Rosacea Research Digest - October 31, 2024
Prescriber phenotypes, benzene, azaleic acid, differences between male and female clinical characteristics, and more.
The Rosacea Research Digest from the National Rosacea Society keeps you up to date on recently published basic and clinical research on rosacea, as well as news, reviews, and presentations. It goes out on the last weekday of each month.
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Research
Prescriber phenotypes: variability in topical rosacea treatment patterns among United States dermatologists.
Nicholas, A.; Spraul, A.; Fleischer, A.B., Jr. J Clin Med. 2024, 13, 6275. doi:10.3390/jcm13206275
Background/Objectives: Aggregate prescribing behavior for inflammatory lesions of rosacea has been described, but individual physician behavior has not been characterized. This study aims to assess the modern state of topical rosacea drug selection by analyzing prescribing patterns among individual dermatologists. Methods: We assessed utilization patterns of four topical papulopustular rosacea agents in 2021 Medicare Part-D data. K-means cluster analysis identified prescriber phenotypes based on the proportion of claims for each drug by physician. Results: Cluster analysis identified four prescriber phenotypes for topical rosacea agents, with the majority favoring metronidazole. In each of the other clusters, metronidazole was co-prescribed alongside the primary agent. Significant predictors of phenotype included patient ages, patient risk scores, and a group practice setting. Conclusions: The study reveals nonuniform prescribing patterns for topical papulopustular rosacea treatments among U.S. dermatologists. While aggregate data indicate diverse drug utilization, cluster analysis suggests that individual prescribers tend to use a limited selection of agents.
Rosacea and gastrointestinal diseases: a case-control study in the All of Us database.
Piontkowski AJ, Sharma D, Ungar B. Dermatology. 2024 Sep 26:1-9. Epub ahead of print. doi:10.1159/000541469
Recent reports have suggested a link between rosacea and several gastrointestinal diseases, although the evidence has largely been limited to European and Asian populations. This study seeks to confirm and expand upon the connection between rosacea and gastrointestinal conditions using the diverse All of Us database. Methods: We identified 8,319 rosacea patients and selected 4:1 controls matched (n= 33,276) based on age, race, gender, smoking status, insurance status, annual income, education, and alcohol use. Conditional logistic regression was then performed on the matched cohort to assess the relationship between rosacea and Crohn's disease (CD), microscopic colitis, ulcerative colitis (UC), celiac disease, irritable bowel syndrome (IBS), Helicobacter-associated disease, and gastroesophageal reflux disease (GERD). Results: On logistic regression, rosacea patients were significantly more likely than matched controls to be diagnosed with IBS (odds ratio [OR] 2.35, 95% confidence interval [CI] 2.18-2.53, p<0.001), CD (OR 1.82, 95% CI 1.53-2.15, p<0.001), UC (OR 1.70, 95% CI 1.44-2.02, p<0.001), celiac disease (OR 1.93, 95% CI 1.59-2.34, p<0.001), Helicobacter-associated disease (OR 1.79, 95% CI 1.50-2.14, p<0.001), and GERD (OR 2.07, 95% CI 1.97-2.18, p<0.001). However, there was no statistically significant association between rosacea and microscopic colitis (OR 1.47, 95% CI 0.91-2.37, p=0.12). Conclusion: This study highlights the presence of notable gastrointestinal comorbidities among individuals with rosacea in a diverse cohort. Consequently, more targeted monitoring of gastrointestinal diseases in rosacea patients may be warranted, as well as potential further investigation into the gut-skin axis in terms of rosacea pathophysiology.
Exploring the association between skin microbiota and inflammatory skin diseases: a two-sample Mendelian randomization analysis.
