Novel insights into rosacea's role in cancer risk: A Mendelian randomization approach.

BACKGROUND: Chronic inflammation has been shown to promote cancer progression. Rosacea is indeed a long-term inflammatory skin condition and had been reported to link with increased risk for several types of malignancies, but evidence for causality is lacking. OBJECTIVES: To systematically estimate the causal relationship between rosacea and several types of cancer, including cutaneous malignant melanoma (CMM), cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC), actinic keratosis (AK), thyroid cancer, breast cancer, glioma and hepatic cancer, as well as explore the potential underlying pathogenesis. METHODS: We conducted a bidirectional two-sample Mendelian randomization study to probe the potential causal relationships between rosacea and several types of cancer. Instrumental variables were established using genome-wide significant single nucleotide polymorphisms associated with rosacea and cancers. The assessment of causality was carried out through multiple methods, and the robustness of the results was evaluated via sensitivity analyses. RESULTS: There was no significant indication of causal effects of rosacea on CMM (pivw = 0.71), cSCC (pivw = 0.45), BCC (pivw = 0.90), AK (pivw = 0.73), thyroid cancer (pivw = 0.59), glioma (pivw = 0.15), and hepatic cancer (pivw = 0.07), but the genetic risk of rosacea was associated with an increased susceptibility to human epidermal growth factor receptor (HER)-negative malignant neoplasm of breast (odds ratio [OR], 1.10; 95% confidence interval [CI], 1.02-1.18; pivw = 0.01). TANK (TRAF family member associated nuclear factor kappa B (NFKB) activator) was identified as a common protective gene for both rosacea (OR, 0.90; 95% CI, 0.82-0.99; pivw = 0.048) and HER-negative malignant neoplasm of the breast (OR, 0.86; 95% CI, 0.75-0.98; pivw = 0.032), which was primarily enriched in the negative regulation of NF-κB signal transduction and may contribute to the genetic links between rosacea and this subtype of breast cancer. CONCLUSIONS: Our findings provide suggestive evidence for causal links between rosacea and HER-negative malignant neoplasm of the breast risk.

Which factors influence Demodex mite density in standardized superficial skin biopsy in patients with rosacea? A prospective cross-sectional analysis.

Rosacea is a chronic cutaneous disease that manifests with facial erythema, telangiectasia, papules and pustules on the central face. Although the pathogenesis is not well established, rosacea appears to have a close relationship with Demodex mites. The aim of the study was to elucidate the factors influencing Demodex mite density by standardized superficial skin biopsy (SSSB) in patients with rosacea. This prospective, cross-sectional study included 200 patients with rosacea. Clinical characteristics of the patients were recorded and SSSB was used to measure Demodex density (Dd). If Dd was < 5 D/cm2 in the first SSSB, SSSB was repeated 4 more times to avoid false negative results. Of 200 patients, 152 (76%) were females and 48 (24%) males with a mean age of 43.47 ± 11.87 years. Ninety-nine patients (49.5%) had erythematotelangiectatic (ETR) and 101 patients (50.5%) had papulopustular (PPR) subtype of rosacea. Among 200 patients, the ratio of cumulative positive results of the consecutive SSSBs were as follows: 1st SSSB = 125 (62.5%), 2nd SSSB = 155 (77.5%), 3rd SSSB = 170 (85%), 4th SSSB = 173 (86.5%) and 5th SSSB = 174 (87%). The ratio of detecting Demodex infestation in the first SSSB was significantly lower in patients with PPR (55/101, 54.5%) than in patients with ETR (70/99, 70.7%). Median total Demodex mite density and D. folliculorum density were significantly higher in the ETR group than in the PPR group. There was a statistically significant relationship between density of Demodex tails in dermoscopy and positive/negative results of Demodex infestation in SSSB. As a conclusion, Demodex mite density by SSSB was influenced by various factors such as subtypes of rosacea, types of Demodex species, and dermoscopic findings.

The role of vitamins and nutrients in rosacea.

