Angiogenesis in Chronic Inflammatory Skin Disorders.

Angiogenesis, the growth of new blood vessels from preexisting vessels, is associated with inflammation in various pathological conditions. Well-known angiogenetic factors include vascular endothelial growth factor (VEGF), angiopoietins, platelet-derived growth factor, transforming growth factor-ß, and basic fibroblast growth factor. Yes-associated protein 1 (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) have recently been added to an important angiogenic factor. Accumulating evidence indicates associations between angiogenesis and chronic inflammatory skin diseases. Angiogenesis is deeply involved in the pathogenesis of psoriasis. VEGF, angiopoietins, tumor necrosis factor-a, interleukin-8, and interleukin-17 are unregulated in psoriasis and induce angiogenesis. Angiogenesis may be involved in the pathogenesis of atopic dermatitis, and in particular, mast cells are a major source of VEGF expression. Angiogenesis is an essential process in rosacea, which is induced by LL-37 from a signal cascade by microorganisms, VEGF, and MMP-3 from mast cells. In addition, angiogenesis by increased VEGF has been reported in chronic urticaria and hidradenitis suppurativa. The finding that VEGF is expressed in inflammatory skin lesions indicates that inhibition of angiogenesis is a useful strategy for treatment of chronic, inflammatory skin disorders.

Keratinocyte-Immune Cell Crosstalk in a STAT1-Mediated Pathway: Novel Insights Into Rosacea Pathogenesis.

Rosacea is a common chronic inflammatory condition that mainly affects the central face. However, the molecular background of the normal central face and the transcriptional profiling and immune cell composition of rosacea lesions remain largely unknown. Here, we performed whole-skin and epidermal RNA-seq of central facial skin from healthy individuals, lesions and matched normal skin from rosacea patients. From whole-skin RNA-seq, the site-specific gene signatures for central facial skin were mainly enriched in epithelial cell differentiation, with upregulation of the activator protein-1 (AP1) transcription factor (TF). We identified the common upregulated inflammatory signatures and diminished keratinization signature for rosacea lesions. Gene ontology, pathway, TF enrichment and immunohistochemistry results suggested that STAT1 was the potential core of the critical TF networks connecting the epithelial-immune crosstalk in rosacea lesions. Epidermal RNA-seq and immunohistochemistry analysis further validated the epithelial-derived STAT1 signature in rosacea lesions. The epidermal STAT1/IRF1 signature was observed across ETR, PPR, and PhR subtypes. Immune cell composition revealed that macrophages were common in all 3 subtypes. Finally, we described subtype-specific gene signatures and immune cell composition correlated with phenotypes. These findings reveal the specific epithelial differentiation in normal central facial skin, and epithelial-immune crosstalk in lesions providing insight into an initial keratinocyte pattern in the pathogenesis of rosacea.

Cutaneous and ocular rosacea: Common and specific physiopathogenic mechanisms and study models.

Rosacea is a chronic inflammatory disease that affects the face skin. It is clinically classified into the following four subgroups depending on its location and severity: erythematotelangiectatic, papulopustular, phymatous, and ocular. Rosacea is a multifactorial disease triggered by favoring factors, the pathogenesis of which remains imperfectly understood. Recognized mechanisms include the innate immune system, with the implication of Toll-like receptors (TLRs) and cathelicidins; neurovascular deregulation involving vascular endothelial growth factor (VEGF), transient receptor potential (TRP) ion channels, and neuropeptides; and dysfunction of skin sebaceous glands and ocular meibomian glands. Microorganisms, genetic predisposition, corticosteroid treatment, and ultraviolet B (UVB) radiation are favoring factors. In this paper, we review the common and specific molecular mechanisms involved in the pathogenesis of cutaneous and ocular rosacea and discuss laboratory and clinical studies, as well as experimental models.

Emerging topical drugs for the treatment of rosacea.

Introduction: Rosacea is a common, chronic and relapsing inflammatory skin disease of the centrofacial area. Despite advancing knowledge on its pathogenesis, diagnosis, and treatment, some major unknowns still remain, including systematic evidence-based guidelines useful both for clinical assessment and therapeutic management. Topical treatment is regarded as a first-line option for mild to moderate rosacea and includes traditional and new FDA-approved prescription drugs, as well as off-label alternative topical agents.Areas covered: Since improved awareness of rosacea pathogenetic mechanisms has led to the development of new potential therapeutic agents, a search was performed on the ClinicalTrial.gov registry. The results identified several investigational topical drugs able to target one or more of the pathogenetic factors of rosacea.Expert opinion: The main unmet needs in the topical treatment of rosacea remain the management of vasomotor flushes and telangiectasias, as well as of troublesome symptoms such as burning and/or stinging. No single agent effective on all rosacea phenotypes is available so far, and preventive treatments capable of halting disease progression have not been identified yet. Finally, data on long-term efficacy and tolerability are still incomplete, especially for drugs more recently introduced in the market.

