Rosacea Core Domain Set for Clinical Trials and Practice: A Consensus Statement.

Importance: Inconsistent reporting of outcomes in clinical trials of rosacea is impeding and likely preventing accurate data pooling and meta-analyses. There is a need for standardization of outcomes assessed during intervention trials of rosacea. Objective: To develop a rosacea core outcome set (COS) based on key domains that are globally relevant and applicable to all demographic groups to be used as a minimum list of outcomes for reporting by rosacea clinical trials, and when appropriate, in clinical practice. Evidence Review: A systematic literature review of rosacea clinical trials was conducted. Discrete outcomes were extracted and augmented through discussions and focus groups with key stakeholders. The initial list of 192 outcomes was refined to identify 50 unique outcomes that were rated through the Delphi process Round 1 by 88 panelists (63 physicians from 17 countries and 25 patients with rosacea in the US) on 9-point Likert scale. Based on feedback, an additional 11 outcomes were added in Round 2. Outcomes deemed to be critical for inclusion (rated 7-9 by ≥70% of both groups) were discussed in consensus meetings. The outcomes deemed to be most important for inclusion by at least 85% of the participants were incorporated into the final core domain set. Findings: The Delphi process and consensus-building meetings identified a final core set of 8 domains for rosacea clinical trials: ocular signs and symptoms; skin signs of disease; skin symptoms; overall severity; patient satisfaction; quality of life; degree of improvement; and presence and severity of treatment-related adverse events. Recommendations were also made for application in the clinical setting. Conclusions and Relevance: This core domain set for rosacea research is now available; its adoption by researchers may improve the usefulness of future trials of rosacea therapies by enabling meta-analyses and other comparisons across studies. This core domain set may also be useful in clinical practice.

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.

Racial, ethnic, and biologic sex disparities in outpatient laboratory monitoring of isotretinoin use: a cross-sectional study.

BACKGROUND: Isotretinoin is commonly used for the treatment of acne. Despite high efficacy, isotretinoin has a side effect profile that prompts regular outpatient laboratory monitoring. Emerging evidence suggests clinically significant lab abnormalities are rare. Racial, ethnic, and biologic sex disparities in laboratory monitoring of isotretinoin have yet to be characterized. METHODS: This study explores disparities in laboratory monitoring of patients prescribed isotretinoin, factoring in the COVID-19 pandemic given its impacts on laboratory monitoring. Two populations were evaluated: all patients taking isotretinoin, and patients taking isotretinoin with no metabolic, cardiovascular, hematologic, hepatic, or renal comorbidities. The latter population was included to screen out patients who might receive increased laboratory testing for conditions besides isotretinoin use. RESULTS: Our data reveal that African-American, Asian, and Hispanic patients prescribed isotretinoin were more likely than Caucasian patients to receive orders for outpatient laboratory monitoring. These disparities persisted independent of comorbidities that may prompt additional testing, suggesting that non-Caucasian patients bear an additional testing burden even when their comorbidities were matched to their peers. Disparities persisted in the setting of reduced laboratory monitoring due to the COVID-19 pandemic. CONCLUSIONS: These data reveal that patients of color are more likely to receive outpatient laboratory monitoring for isotretinoin prescriptions. There is an opportunity for testing standardization to improve medication access, decrease burden and costs for patients and the healthcare system, and decrease racial disparities in prescribing and monitoring of isotretinoin. Dermatology clinics may benefit from standard operating procedures outlining for whom regular monitoring is needed.

Reinforcing Photoprotection for Skin of Color: A Narrative Review.

Skin of color (SOC) is characterized by increased tendency for tanning and decreased likelihood of sunburns due to the attenuation of sunlight by epidermal melanin. Although this contributes to the decreased incidence of skin cancer among SOC populations, individuals with SOC remain susceptible to various health consequences associated with sun exposure, including non-melanoma skin cancer, photoaging, pigmentary disorders, and photodermatoses - many of which not only present differently, but also disproportionately affect SOC. Prior epidemiological studies have found lower prevalence of sun protection behaviors among individuals with SOC, particularly in sunscreen use, signifying an unmet area for improvement in the prevention of sun-induced dermatologic conditions in these populations. The objective of this narrative review was to summarize the biology and health consequences of sun exposure in SOC, as well as cognitive and behavioral factors that affect the practice of photoprotection behaviors in SOC populations. We also review prior interventions that have been used to enhance photoprotection knowledge and behaviors among individuals with SOC, either in racially and ethnically diverse communities or within specific SOC populations.