Rosacea is a common inflammatory skin condition displaying symptoms like flushing, erythema, papules, and pustules. Oral antibiotics, despite long-term adverse effects, are often used due to topical treatment limitations, underscoring the need for cost-effective choices like dietary modifications. Our review investigates the role of vitamins and minerals in rosacea, and provides evidence-based recommendations for supplementation and topical treatment of these nutrients for rosacea. An online search was performed on PubMed, Web of Science, Science Direct, Google Scholar, and ClinicalTrials.gov from 1998 to 2023. Included studies were summarized and assessed for quality and relevance in rosacea management. Varied outcomes emerged concerning the impact of essential vitamins and minerals on rosacea treatment. Vitamin A derivatives, specifically oral isotretinoin, demonstrated significant efficacy, with a 90% reduction in lesions, complete remission in 24% of patients, and marked improvement in 57% of patients. Vitamin B3 derivatives, such as topical 1-methylnicotinamide 0.25% and NADH 1%, improved symptoms in 76.4% (26/34) and 80% of patients, respectively. Outcomes for vitamin D, vitamin C, and zinc supplementation varied across studies. However, zinc sulfate solution 5% significantly reduced acne rosacea severity for patients with 40% and 60% exhibiting a moderate or good response, respectively. Omega-3 fatty acids showed significant improvement in alleviating xerophthalmia in 64% of patients with ocular rosacea. Vitamins and minerals hold potential in managing rosacea symptoms, offering a safe and cost-effective alternative or adjunctive treatment option. Currently, there are no established recommendations regarding their supplementation for rosacea. Studies assessing serum levels of vitamins and minerals in relation to rosacea are warranted, as this avenue holds potential for future advancements in the field.

Rosacea is strongly associated with melanoma in Caucasians.

Rosacea is often considered a cosmetic problem but is known to be associated with a variety of comorbidities. To identify such risks, we generated two age- and sex-matched real-world cohorts of 122,444 patients each with and without rosacea. In contrast to earlier studies, we found significant associations with malignant melanoma (OR 6.02, 95% CI 5.76-6.32). This association does not exist for an Asian sub-cohort, which could explain previous inconclusive or conflicting reports. Several strongly associated comorbidities like visual disturbances (ICD-10: H53-H54; OR 4.80, 4.68-4.92), metabolic disorders (E73-E79; OR 3.17, 3.11-3.22), joint problems (M25; OR 4.16, 4.08-4.25) and type 2 diabetes (E11; OR 1.62, 1.58-1.65) should be watched as a risk for rosacea patients. Rosacea is associated with some comorbidities and ethnicity may be a risk factor in melanoma development. The retrospective nature of this study and the sole use of ICD-10 code based filtering calls for future validation of our findings. Additionally, confounding factors such as skin type and previous UV exposure should be included in future studies.

Quercetin attenuates inflammation in rosacea by directly targeting p65 and ICAM-1.

AIMS: Rosacea is an inflammatory skin disease with immune and vascular dysfunction. Although there are multiple treatment strategies for rosacea, the clinical outcomes are unsatisfactory. MAIN METHODS: Combining transcriptome data and the Connectivity Map database quercetin was identified as a novel candidate for rosacea. Next, the therapeutic efficacy of quercetin was substantiated through proteomic analyses, in vivo experiments, and in vitro assays. Additionally, the utilization of DARTS, molecular docking and experimental verification revealed the therapeutic mechanisms of quercetin. KEY FINDINGS: Treatment with quercetin resulted in the following effects: (i) it effectively ameliorated rosacea-like features by reducing immune infiltration and angiogenesis; (ii) it suppressed the expression of inflammatory mediators in HaCaT cells and HDMECs; (iii) it interacted with p65 and ICAM-1 directly, and this interaction resulted in the repression of NF-κB signal and ICAM-1 expression in rosacea. SIGNIFICANCE: We show for the first time that quercetin interacted with p65 and ICAM-1 directly to alleviated inflammatory and vascular dysfunction, suggesting quercetin is a novel, promising therapeutic candidate for rosacea.

Rosacea in Older Adults and Pharmacologic Treatments.

