reported in male than female (69% vs 31%). Clinically, MD affects the eyelids, cheeks, and forehead most commonly, presenting as non-pitting, erythematous edema or an edematous plaque. On biopsy, the pathologic features, such as dermal edema, sebaceous hyperplasia, perivascular and periadnexal inflammatory infiltrate, and granulomatous reaction, are frequently reported. Out of 55 patients who were able to achieve complete response without recurrence, 35% of patients were treated with isotretinoin and 22% were treated with tetracycline antibiotics with a daily dosage range of 20-80 mg and 40-200 mg, respectively. Out of those 55 patients, 22% and 7% were treated successfully with surgical intervention and intralesional injection of steroids, respectively. Additionally, lymphatic drainage has been shown to be an effective adjunctive therapeutic tool. More studies are necessary to understand the disease mechanism to improve the diagnosis of and develop evidence-based therapies for MD.

A Review of Applications and Intracellular Mechanisms of Intense Pulsed Light in Eyelid Inflammatory Diseases.

Objective: To evaluate relevant clinical outcomes and conclude possible mechanisms of intense pulsed light (IPL) in eyelid inflammation. Background: IPL devices were primarily applied in cutaneous vascular malformations and have been used in ocular diseases for about 20 years, mostly including meibomian gland dysfunction (MGD), blepharitis, and ocular rosacea. Recent findings: Seventy-two original clinical researches were included, 57 for MGD, 4 for blepharitis or blepharitis-related keratoconjunctivitis, and 11 for rosacea. Dry eye symptoms, (tear) break-up time (BUT), and meibomian structure and/or functions were improved in most patients, but production of reactive oxygen species is an important link in the photobiomodulation mediated by IPL, which can influence numerous signal pathways to achieve anti-inflammatory, anti-infective, and prodifferentiation effects. Conclusions: The evidence suggests that IPL is an effective therapeutic tool for most patients with MGD, but more clinical evidence is needed for other indications.

Dietary supplementation of n-3 PUFAs ameliorates LL37-induced rosacea-like skin inflammation via inhibition of TLR2/MyD88/NF-κB pathway.

Rosacea is a facial chronic inflammatory skin disease with dysfunction of immune and neurovascular system and treatments for rosacea are challenging. N-3 polyunsaturated fatty acids (PUFAs), one of essential fatty acids, are needed for health maintenance and exert anti-inflammation and immunomodulatory effects in a series of cutaneous diseases such as atopic dermatitis and photoaging through dietary supplementation. However, the role of n-3 PUFAs on rosacea remains to be elucidated. In this study, KEGG enrichment analysis and GO analysis indicated that the biological process and signaling pathways, including chemokine signaling pathway, regulated by n-3 PUFAs highly overlapped with those in the pathogenic biological process of rosacea, especially the erythema telangiectasia type. Next, mice were randomized to fed with a customized n-3 PUFAs diet. We showed that n-3 PUFAs ameliorated skin erythema, inhibited dermal inflammatory cell infiltration (mast cells, neutrophils, and CD4 +T cells) and suppressed elevated pro-inflammatory cytokines in LL37-induced rosacea-like mice. Besides, n-3 PUFAs were also verified to repress angiogenesis in LL37-induced mice skin. Further investigation revealed that n-3 PUFAs attenuated LL37-induced inflammation via TLR2/ MyD88/ NF-κB pathway both in mice and in keratinocytes. In conclusion, our findings underscore that dietary supplementation of n-3 PUFAs have the potential to become an efficient and safe clinical therapeutic candidate for rosacea.

Combined therapy of 5-aminolevulinic acid photodynamic therapy and intense pulsed light for rosacea.