Efficacy of Topical Ivermectin for the Treatment of Cutaneous and Ocular Rosacea.

Purpose: To investigate the efficacy of once-daily topical treatment of ocular and cutaneous rosacea with ivermectin 1% cream (Soolantra®, Galderma).Methods: Ten patients with rosacea were evaluated in a retrospective monocentric pilot study. Subjective symptoms (measured with the Ocular Surface Disease Index), skin findings, and ocular changes (blepharitis with telangiectasia and meibomian gland dysfunction, conjunctival redness, tear breakup time (TBUT), and fluorescein staining of the cornea) were evaluated. The follow-up was 8 months (range: 5-12 months).Results: The OSDI score decreased in the 8th week of treatment (38.5 ± 21.7, P = .004). After 16 weeks, blepharitis (P = .004), and conjunctival redness (P = .008) had strongly improved, and grade 1 was seen in all patients until the end of follow-up. Fluorescein staining of the cornea (P = .001) and TBUT (P = .016) showed significant improvement until the last follow-up visit. No side effects were observed. Conclusion: Topical ivermectin cream 1% given daily is an effective and safe therapy against rosacea.

Use of beta-blockers for rosacea-associated facial erythema and flushing: A systematic review and update on proposed mode of action.

BACKGROUND: Flushing and erythema are frequent skin symptoms in rosacea. Because their adequate treatment remains a clinical challenge, new treatment options are explored, such as oral ß-blockers. OBJECTIVES: To evaluate the efficacy of oral ß-blockers for rosacea-associated facial flushing and erythema. METHODS: PubMed, Embase, Web of Science, and Cochrane Library were systematically searched, including studies providing original data on the efficacy of oral ß-blockers in rosacea patients with facial flushing and/or persistent erythema. Risk of bias was assessed using the Cochrane Risk of Bias tool, Newcastle-Ottawa scale, and Quality in Prognosis Studies tool. RESULTS: Nine studies evaluating the use of carvedilol, propranolol, nadolol, and ß-blockers in general were included. Articles studying carvedilol and propranolol showed a large reduction of erythema and flushing during treatment with a rapid onset of symptom control. Bradycardia and hypotension were the most commonly described adverse events. LIMITATIONS: Most studies had a retrospective design with a small sample size, and outcome measurement was often subjective. CONCLUSIONS: Oral ß-blockers could be an effective treatment option for patients with rosacea with facial erythema and flushing that does not respond to conventional therapy. Larger prospective trials with objective outcome assessment are needed to validate the promising results of these studies.

Ocular surface changes in the treatment of rosacea: comparison between low-dose oral isotretinoin and doxycycline / Alterações da superfície ocular no tratamento da Rosácea: comparação entre isotretinoína oral em baixa dosagem e doxiciclina

ABSTRACT Purpose: To compare the impact of ocular changes between systemic treatment with doxycycline and low-dose oral isotretinoin in patients with moderate-to-severe papulopustular rosacea. Methods: Patients were randomized to receive either isotretinoin 0.3-0.4 mg/kg (group A) or doxycycline 100 mg/day (group B) for 16 weeks. Ocular symptoms were searched and evaluated, including best-corrected visual acuity (BCVA), Schirmer test, breakup time, rose bengal staining score, and meibomian gland dysfunction grading. The patients were retested at the end of treatment. Results: The present study included 39 patients (30 females and 9 males). Best-corrected visual acuity was > 20/30 in >90% of patients in both groups and did not change after treatment. After treatment, improvement in ocular symptoms and meibomian gland dysfunction was more pronounced in group B (p<0.05); the other parameters did not reach statistical significance. Conclusion: Doxycycline improved meibomian gland dysfunction, ocular symptoms, and ocular surface in patients with rosacea. Even though some patients experienced worsening meibomian gland dysfunction and symptoms, no subject experienced any serious complications after administration of low-dose isotretinoin.