Rosacea is a chronic inflammatory skin condition that is often more severe in older patients. The main clinical features are erythema, telangiectasia, and inflammatory lesions of the face. The pathogenesis of this condition is not fully understood but certainly multifaceted. Immune and inflammatory dysregulation, genetics, neurogenic dysregulation, microbiome dysbiosis, and systemic disease have all been implicated in rosacea pathogenesis. As we better understand the various pathways that lead to rosacea, we acknowledge that the different symptoms may have unique underlying triggers and mechanisms. Aging also impacts rosacea diagnosis and treatment. Older adults have more severe rosacea symptoms while also having more sensitive and fragile skin than younger patients; therefore, rosacea treatments for older patients require a balance between delivering adequate potency while also minimizing skin irritation and other adverse effects. Until recently, rosacea diagnoses were based on concrete subtypes that did not necessarily capture each patient's manifestation of rosacea. There is now an emphasis on more personalized phenotype-based diagnoses and treatments, which allows for more emphasis on treating individual symptoms and accounting for the unique characteristics of older patients. Centrofacial erythema is best treated with brimonidine and oxymetazoline, while phymatous change and telangiectasia are best treated with surgery and laser ablation. Treatment for rosacea papules and pustules ranges from topicals, such as azelaic acid, ivermectin, metronidazole, minocycline, and encapsulated benzoyl peroxide, to systemics, such as doxycycline and isotretinoin. It is important to understand these treatments in relation to adverse effects and drug interactions that may specifically arise in older populations to provide optimal care. As we advance in understanding rosacea's pathogenesis and adopt personalized phenotype-based approaches, optimizing care for older patients becomes crucial. Continued research into novel treatments is essential to address their unique needs.

Association between rosacea and helicobacter pylori infection: A meta-analysis.

BACKGROUND AND OBJECTIVES: The potential association between rosacea and a heightened prevalence of Helicobacter pylori (HP) infection has been previously suggested. However, existing studies offer inconsistent results. This systematic review and meta-analysis aimed to elucidate the relationship between rosacea and HP infection. METHODS: We conducted comprehensive searches of PubMed, Embase, and Web of Science databases to identify relevant observational studies for our investigation. We utilized the random-effects model to aggregate the data to address the potential influence of heterogeneity among the studies on the outcome. RESULTS: Our analysis incorporated twenty-five datasets from 23 case-control and cross-sectional studies, encompassing 51,054 rosacea patients and 4,709,074 controls without skin disease. The pooled results revealed a significantly higher prevalence of HP infection in individuals with rosacea compared to controls (odds ratio [OR]: 1.51, 95% confidence interval [CI]: 1.17-1.95, p<0.001; I2 = 79%). Subgroup analysis indicated an increased prevalence of HP infection in rosacea studies that utilized one (OR: 1.72, 95% CI: 1.11-2.66, p = 0.02; I2 = 76%) or more tests for HP infection (OR: 2.26, 95% CI: 1.29-3.98, p = 0.005; I2 = 56%). However, this association was not observed in population-based studies that determined HP infection based on prescription records for HP eradication drugs (OR: 0.90, 95% CI: 0.76-1.07, p = 0.024; I2 = 54%). CONCLUSION: Rosacea may be significantly associated with a higher prevalence of HP infection. High-quality prospective studies with delicately controlled confounding factors are needed to determine if HP infection is a risk factor for rosacea.

Omalizumab in the treatment of Morbihan syndrome in an adolescent girl - case report and literature review.

Morbihan syndrome (MS) is characterized by solid facial edema, usually related to rosacea or acne vulgaris. The facial edema deforms the patient's features, can impair peripheral vision, and affects quality of life. Its pathophysiology remains unclear. The disease usually has a slow and chronic course. MS most commonly affects middle-aged Caucasian men with rosacea and is rare in people below 20 years of age. MS is a diagnosis of exclusion. There is no standard treatment for MS, though systemic isotretinoin and antihistamines are mainly used. We present the case of an adolescent girl with MS nonresponding to 19 months of isotretinoin treatment with add-on antihistamines. Therapy with monthly administration of omalizumab (anti-IgE) for 6 months was an effective therapeutic option, improving the quality of life. Our case is the second description of omalizumab use in Morbihan syndrome, the first in an adolescent.

The impact of smoking and alcohol consumption on rosacea: a multivariable Mendelian randomization study.