Rosacea is difficult to treat. Therefore, new alternative modalities are necessary to demonstrate. The present study was conducted to assess the efficacy and safety of the combined therapy of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) and intense pulsed light (IPL) for rosacea to provide a new treatment option for rosacea. The study was conducted from November 2017 to April 2019 at the Department of Dermatology, The First Hospital of China Medical University. Patients aged 18-65 years and diagnosed clinically as erythematotelangiectatic (ET) or papulopustular (PP) rosacea were enrolled. Three times of ALA-PDT at 10 days interval followed by 3 times of IPL at 3-4 weeks interval were defined as 1 session and applied to the whole face of each patient. ALA-PDT: 5% ALA, red light (fluency dose 60-100 mW/cm2, 20 min); IPL: 560/590/640 nm, double/triple-pulse mode, pulse width 3.0 to 4.5 ms, delay time 30-40 ms, energy fluency 14-17 J/cm2. Ten patients were enrolled in the study. Among them, 4 patients received only 1 session, while 6 patients received 2 sessions. After all treatments, 50% of patients achieved 75-100% improvement, and 30% achieved 50-75% improvement. Forty percent of patients were graded very satisfaction and 30% graded moderate satisfaction. All noninvasive measurements showed no significant differences among all time points (p > 0.05). The side effects were pain, burning sensation, itching, erythema, desquamation, slight edema, slight exudation, and hyperpigmentation. All of which were tolerable and recovered in a few days. The combined therapy of ALA-PDT and IPL showed an effective option for rosacea with a safety profile.

Paediatric ocular rosacea: diagnosis and management with an eyelid-warming device and topical azithromycin 1.5.

BACKGROUND: Ocular rosacea is a chronic inflammatory disorder with periods of exacerbation and remission, often underdiagnosed in children. When diagnosed, its management is challenging because of a lack of effective long-term treatment options. OBJECTIVE: To report our experience in cases of pediatric ocular rosacea treated with moist heat therapy and topical azithromycin 1.5%. METHODS: The medical records of six children diagnosed with ocular rosacea based on a careful medical history and slit-lamp examination of the eyelids and ocular surface were reviewed. Previous treatments were discontinued, and children/parents were instructed to use the eyelid-warming device for 1 or 2 sessions of 10minutes each day, followed by eyelid massage and cleansing, in combination with azithromycin 1.5% eye drops. RESULTS: The diagnosis of ocular rosacea in these children was delayed for several months or years from the first identifiable clinical sign or symptom. All the children presented with corneal sequelae and decreased vision. Ocular manifestations included meibomian gland disease, recurrent chalazia, and phlyctenular keratoconjunctivitis. Cutaneous signs were not always associated with the condition. Ocular rosacea was usually resistant to initial treatments with antibiotics and topical corticosteroids. Treatment with the eyelid-warming device in combination with azithromycin 1.5% led to a rapid improvement in the clinical signs and was well tolerated by all patients. CONCLUSIONS: Childhood ocular rosacea is potentially sight threatening. Practitioners should consider this condition in order to minimise diagnostic delay and subsequent complications. Combined therapy of eyelid hygiene (including an eyelid warming device) and azithromycin 1.5% eye drops was effective in treating ocular rosacea in children.

Advances in pharmacotherapy for rosacea: what is the current state of the art?

INTRODUCTION: Rosacea is a chronic and relapsing facial dermatosis that encompasses a wide spectrum of clinical phenotypes (transient/persistent erythema, telangiectasias, papules/pustules, edema, phymatous changes, and ocular symptoms) often with uncomfortable symptoms such as flushing, pain, burning, edema, and dryness. Current pharmacological treatment includes topical agents, spanning from several conventional (azelaic acid, metronidazole, sodium sulfacetamide) to new ones (brimonidine, oxymetazoline, ivermectine, minocycline), and systemic agents (doxycycline 40 mg modified-release), all Food and Drug Administration approved. AREAS COVERED: The aim of our article is to review the state of art of pharmacological treatment, either as monotherapy or in combination therapy, tailored to the most common rosacea phenotypes (persistent erythema, inflammatory papules/pustules). Other off-label topical or systemic drugs and several adjuvant phytotherapeutic agents are considered. EXPERT OPINION: Combined therapies to target different phenotypes, when present in the same patient, represent one of the major achievements in the management of vascular and inflammatory papules and pustules of rosacea. Future investigations should be addressed to early inflammatory phyma or ocular rosacea, which have actually been neglected. Finally, there is still an ongoing need for therapeutic interventions able to relieve symptoms and social burden, all factors that greatly contribute to improve rosacea quality of life.