Characterizing viscoelastic properties of human melanoma tissue using Prony series.

Melanoma is the most invasive and deadly skin cancer, which causes most of the deaths from skin cancer. It has been demonstrated that the mechanical properties of tumor tissue are significantly altered. However, data about characterizing the mechanical properties of in vivo melanoma tissue are extremely scarce. In addition, the viscoelastic or viscous properties of melanoma tissue are rarely reported. In this study, we measured and quantitated the viscoelastic properties of human melanoma tissues based on the stress relaxation test, using the indentation-based mechanical analyzer that we developed previously. The melanoma tissues from eight patients of different ages (57-95), genders (male and female patients), races (White and Asian), and sites (nose, arm, shoulder, and chest) were excised and tested. The results showed that the elastic property (i.e., shear modulus) of melanoma tissue was elevated compared to normal tissue, while the viscous property (i.e., relaxation time) was reduced. Moreover, the tissue thickness had a significant impact on the viscoelastic properties, probably due to the amount of the adipose layer. Our findings provide new insights into the role of the viscous and elastic properties of melanoma cell mechanics, which may be implicated in the disease state and progression.

Treatment recommendations for acne-associated hyperpigmentation: Results of the Delphi consensus process and a literature review.

Acne vulgaris can be associated with hyperpigmentation, particularly in individuals with skin of color. This acne-induced macular hyperpigmentation (AMH), also called postinflammatory hyperpigmentation, is often long lasting and negatively impacts quality of life. Large-scale, randomized, controlled clinical trials with regard to the treatment of acne and AMH are lacking. For this reason, evidence-based treatment recommendations cannot be made. However, AMH is a common condition, and it is important for clinicians to have guidance on management strategies. The authors, a group of 10 board-certified dermatologists, conducted a modified Delphi consensus process to reach a consensus on first-line therapy for AMH and determine whether therapeutic choices change in different patient subgroups. We reached a consensus that most patients with acne and AMH should receive early and efficacious acne treatment with a topical retinoid and benzoyl peroxide. Therapies aimed at addressing AMH-including hydroquinone, azelaic acid, chemical peel, or antioxidants-may also be considered for enhancing the effect of the treatment regimen on acne and pigmentation. Chemical peels may be used as adjunctive or second-line therapy. This article details the results of the Delphi process, reviews relevant literature for providing recommendations for AMH, and discusses appropriate treatment options.

Sex-specific differences in oxidative stress markers and collagen expression in perioral skin wrinkling.

Wrinkling is the hallmark of skin ageing. We previously reported that perioral wrinkling is more severe in females; however, the molecular basis is unknown. This study assessed sex differences in the molecular expression of key ageing regulators in perioral skin. Twelve subjects (n = 6 male/female) were enrolled in this cross-sectional study and biopsies were taken from the perioral and periocular regions. RNA expression of collagen I, collagen III, cysteine-rich angiogenic inducer 61 (CYR61) and insulin-like growth factor 1 (IGF-1) was assessed by qPCR. There was no difference between females' and males' Griffith's grades (6 and 5.67, respectively, p = 0.092) or periocular wrinkling grades (3.2 and 2.6, p = 0.421), but females had more severe perioral wrinkling grades than males (6.2 and 2.8, p = 0.020). Females not only expressed significantly more CYR61 (p = 0.018) in the perioral region than malesm but also expressed more collagen III (p = 0.016). There was no difference in collagen I (p = 0.115) or IGF-1 (p = 0.124) expression in the perioral region between sexes. In the periocular region, there were no significant differences between sexes in the expression of all four markers. The significant molecular differences in the perioral region between the sexes may contribute to the greater perioral skin wrinkling seen clinically in females.

Clinical and molecular change induced by repeated low-dose visible light exposure in both light-skinned and dark-skinned individuals.