Backgrounds: Observational studies have shown that cigarette smoking is inversely associated with risk of rosacea, However, it remains uncertain whether this association is causal or it is a result of reverse causation, and whether this association is affected by drinking behaviors. Methods: This study utilized the summary-level data from the largest genome-wide association study (GWAS) for smoking, alcohol consumption, and rosacea. The objective was to investigate the effect of genetically predicted exposures to smoking and alcohol consumption on the risk of developing rosacea. Two-sample bidirectional Mendelian randomization (MR) was applied, accompanied by sensitive analyses to validate the robustness of findings. Furthermore, multivariable MR was conducted to evaluate the direct impact of smoking on rosacea. Results: A decreased risk of rosacea was observed in individuals with genetically predicted lifetime smoking [odds ratio (OR)MR - IVW = 0.53; 95% confidence interval (CI), 0.318-0.897; P = 0.017], and number of cigarettes per day (ORMR - IVW = 0.55; 95% CI, 0.358-0.845; P = 0.006). However, no significant associations were found between initiation of regular smoking, smoking cessation, smoking initiation, alcohol consumption and rosacea. Reverse MR analysis did not show any associations between genetic liability toward rosacea and smoking or alcohol drinking. Importantly, the effect of lifetime smoking and the number of cigarettes per day on rosacea remained significant even after adjusting for alcohol consumption in multivariable MR analysis. Conclusion: Smoking was causally related to a lower risk of rosacea, while alcohol consumption does not appear to be associated with risk of rosacea.

Omalizumab in the treatment of Morbihan syndrome in an adolescent girl – case report and literature review

Morbihan syndrome (MS) is characterized by solid facial edema, usually related to rosacea or acne vulgaris. The facial edema deforms the patient’s features, can impair peripheral vision, and affects quality of life. Its pathophysiology remains unclear. The disease usually has a slow and chronic course. MS most commonly affects middle-aged Caucasian men with rosacea and is rare in people below 20 years of age. MS is a diagnosis of exclusion. There is no standard treatment for MS, though systemic isotretinoin and antihistamines are mainly used. We present the case of an adolescent girl with MS nonresponding to 19 months of isotretinoin treatment with add-on antihistamines. Therapy with monthly administration of omalizumab (anti-IgE) for 6 months was an effective therapeutic option, improving the quality of life. Our case is the second description of omalizumab use in Morbihan syndrome, the first in an adolescent. (AU)

Rosacea: Pathogenesis and Therapeutic Correlates.

Rosacea is a chronic inflammatory condition of which there is no cure. The pathogenesis of rosacea is likely multifactorial, involving genetic and environmental contributions. Current understanding suggests that pro-inflammatory pathways involving cathelicidins and inflammasome complexes are central to rosacea pathogenesis. Common rosacea triggers modulate these pathways in a complex manner, which may contribute to the varying severity and clinical presentations of rosacea. Established and emerging rosacea treatments may owe their efficacy to their ability to target different players in these pro-inflammatory pathways. Improving our molecular understanding of rosacea will guide the development of new therapies and the use of combination therapies.

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.

Idiopathic aseptic facial granuloma: A retrospective study of 43 cases.

BACKGROUND: Idiopathic aseptic facial granuloma (IAFG) is an underrecognized pediatric skin disease, currently considered within the spectrum of rosacea. It usually manifests as a solitary, reddish, asymptomatic nodule on the cheek that resolves spontaneously. METHODS: Retrospective and descriptive observational study of 43 pediatric patients with a clinical diagnosis of IAFG, followed between 2004 and 2022, at two general hospitals in Argentina. RESULTS: IAFG predominated in girls (65%) and the average age of onset was about 6 years. A single asymptomatic nodule was seen in 79% of patients. The most common localization was the cheek (58%) followed by lower eyelids (41%). Family history of rosacea was present in 16% of patients. A concomitant diagnosis of rosacea and periorificial dermatitis was made in 14% and 9% of our population, respectively. Past or present history of chalazia was detected in 42% of the children. IAFG diagnosis was mainly clinical (88% of cases). Oral antibiotics were the most common indicated treatment (84%). Complete healing was achieved by the majority, but 18% of those with eyelid compromise healed with scars. CONCLUSIONS: IAFG is a benign pediatric condition that physicians should recognize in order to manage correctly. We herein refer to a particular morphologic aspect of IAFG lesions affecting the lower eyelids, where nodules adopt a linear distribution and have a higher probability of involute leaving a scar. Also, we consider that the concomitant findings of rosacea, periorificial dermatitis and chalazia in our patients, reinforce the consideration of IAFG within the spectrum of rosacea.