Efficacy and safety of topical brimonidine in dermatology: A review article.

Brimonidine is a vasoconstrictive agent used to treat several dermatologic disorders. Here, we review the uses of brimonidine in different aspects of dermatology. We searched keywords including rosacea, erythema, topical brimonidine, dermatology, and skin disease in PubMed, Cochrane, and Google Scholar to collect the related published articles. In a review of 15 articles, we found topical brimonidine improved the facial erythema of rosacea. In addition, it reduced the erythema associated with alcohol flushing syndrome, intense pulsed light therapy, and photodynamic therapy. Furthermore, topical brimonidine was used as a hemostatic agent in dermatosurgery procedures such as Mohs surgery and nail surgery to reduce intra-operative and postoperative bleeding. Some side effects such as erythema, flushing, and burning were reported in a few patients. Based on our findings, brimonidine is a beneficial drug that can be used in various dermatologic disorders with negligible side effects.

Intense pulsed light treatment for inflammatory skin diseases: a review.

Although intense pulsed light (IPL) has been commonly used in the field of medical cosmetics in recent years, the exact outcomes of IPL in the treatment of inflammatory skin diseases remain unclear. To assess the clinical evidence for the use of IPL in the treatment of various inflammatory skin diseases and propose evidence-based recommendations, we searched for relevant publications in the PubMed and Web of Science databases and provided updated information. The inflammatory skin diseases treated with IPL consisted of acne vulgaris, rosacea, psoriasis, hidradenitis suppurativa (HS), atopic dermatitis (AD), Riehl's melanosis, lupus erythematosus, cutaneous sarcoidosis, pilonidal cysts, and pigmented actinic lichen planus (PALP). The efficacy of IPL treatment for these inflammatory skin diseases was described and evaluated. Forty-two studies were included to provide this assessment. The evidence suggests that IPL can effectively and safely improve acne vulgaris and rosacea (recommendation grade B). For other described inflammatory skin diseases, IPL can be used as a tentative or supplementary treatment (recommendation grade C and D). The main complications include transitory erythema, edema, and pain, with the possibility of hyperpigmentation, blisters, and a burning sensation in some individuals.

Integrative skincare trial of intense pulsed light followed by the phyto-corrective mask, phyto-corrective gel, and resveratrol BE for decreasing post-procedure downtime and improving procedure outcomes in patients with rosacea.

BACKGROUND: Rosacea is a chronic inflammatory skin condition of varying severity that can significantly impact patient quality of life. Intense pulsed light (IPL) is an established treatment for rosacea-associated telangiectasia, inflammation, and erythema. This study assessed whether application of a phyto-corrective mask, gel, and resveratrol antioxidant serum after IPL treatment can improve outcomes and reduce procedure-related adverse effects. METHODS: In a prospective, open-label, split-face, 3-month study, 10 subjects with moderate-to-severe facial rosacea underwent IPL treatment on both sides of the face. The following were applied to the right side of the face only: phyto-corrective mask once weekly starting immediately after IPL; phyto-corrective gel twice daily; and resveratrol antioxidant treatment at night. Both sides of the face were treated with sunscreen. Subjects were assessed on Day 1, 1 and 3 months after IPL by three, independent evaluators using the 5-point Global Aesthetic Improvement Scale (GAIS). All subjects rated skin redness, hydration, and overall improvement on Day 1 and completed a patient satisfaction questionnaire at the 1- and 3-month visits. RESULTS: Ten women were enrolled, aged 44-72 years old, with moderate (n = 6) to severe (n = 4) rosacea. IPL was effective at reducing symptoms with rosacea classified as absent in five women and mild in five at the final 3-month visit. GAIS scores also revealed improvements on both sides of the face, but the skincare treated side showed continuous improvement over 3 months with all patients remaining at least "Improved", whereas there appeared to be a waning effect after 1 month with IPL alone. On Day 1 after IPL, all women reported less redness, improved hydration, and improved skin appearance on the right side of the face. Patient satisfaction was consistently rated higher on the right side of the face. CONCLUSION: Application of a phyto-corrective mask, gel, and resveratrol antioxidant serum may complement IPL treatment for rosacea by enhancing treatment outcomes and reducing procedure-related symptoms.