BACKGROUND: Visible light (VL) is known to induce pigmentation in dark-skinned individuals and immediate erythema in light-skinned individuals. However, the effects of accumulated low-dose VL exposure across skin types are not well established. METHODS: Thirty-one healthy subjects with light (Fitzpatrick skin types [FST] I-II, n = 13) and dark (FST V-VI, n = 18) skin types were enrolled. Subjects' buttocks were exposed daily to VL, wavelength 400-700 nm, with a dose of 120 J/cm2 at 50 mW/cm2 , for four consecutive days. Microarray using Affymetrix GeneChip (49,395 genes) was performed followed by qRT-PCR on skin samples. RESULTS: Repeated low-dose VL irradiation induced immediate pigment darkening and delayed tanning in dark-skinned individuals while no discernable pigmentation and erythema were observed in light-skinned individuals. Top ten upregulated genes by repeated VL exposure in microarray included melanogenic genes such as tyrosinase (TYR), tyrosinase-related protein-1 (TYRP1), dopachrome tautomerase (DCT), premelanosome protein (PMEL), melan-A (MLANA), and solute carrier family 24, member 5 (SLC24A5) and genes involved in inflammation/matrix remodeling/cell signaling including chemokine (C-C motif) ligand 18 (CCL18), BCL2-related protein A1 (BCL2A1), and cartilage oligomeric matrix protein (COMP). In qRT-PCR CCL18 was upregulated in light skin with a greater extent (mean fold change ± SD; 4.03 ± 3.28, p = .04) than in dark-skinned individuals (1.91 ± 1.32, p = .07) while TYR was not significantly upregulated in both skin types. CONCLUSION: This study highlights the genes upregulated by cumulative VL exposure involved in pigmentation, immune response, oxidation/reduction, and matrix remodeling across skin types providing relevant information on daily solar exposure.

Association of Early Clinical Response to Laser Rejuvenation of Photoaged Skin with Increased Lipid Metabolism and Restoration of Skin Barrier Function.

Laser resurfacing treatments for photoaged skin have improved dramatically over the past decades, but few studies have examined the molecular mechanisms underlying differences in clinical response. Seventeen white female participants with moderate-to-severe photoaging received nonablative fractional laser treatment on the face and forearm once monthly for 6 months. Biopsies for microarray analysis were performed at baseline and 7 days after facial treatment and at baseline and 1, 7, 14, and 29 days after forearm treatment in each participant, resulting in 119 total samples. Participants were stratified into fast (n = 11) and slow (n = 6) responders on the basis of the presence of clinical improvement after the first treatment. Microarray analysis revealed the upregulation of genes associated with matrix metalloproteinases, collagen and extracellular components, TGF-ß signaling, double-stranded RNA signaling, and retinoic acid synthesis after treatment that did not differ significantly between fast and slow responders. Cluster and enrichment analyses suggested significantly greater activation of lipid metabolism and keratinocyte differentiation in fast responders, who showed greater upregulation of acyltransferases, fatty acid elongases, fatty acid 2-hydroxylase, fatty acid desaturases, and specific keratins that may contribute to epidermal barrier function. These results create, to our knowledge, a previously unreported atlas of molecular changes that correlate with improvements in photoaging after laser therapy.

Skin type specific photobiological response to visible light is mediated by constitutional melanin.

BACKGROUND: Visible light (VL) induces varying photobiological responses between skin types, likely influenced by inherent melanization. Individual typology angle (ITA) objectively measures skin types. We hypothesize that epidermal melanin content and distribution determine VL response. OBJECTIVES: This study describes clinical and histologic responses to VL and examines the potential role of melanin in the underlying mechanistic pathways. METHODS: We grouped enrolled participants by ITA (Light = 5, Intermediate = 4, Dark = 7) per colorimetry (CR-400, Konica Minolta). Photoprotected sites were exposed daily to 480 J/cm2 of VL (Fiber-Lite High Intensity Illuminator, Series 180, Dolan Jenner Industries Inc.) for 4 days (total = 1920 J/cm2 ), as tolerated. Treated and control sites were biopsied 96 h after first exposure. We used hematoxylin and eosin and Fontana-Mason to assess histological changes and melanin deposition, respectively. p53 and Ki67 immunohistochemical stains were done to assess DNA damage and proliferation. Matrix metalloproteinase (MMP)-1 expression was detected by immunohistochemical staining and immunofluorescence microscopy. RESULTS: Darker skin did not tolerate the full VL regimen with blistering occurring in most subjects at doses of 220-880 J/cm2 . Intermediate and Dark skin showed tanning. Light skin developed erythema. p53 counts were highest in Intermediate, followed by Light skin, although this was not statistically significant. VL treatment led to MMP-1 expression and nuclear localization in keratinocytes in Dark and Intermediate but not in Light skin, however differences between groups were not statistically significant. CONCLUSIONS: Skin types demonstrate unique biological responses to VL. The role of melanin in photoprotection is well-defined. However, given the pro-apoptotic function of nuclear MMPs, we suggest a potential mechanism by which melanin may mediate VL-induced phototoxicity.