Pan L, Li C, Liang Z, Shi J. Arch Dermatol Res. 2024 Oct 14;316(10):677. doi:10.1007/s00403-024-03433-y
Dysbiosis in the skin microbiome is closely associated with various inflammatory skin diseases. However, current research on the causal relationship between the skin microbiome and inflammatory skin diseases lacks comprehensive and detailed investigation. We used a two-sample Mendelian randomization (MR) approach to explore associations between the skin microbiome and seven inflammatory skin diseases, including acne, atopic dermatitis, erysipelas, vitiligo, psoriasis, rosacea, and urticaria. The GWAS summary data for the skin microbiome was derived from 647 participants in two German population-based cohorts, and for the inflammatory skin diseases, they were sourced from the FinnGen consortium. Our primary MR analysis method was the inverse variance weighted (IVW) method, complemented by alternatives like MR-Egger regression, weighted median estimation, and constrained maximum likelihood. Sensitivity analyses, including Cochran's Q test, MR-Egger intercept test, and MR-PRESSO outlier detection, were conducted to validate and stabilize our findings. We identified significant causal relationships between the skin microbiome and seven inflammatory skin diseases: acne, atopic dermatitis, erysipelas, vitiligo, psoriasis, rosacea, and urticaria, with 7, 6, 9, 1, 7, 4, and 7 respective causal relationships for each disease. These relationships comprise 20 protective and 14 risk causal relationships. We applied the false discovery rate correction to these results. Sensitivity analysis revealed no significant pleiotropy or heterogeneity. Our study revealed both beneficial and detrimental causal relationships between diverse skin microbiota and inflammatory skin diseases. Additionally, the ecological niche of the skin microbiome was crucial to its functional impact. This research provided new insights into how skin microbiota impacted skin diseases and the development of therapeutic strategies.
IL-17A-neutralizing antibody ameliorates inflammation and fibrosis in rosacea by antagonizing the CXCL5/CXCR2 axis.
Zhang C, Jin H, Kang Y, et al. FASEB J. 2024 Oct 15;38(19):e70096. doi:10.1096/fj.202400006R
Rosacea is a chronic inflammatory skin disorder that can lead to fibrosis. However, the mechanisms underlying fibrosis in the later stages of rosacea have been less thoroughly investigated. Interleukin-17A (IL-17A) has been implicated in both inflammation and organ fibrosis; however, the effectiveness and mechanism of IL-17A-neutralizing antibodies in the later stages of rosacea-related fibrosis remain unclear. In this study, we induced rosacea-like lesions in mice using LL-37 and administered IL-17A-neutralizing antibodies. The results indicated that the IL-17A-neutralizing antibodies alleviated skin damage, reduced skin thickness, and decreased the secretion of inflammatory factors (TNF-α, CAMP, TLR4, P-NF-kB), angiogenesis-related factors (CD31, VEGF), and the TGF-β1 signaling pathway, along with factors associated with epithelial-mesenchymal transition and the deposition of fibrosis-related proteins (COL1) in the rosacea-like mouse models. Furthermore, the IL-17A-neutralizing antibodies effectively diminished the expression of IL-17, IL-17R, CXCL5, and CXCR2 in the skin. Our findings demonstrate that IL-17A-neutralizing antibodies inhibit the activation of the CXCL5/CXCR2 axis in rosacea-like skin tissue, thereby ameliorating inflammation and fibrosis associated with the condition.
Evaluation of benzene presence and formation in benzoyl peroxide drug products.
Kucera K, Zenzola N, Hudspeth A, et al. J Invest Dermatol. 2024 Sep 27:S0022-202X(24)02155-9. Epub ahead of print. doi:10.1016/j.jid.2024.09.009
The potent carcinogen, benzene, is a known degradation product of benzoyl peroxide (BPO) and was recently reported to form when BPO drug products, used for acne and rosacea treatment, are incubated at body temperature and elevated temperatures expected during storage and transportation. This study provides evidence for a wide range of benzene concentrations (0.16 ppm to 35.30 ppm) detected by GC-MS in 111 over-the-counter BPO drug products tested and maintained at room temperature. A prescription encapsulated BPO drug product was stability tested at cold (2°C) and elevated temperature (50°C), resulting in no apparent benzene formation at 2°C, and high levels of benzene formation at 50°C, suggesting that encapsulation technology may not stabilize BPO drug products but cold storage may greatly reduce benzene formation. Face model experiments where BPO drug product was applied to PolyMethyl MethAcrylate (PMMA) photoprotection test skin plates and benzene was detected in surrounding air by SIFT-MS, showed detectable benzene through evaporation and substantial benzene formation when exposed to UV light at levels below peak sunlight. Results suggest that potential benzene exposure from formation during BPO drug product use poses significant risks independent of the starting benzene concentration.
Cell-free adipose tissue extracts as a novel treatment for rosacea by downregulating TRPV1.