Evaluation of Therapeutic Effect and Prognosis of Danzhi Xiaoyao Powder Combined with Photodynamic Therapy in the Treatment of Rose Acne.

Background: Rose acne is a chronic inflammatory skin disease that can cause paroxysmal flushing, persistent erythema, papules or papules on the face, and pustules, and it has a greater impact on the life of patients, so it is important to treat it. Objective: To investigate the effect of Danzhi Xiaoyao Powder combined with photodynamic therapy (PDT) on the curative effect evaluation and prognosis of patients with rose acne. Patients and Methods. The clinical data of 110 rose acne patients who were treated in our hospital from January 2019 to January 2021 were selected as the subject of this retrospective study. They were divided into a control group and a treatment group according to the random residue grouping method. The new crown epidemic, loss to follow-up, etc. fell out of 5 cases in each group, and finally, 50 cases in each group were left. Among them, the control group was treated with PDT, and the treatment group was combined with Danzhi Xiaoyao Powder on the basis of the control group. Then we observe and compare the effects of skin lesion scores and clinical symptom scores and differences in clinical efficacy between the two groups. Results: The comparison of the clinical symptom scores of the two groups of patients before treatment was not statistically significant (P > 0.05), while the burning score, tingling score, dryness score, and pruritus score of the treatment group after treatment were significantly different. The internal comparison after treatment was lower than before treatment, and the comparison between the treatment groups was significantly higher than the control group, which was statistically significant (P < 0.05). There was no statistically significant difference in the skin lesion scores of the two groups before treatment (P > 0.05), while the papules score, pustule score, erythema score, and telangiectasia score of the treatment group after treatment were significantly different and compared within the group. After treatment, the treatment group was significantly higher than the control group, and the comparison was statistically significant (P < 0.05). The effective rate of 98.00% in the treatment group was significantly higher than the 76.00% in the control group, and the difference was statistically significant (P < 0.05). The clinical efficacy of the two groups of patients showed that the rash, chest tightness, nausea, and diarrhea of the treatment group were significantly lower than those of the control group, and the difference was statistically significant (P < 0.05). Conclusion: Danzhi Xiaoyao Powder combined with PDT to treat rose acne is effective, can quickly control inflammatory papules and inflammatory erythema, effectively improve the clinical symptoms of patients, and reduce adverse reactions.

The impact of clinical nutrition on inflammatory skin diseases.

The influence of nutrition on the pathophysiology and clinical severity of inflammatory facial dermatoses such as acne, rosacea, seborrheic dermatitis, and perioral dermatitis has been controversially discussed for years. As part of a modern treatment approach, clinicians should provide patients with information on how their choice of diet might impact their dermatologic diagnosis and could potentially enhance therapeutic outcome. Recently, the concept of a gut-skin axis has gained momentum in the understanding of inflammatory dermatoses, with nutrition considered a contributing factor in this context. For example, gastrointestinal symptoms in rosacea patients may indicate a dysbiosis of the gut microbiome, treatment of which may also improve severity of the skin disease. New research efforts were recently made for acne patients addressing the clinical effects of omega-3 fatty acids and probiotics. In contrast, due to the limited data available, no comparable specific dietary recommendations can yet be made for seborrheic or perioral dermatitis. However, there are promising signs that clinical nutrition and dermatology will be more extensively interlinked in the future, both clinically and scientifically.