Leveraging Tissue Engineering for Skin Cancer Models.

Bioengineered in vitro three-dimensional (3D) skin model has emerged as a promising tool for recapitulating different types of skin cancer and performing pre-clinical tests. However, a full-thickness 3D model including the epidermis, dermis, and hypodermis layers is scarce despite its significance in human physiology and diverse biological processes. In this book chapter, an attempt has been made to summarize various skin cancer models, including utilized skin layers, materials, cell lines, specific treatments, and fabrication techniques for three types of skin cancer: melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). Subsequently, current limitations and future directions of skin cancer models are discussed. The knowledge of the current status of skin cancer models can provide various potential applications in cancer research and thus a more effective way for cancer treatment.

FACES: A Deep-Learning-Based Parametric Model to Improve Rosacea Diagnoses.

Rosacea is a chronic inflammatory skin disorder that causes visible blood vessels and redness on the nose, chin, cheeks, and forehead. However, visual assessment, the current standard method used to identify rosacea, is often subjective among clinicians and results in high variation. Recent advances in artificial intelligence have allowed for the effective detection of various skin diseases with high accuracy and consistency. In this study, we develop a new methodology, coined "five accurate CNNs-based evaluation system (FACES)", to identify and classify rosacea more efficiently. First, 19 CNN-based models that have been widely used for image classification were trained and tested via training and validation data sets. Next, the five best performing models were selected based on accuracy, which served as a weight value for FACES. At the same time, we also applied a majority rule to five selected models to detect rosacea. The results exhibited that the performance of FACES was superior to that of the five individual CNN-based models and the majority rule in terms of accuracy, sensitivity, specificity, and precision. In particular, the accuracy and sensitivity of FACES were the highest, and the specificity and precision were higher than most of the individual models. To improve the performance of our system, future studies must consider patient details, such as age, gender, and race, and perform comparison tests between our model system and clinicians.

Effects of Frankincense Compounds on Infection, Inflammation, and Oral Health.

Boswellia trees, found throughout the Middle East and parts of Africa and Asia, are the source of frankincense oil. Since antiquity, frankincense has been traded as a precious commodity, but it has also been used for the treatment of chronic disease, inflammation, oral health, and microbial infection. More recently, the bioactive components of Boswellia trees have been identified and characterized for their effects on cancer, microbial infection (especially infection by oral pathogens), and inflammation. Most studies have focused on cell lines, but more recent research has also investigated effects in animal models of disease. As natural products are considered to be safer than synthetic drugs, there is growing interest in further developing the use of substances such as frankincense oil for therapeutic treatment.

Biomarkers of Tretinoin Precursors and Tretinoin Efficacy in Patients With Moderate to Severe Facial Photodamage: A Randomized Clinical Trial.