RESUMO Objetivos: Comparar o impacto das alterações oculares entre o tratamento sistêmico de doxiciclina e isotretinoína em baixa dosagem em pacientes com rosácea papulopustulosa moderada a grave. Métodos: Os pacientes form randomizados para receber isotretinoína 0,3 a 0,4 mg/kg (grupo A) ou doxiciclina 100mg/dia (grupo B) por 16 semanas. Os sintomas oculares foram pesquisados e avaliados, incluindo melhor acuidade visual corrigida, teste de Schirmer, tempo de ruptura do filme lacrimal, coloração de rosa bengala e graduação da disfunção de glândula de Meibomius. Os pacientes foram novamente testados no final do tratamento. Resultados: O presente estudo incluiu 39 pacientes (30 mulheres e 9 homens). A melhor acuidade visual corrigida foi >20/30 em >90% dos pacientes em ambos os grupos e não se alterou após o tratamento. A melhora dos sintomas oculares e da disfunção de glândula de Meibomius foi mais pronunciada no grupo B (p<0,05) após o tratamento; as demais variáveis não atingiram significância estatística. Conclusão: A doxiciclina melhorou a disfunção de glândula de Meibomius, os sintomas oculares e a superfície ocular de pa cientes com rosácea. Mesmo que alguns pacientes tenham piorado a disfunção e os sintomas da glândula de Meibomius, nenhum indivíduo apresentou complicações graves após a admi nistração de baixas doses de isotretinoína.

Oily sensitive skin: A review of management options.

BACKGROUND: Due to the ever-increasing demands for the personalized care, people seek for the tailored management according to the accurate identification of their skin type. The Baumann Skin Type Indicator, which was proposed by Leslie Baumann, is composed of four parameters: oily or dry, resistant or sensitive, pigmented or nonpigmented, and wrinkled or tight. Among these, oily sensitive skin experiences significant discomfort and resists ordinary treatment. AIMS: In this article, we will review the clinical manifestations, underlying pathogenesis and recommendations on treatment options that may be utilized to help patients with oily sensitive skin. PATIENTS/METHODS: Literature search was conducted using PubMed. The literature concerning Baumann Skin Type Indicator and oily sensitive skin type were considered. RESULTS: Oily sensitive (OS)-type skin is a complex of oily and sensitive skin that causes significant discomfort and undergoes stubborn resistance to treatments. Sebum dysfunction and hypersensitivity may play a key role in the development of sensitive skin. Considering the pathogenesis of OS-type skin, treatment should focus on both seborrhea and hypersensitivity. CONCLUSION: Clinicians can effectively treat the oily sensitive skin by understanding underlying pathogenesis of it. Further investigations are necessary to reach a consensus on the basic pathophysiology and optimal management guidelines for oily sensitive skin.

Characterization and Analysis of the Skin Microbiota in Rosacea: A Case-Control Study.

BACKGROUND: The efficacy of antibiotics in rosacea treatment suggests a role for microorganisms in its pathophysiology. Growing concern over the adverse effects of antibiotic use presents a need for targeted antimicrobial treatment in rosacea. OBJECTIVE: We performed a case-control study to investigate the skin microbiota in patients with rosacea compared to controls matched by age, sex, and race. METHODS: Nineteen participants with rosacea, erythematotelangiectatic, papulopustular, or both, were matched to 19 rosacea-free controls. DNA was extracted from skin swabs of the nose and bilateral cheeks of participants. Sequencing of the V3V4 region of the bacterial 16S ribosomal RNA gene was performed using Illumina MiSeq and analyzed using QIIME/MetaStats 2.0 software. RESULTS: Compared with controls, skin microbiota in erythematotelangiectatic rosacea was depleted in Roseomonas mucosa (p = 0.004). Papulopustular rosacea was enriched in Campylobacter ureolyticus (p = 0.001), Corynebacterium kroppenstedtii (p = 0.008), and the oral flora Prevotella intermedia (p = 0.001). The highest relative abundance of C. kroppenstedtii was observed in patients with both erythematotelangiectatic and papulopustular rosacea (19.2%), followed by papulopustular (5.06%) and erythematotelangiectatic (1.21%) rosacea. C. kroppenstedtii was also associated with more extensive disease, with the highest relative abundance in rosacea affecting both the cheeks and nose (2.82%), followed by rosacea sparing the nose (1.93%), and controls (0.19%). CONCLUSIONS: The skin microbiota in individuals with rosacea displays changes from that of healthy skin, suggesting that further studies examining a potential role for the skin microbiota in the pathophysiology of rosacea may be warranted.

Ocular surface changes in the treatment of rosacea: comparison between low-dose oral isotretinoin and doxycycline.