Zhou L, Chen L, Li T, et al. Sci Rep. 2024 Sep 18;14(1):21759. doi:10.1038/s41598-024-72593-8
Rosacea is a chronic inflammatory skin disease that typically affects the central facial area. Its main clinical symptoms include paroxysmal flushing, telangiectasia, and non-temporary erythema. Cell-free adipose tissue extracts (ATEs) are liquid components extracted from human adipose tissue that contain large amounts of growth factors. Despite the scar-reducing, anti-aging, and wound-healing effects of ATEs, the efficacy of ATEs in rosacea remains unknown. Therefore, the anti-rosacea effects of ATEs were investigated in human cathelicidin peptide (LL-37) induced rosacea mice and capsaicin (CAP)-stimulated HaCaT keratinocytes. In vitro, ATEs significantly reduced TRPV1 expression, intracellular calcium ions influx and the release of inflammatory factors (such as KLK5, IL-6, IL-8 and TNF-α) after intervening in CAP-stimulated cells. The in vivo results revealed that ATEs alleviated rosacea symptoms, such as erythema score, erythema area, transepidermal water loss, abnormal epidermal thickness, mast cell infiltration and telangiectasia upon downregulating TRPV1 and CD31 expression. Moreover, the up-regulated TRPV1 protein expression was also recovered by ATEs administration in vivo and in vitro. Meanwhile, ATEs demonstrated good biocompatibility. In summary, ATEs could be a potential therapeutic agent for rosacea by regulating inflammation and alleviating telangiectasia.
Differences in the clinical characteristics of male patients with different ages of rosacea: a retrospective study of 215 male outpatients.
Huang Y, Chen S, Liu X, et al. J Cosmet Dermatol. 2024 Oct 7. Epub ahead of print. doi:10.1111/jocd.16620
Background: Rosacea is more common in women and Caucasians, leading to little research on rosacea in Asian men. Additionally, there is limited research on the patients across different age groups. Aims: The aim of this study is to analyze and compare the characteristics of male patients of rosacea among different age groups. Methods: A retrospective analysis was conducted on 215 male patients with rosacea, investigating their characteristics, clinical symptoms, exacerbating factors, complications, psychological status, and treatment, as well as exploring factors influencing the early onset of male rosacea. Results: The patients were divided into three age groups (≤ 30 years, 31-44 years, and ≥ 45 years), with the study revealing an average age of 38.59 ± 13.13 years among the patients. The most common subtype of rosacea in men was erythematotelangiectatic rosacea (ETR), followed by phymatous rosacea (PhR). The main reported features included persistent erythema (87.4%) and telangiectasia (71.2%), predominantly affecting the nose (58.6%) and cheeks (56.3%). Twenty-six percent of patients reported concurrent skin diseases, with 14.0% reporting systemic diseases. Significant differences were observed among different age groups regarding family history, clinical features, lesion distribution, symptom severity, aggravating factors, presence of systemic diseases, and treatment preferences. Subjective skin typing, Fitzpatrick phototype, and positive family history were identified as factors influencing the age of onset of rosacea in men. Conclusion: Male patients with rosacea exhibit distinct clinical characteristics, with a greater prevalence of nasal involvement and nasal lesions among male patients. Clinical features vary among different age groups, with patients aged ≥ 45 experiencing more complex and severe symptoms. Patients aged ≤ 30 may be more influenced by genetic factors and have higher treatment expectations.
Signaling pathways and targeted therapy for rosacea.
Yang F, Wang L, Song D, et al. Front Immunol. 2024 Sep 16;15:1367994. doi:10.3389/fimmu.2024.1367994
Rosacea is a chronic skin inflammatory disease with a global prevalence ranging from 1% to 20%. It is characterized by facial erythema, telangiectasia, papules, pustules, and ocular manifestations. Its pathogenesis involves a complex interplay of genetic, environmental, immune, microbial, and neurovascular factors. Recent studies have advanced our understanding of its molecular basis, focusing on toll-like receptor (TLR) 2 pathways, LL37 expression, mammalian target of rapamycin (mTOR) activation, interleukin (IL)-17 signaling, transient receptor potential vanilloid (TRPV) functions, and the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways. LL37-associated signaling pathways, particularly involving TLR2 and mTORC1, are critical in the pathogenesis of rosacea. LL37 interacts with signaling molecules such as extracellular signal-regulated kinases 1 and 2 (ERK1/2), nuclear factor kappa B (NF-κB), inflammasomes, C-X-C motif chemokine ligand 8 (CXCL8), mas-related G-protein-coupled receptor X2 (MRGPRX2)-TRPV4, and vascular endothelial growth factor (VEGF). This interaction activates macrophages, neutrophils, mast cells, and vascular endothelial cells, leading to cytokine release including tumor necrosis factor-alpha (TNF-α), IL-6, IL-1β, C motif chemokine ligand (CCL) 5, CXCL9, and CXCL10. These processes contribute to immune response modulation, inflammation, and angiogenesis in rosacea pathophysiology. The IL-17 signaling pathway also plays a crucial role in rosacea, affecting angiogenesis and the production of inflammatory cytokines. In addition, recent insights into the JAK/STAT pathways have revealed their integral role in inflammatory and angiogenic mechanisms associated with rosacea. Rosacea treatment currently focuses on symptom management, with emerging insights into these molecular pathways providing more targeted and effective therapies. Biological agents targeting specific cytokines, IL-17 inhibitors, JAK inhibitors, and VEGF antagonists are promising for future rosacea therapy, aiming for enhanced efficacy and fewer side effects. This review provides a comprehensive overview of the current knowledge regarding signaling pathways in rosacea and potential targeted therapeutic strategies.