PURPOSE: To compare the impact of ocular changes between systemic treatment with doxycycline and low-dose oral isotretinoin in patients with moderate-to-severe papulopustular rosacea. METHODS: Patients were randomized to receive either isotretinoin 0.3-0.4 mg/kg (group A) or doxycycline 100 mg/day (group B) for 16 weeks. Ocular symptoms were searched and evaluated, including best-corrected visual acuity (BCVA), Schirmer test, breakup time, rose bengal staining score, and meibomian gland dysfunction grading. The patients were retested at the end of treatment. RESULTS: The present study included 39 patients (30 females and 9 males). Best-corrected visual acuity was > 20/30 in >90% of patients in both groups and did not change after treatment. After treatment, improvement in ocular symptoms and meibomian gland dysfunction was more pronounced in group B (p<0.05); the other parameters did not reach statistical significance. CONCLUSION: Doxycycline improved meibomian gland dysfunction, ocular symptoms, and ocular surface in patients with rosacea. Even though some patients experienced worsening meibomian gland dysfunction and symptoms, no subject experienced any serious complications after administration of low-dose isotretinoin.

The Role of IL-17 in Papulopustular Rosacea and Future Directions.

Rosacea is a chronic, progressive, inflammatory condition phenotypically subtyped into diagnostic features, major features, and minor/secondary features. There is currently no cure for rosacea, and it carries a significant negative psychosocial burden for afflicted patients. While there are a number of treatment modalities at the disposal of the clinician, clinical experience has suggested a need for updated treatments. The pathogenesis of rosacea is multifactorial; however, this paper will focus on the pivotal role of interleukin 17 (IL-17) in the development and progression of the disease. Furthermore, this paper will explore the mechanism of action of standard rosacea treatments and their effect on different stages of the IL-17 pathway. The standard treatments for rosacea are usually effective in controlling the symptoms of the disease in its mild-to-moderate form; however, their efficacy is diminished in the setting of severe and treatment-resistant rosacea. We hypothesize that IL-17 inhibitors, currently used successfully in psoriasis and psoriatic arthritis, could perhaps be used to treat severe and treatment-resistant papulopustular rosacea in the future; however, clinical trials and case reports will be needed to dictate expanded indications of IL-17 inhibitors. Furthermore, the high cost of IL-17 inhibitors presently prevents their use in disease states other than psoriasis or psoriatic arthritis.

Comparative effectiveness of purpuragenic 595 nm pulsed dye laser versus sequential emission of 595 nm pulsed dye laser and 1,064 nm Nd:YAG laser: a double-blind randomized controlled study.

INTRODUCTION: Erythematotelangiectatic rosacea is a common condition in Caucasians. The most frequently used lasers to treat this condition are pulsed dye laser (PDL) and neodymium:yttrium-aluminum-garnet laser (Nd:YAG). This study compares the treatment efficacy of purpuragenic PDL with that of sequential emission of 595 nm PDL and 1,064 nm Nd:YAG (multiplexed PDL/Nd:YAG). METHODS: We performed a prospective, randomized, and controlled split-face study. Both cheeks were treated, with side randomization to receive treatment with PDL or multiplexed PDL/Nd:YAG. Efficacy was evaluated by spectrophotometric measurement, visual photograph evaluation, the Dermatology Quality of Life Index questionnaire, and a post-treatment questionnaire. RESULTS: Twenty-seven patients completed the study. Treatment was associated with a statistically significant improvement in quality of life (p < 0.001). PDL and multiplexed PDL/Nd:YAG modalities significantly reduced the erythema index (EI; p < 0.05). When comparing the degree of EI reduction, no differences were observed between the two treatment modalities. PDL was associated with a higher degree of pain and a higher percentage of purpura. Multiplexed PDL/Nd:YAG modality was associated with fewer side effects and greater global satisfaction, and 96.3% of the patients would recommend this treatment to a friend. CONCLUSIONS: Both laser modalities are efficacious in the treatment of erythematotelangiectatic rosacea. The multiplexed PDL/Nd:YAG modality was preferred by the patients.

Assessment of Skin Physiology Change and Safety After Intradermal Injections With Botulinum Toxin: A Randomized, Double-Blind, Placebo-Controlled, Split-Face Pilot Study in Rosacea Patients With Facial Erythema.