Azelaic acid: mechanisms of action and clinical applications.
Feng X, Shang J, Gu Z, et al. Clin Cosmet Investig Dermatol. 2024;17:2359-2371 doi:10.2147/CCID.S485237
AZA is a non-phenolic, saturated dicarboxylic acid with nine carbon atoms, naturally produced by the yeast Malassezia. It has diverse physiological activities, including antibacterial, anti-keratinizing, antimelanogenic, antioxidant and anti-inflammatory effects. AZA is widely used in dermatology and is FDA-approved for treating papulopustular rosacea. It also shows significant efficacy in acne vulgaris and melasma. This review summarizes the mechanisms of action and clinical applications of AZA, aiming to provide theoretical support for its clinical and cosmetic use and to facilitate further research.
Case Reports
Scalp rosacea treated with topical ivermectin.
Dall'Oglio F, Nasca MR, Guglielmi G, Micali G. Skin Appendage Disord. 2024 Oct;10(5):429-432. Epub 2024 May 15. doi:10.1159/000537807
Introduction: Scalp rosacea is often misdiagnosed or overlooked, and few reports deal with this peculiar localization. Furthermore, the pharmacological approach to scalp rosacea remains a therapeutic challenge, as no topical and/or systemic drugs have been approved for this specific area so far. Case presentation: A series of 5 adult patients affected by inflammatory rosacea and concurrent scalp involvement, confirmed by dermoscopy and histopathology with negative microbiologic swabs, and effectively treated with ivermectin 1% cream once daily for 12 weeks is presented. Conclusion: Our experience, although limited, suggests that evaluation of rosacea subjects should also include the scalp and that the treatment with ivermectin 1% cream may be effective on scalp rosacea.
News
Cryomodulation Reduces Rosacea Symptoms
Healio Dermatology
Patients with rosacea experienced an improvement in symptoms following cryomodulation, according to pilot study results presented at the American Society for Dermatologic Surgery Annual Meeting.
Rosacea Changes How and When Sufferers Exercise, Survey Finds
NRS Blog
A diagnosis of rosacea doesn’t stop most people from staying active, even though exercise is one of the most common triggers for flare-ups. In a recent NRS survey of 512 patients, nearly three quarters of respondents work out frequently, including 42% who exercise two or three times a week and 31% who work out every day.
New TRoSA Scale Standardizes Telangiectasia Severity in Rosacea
Dermatology Times
Rosacea prevalence is highly variable, reported between less than 1% and 22%, and it often impacts individuals’ quality of life significantly due to the visible nature of its symptoms. The Rosacea Consensus (ROSCO) recommends a phenotype-based diagnostic approach, focusing on primary manifestations such as erythema, telangiectasia, and inflammatory lesions. Among these, telangiectasia is a prominent feature, and the demand for effective treatments, including laser and light-based therapies, continues to grow. However, accurately assessing telangiectasia severity remains challenging, as there has been no standardized, validated photonumeric scale to date for evaluating this aspect of rosacea. A recent study addressed this gap by developing and validating a 5-point photonumeric scale, known as the Telangiectasia in Rosacea Severity Assessment (TRoSA) scale, to support dermatologists in clinical assessments and treatment planning.
Do your patients with rosacea need a GI referral?
MedCentral
The common inflammatory skin disease roseacea, has been associated with several gastrointestinal (GI) diseases including inflammatory bowel disease (IBD), irritable bowel syndrome, celiac disease, gastroesophageal reflux disease (GERD), Helicobacter pylori infection, and small intestine bacterial overgrowth (SIBO). Although this area of research is in the early stages and the relationships are not fully understood, knowledge of the potential associations may help physicians who work with patients with rosacea.
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