BACKGROUND: Botulinum toxin (BTX) has been used cosmetically with good clinical efficacy and tolerable safety. OBJECTIVE: This randomized, double-blind, split-face clinical study aimed to investigate the efficacy and safety of intradermal BTX in patients with rosacea. MATERIALS AND METHODS: Twenty-four participants were enrolled and randomly given intradermal injections of BTX and normal saline in both cheeks. Clinician Erythema Assessment (CEA) score, Global Aesthetic Improvement Scale (GAIS) score, skin hydration, transepidermal water loss (TEWL), melanin content, erythema index, elasticity, and sebum secretions were evaluated at baseline and 2, 4, 8, and 12 weeks. RESULTS: On the BTX-treated side, the CEA score significantly decreased and the GAIS score significantly increased. The erythema index decreased at Weeks 4 and 8. Skin elasticity was improved at Weeks 2 and 4 and skin hydration, at Weeks 2, 4, and 8. However, TEWL and sebum secretion did not show significant differences. CONCLUSION: Intradermal BTX injections reduced erythema and rejuvenated the skin effectively and safely in patients with rosacea.

Global epidemiology and clinical spectrum of rosacea, highlighting skin of color: Review and clinical practice experience.

Rosacea has been reported less frequently among individuals with skin of color than in those with white skin, but rosacea is not a rare disease in this population. In fact, rosacea might be underreported and underdiagnosed in populations with skin of color because of the difficulty of discerning erythema and telangiectasia in dark skin. The susceptibility of persons with highly pigmented skin to dermatologic conditions like rosacea, whose triggers include sun exposure, is probably underestimated. Many people with skin of color who have rosacea might experience delayed diagnosis, leading to inappropriate or inadequate treatment; greater morbidity; and uncontrolled, progressive disease with disfiguring manifestations, including phymatous rosacea. In this article, we review the epidemiology of rosacea in skin of color and highlight variations in the clinical presentation of rosacea across the diverse spectrum of patient populations affected. We present strategies to aid in the timely diagnosis and effective treatment of rosacea in patients with skin of color, with an aim of promoting increased awareness of rosacea in these patients and reducing disparities in the management of their disease.

Treatment of Rosacea using acupuncture for improving the local skin microcirculation: A case report.

RATIONALE: Rosacea is an irritating disease that affects patients' health and life quality. The current treatments for rosacea have limited efficacy and are generally not satisfying most patients. This report presents a patient diagnosed with rosacea who was treated with acupuncture to a satisfactory effect. Laser Doppler was used to measure the local blood perfusion of the nose before, during, and after acupuncture treatment. The Dermatology Life Quality Index (DLQI) was used to measure the impact of rosacea on the quality of the patient's life. PATIENT CONCERNS: A 52-year-old woman had been diagnosed with rosacea 18 months before this study. She had tried medical treatments in other hospitals with metronidazole cream, antifungal drugs, and steroidal ointments, but the effect was poor and limited. DIAGNOSES: In this study, the diagnosis of rosacea (stage I, subtype Erythematotelangiectatic) was made by a dermatologist according to physical examination). INTERVENTIONS: The patient's treatment included a half-hour of acupuncture 3 times per week. OUTCOMES: The patient experienced significant improvements in the region around the nose after 3 sessions of acupuncture treatment within the first week and reported that there was no relapse for 6 months after acupuncture treatment. The perfusion of blood flow was redistributed during and after acupuncture treatment according to laser Doppler measurements. The patient's DLQI score substantially improved. The patient was generally satisfied with the acupuncture treatment. LESSONS: The results suggested that acupuncture might be an alternative therapy for facial localized rosacea. As well, acupuncture may be effective in treating rosacea through redistributing micro-circulation of blood at the localized area of effect. The overall costs of the rosacea treatment may be reduced, provided that this therapy is demonstrated to be effective in future controlled studies.

The Rosacea-specific Quality-of-Life instrument (RosQol): Revision and validation among Chinese patients.

Rosacea is a common chronic facial disorder that affects patients' health-related quality of life; the only questionnaire designed specifically for rosacea is the Rosacea-specific Quality-of-Life instrument (RosQol). However, the questionnaire has not been validated among Chinese patients. This study aimed to validate the Chinese version of the RosQol. First, we translated the questionnaire into Chinese. Then, rosacea patients completed the RosQol and Dermatology Life Quality Index, indicating the disease's impact on their lives. We also collected patients' demographic and clinical data, including symptom self-evaluation scores and rosacea severity scores. Internal consistency was determined by using Cronbach's alpha, test-retest reliability, and Spearman's correlation. Criterion-related validity and internal construct validity were also determined. Most RosQol items showed good internal consistency. However, items 13 and 19 were not sufficiently sensitive for use in the Chinese population; we deleted them and constructed the adjusted Chinese-version RosQol, which had good reliability and validity. When patients' clinical symptoms changed, the scores on the relevant dimensions of the adjusted RosQol also changed. Some RosQol items were not suitable for use in the Chinese sample. The adjusted Chinese-version RosQol was easy to complete, well received by patients, and demonstrated acceptable validity and reliability.