Importance: Topical formulations of tretinoin precursors (retinol and its ester derivatives) are widely available over the counter and may offer similar clinical benefits to those of tretinoin for treatment of photoaging. However, which of the many purported molecular effects of retinoids most strongly drives clinical improvements in tretinoin-treated skin remains unclear. Objectives: To evaluate the clinical efficacy of topical tretinoin precursors (TTP) vs tretinoin (RA) in treating moderate to severe facial photodamage and to identify potential biomarkers that correlate with clinical efficacy. Design, Setting, and Participants: This randomized, double-blind, single-center, parallel-arm study of 24 patients with moderate to severe facial photodamage was conducted at an academic referral center from November 2010 to December 2011, with data analysis performed from January 2012 to December 2021. Interventions: Daily topical application of 0.02% RA or 1.1% TTP formulation containing retinol, retinyl acetate, and retinyl palmitate for 24 weeks. Main Outcomes and Measures: Photoaging and tolerability were assessed by dermatologist evaluations and patient-reported outcomes. Target gene expression was assessed by real-time quantitative polymerase chain reaction of biopsied tissue from treated areas. Results: A total of 20 White women were ultimately analyzed (9 randomized to TTP, 11 randomized to RA). At week 24, there was no significant difference in Griffiths photoaging scores among patients receiving TTP vs RA (median, 4 vs 5) (TTP - RA difference: -1; 95% CI, -2 to 1; P = .27). Treatment with TTP was associated with erythema 6 times less frequently than RA (11% vs 64%) (TTP - RA difference: -0.53; 95% CI, -0.88 to -0.17; P = .01). Target gene analysis showed significant CRABP2 messenger RNA (mRNA) induction (confirming retinoic acid receptor signaling) but no significant changes in procollagen I or MMP1/3/9 mRNA in TTP-treated samples. Instead, MMP2 mRNA, which encodes a type IV collagenase, was significantly reduced in TTP-treated samples (week 24 - baseline mRNA difference: -5; 96% CI, -33 to 1.6; P = .02), and changes in MMP2 were strongly correlated with changes in fine wrinkles (r = 0.54; 95% CI, 0.12 to 0.80; P = .01). Interestingly, patients with severe baseline wrinkles exhibited greater improvements (r = -0.74; 95% CI, -0.89 to -0.43; P < .001). This trend was mirrored in MMP2 mRNA, with initial expression strongly predicting subsequent changes (r = -0.78; 95% CI, -0.89 to -0.43; P < .001). Conclusions and Relevance: In this randomized clinical trial, there was no significant difference in efficacy between this particular formulation of TTP and tretinoin 0.02%. However, the results of these mechanistic studies highlight MMP2 as a possible mediator of retinoid efficacy in photoaging. Trial Registration: ClinicalTrials.gov Identifier: NCT01283464.

UVB-mediated DNA damage induces matrix metalloproteinases to promote photoaging in an AhR- and SP1-dependent manner.

It is currently thought that UVB radiation drives photoaging of the skin primarily by generating ROS. In this model, ROS purportedly activates activator protein-1 to upregulate MMPs 1, 3, and 9, which then degrade collagen and other extracellular matrix components to produce wrinkles. However, these MMPs are expressed at relatively low levels and correlate poorly with wrinkles, suggesting that another mechanism distinct from ROS and MMP1/3/9 may be more directly associated with photoaging. Here we show that MMP2, which degrades type IV collagen, is abundantly expressed in human skin, increases with age in sun-exposed skin, and correlates robustly with aryl hydrocarbon receptor (AhR), a transcription factor directly activated by UV-generated photometabolites. Through mechanistic studies with HaCaT human immortalized keratinocytes, we found that AhR, specificity protein 1 (SP1), and other pathways associated with DNA damage are required for the induction of both MMP2 and MMP11 (another MMP implicated in photoaging), but not MMP1/3. Last, we found that topical treatment with AhR antagonists vitamin B12 and folic acid ameliorated UVB-induced wrinkle formation in mice while dampening MMP2 expression in the skin. These results directly implicate DNA damage in photoaging and reveal AhR as a potential target for preventing wrinkles.

Photoprotection for Skin of Color.

Photoprotection behaviors can mitigate skin damage caused by ultraviolet radiation, and common methods include seeking shade, avoiding sun exposure during peak daylight hours, wearing sun-protective clothing, applying sunscreen, and using sunglasses. While the role of sun protection in preventing sunburns, photoaging, and skin cancer is well established in fair-skinned populations, individuals with skin of color (SOC) are presumed to suffer fewer negative effects from solar radiation. Thus, the importance of photoprotection in this population is understudied and may be underestimated. In SOC populations, sun exposure is known to cause pigmentary disorders, photoaging, and basal cell carcinoma (BCC), highlighting the potential benefits of photoprotection. Although SOC populations tend to practice photoprotection by seeking shade and wearing sun-protective clothing, survey and interview-based studies have consistently found relatively low use of sunscreen among these populations. Common motivators for photoprotection in individuals with SOC include preventing sunburn and pigmentation, with the prevention of skin cancer being a less important reason. As a skin cancer risk behavior, indoor tanning is relatively rare in SOC populations, but its use may increase with acculturation to US norms. While more studies are necessary to clarify whether photoprotection behaviors may decrease skin cancer-related mortality in SOC populations, regular dermatologic care and counseling on photoprotection remain essential in patients with SOC for overall skin health.

A consistent skin care regimen leads to objective and subjective improvements in dry human skin: investigator-blinded randomized clinical trial.

BACKGROUND: Dry, itchy skin can lower quality of life (QoL) and aggravate skin diseases. Moisturizing skin care products can have beneficial effects on dry skin. However, the role of a daily skin care routine is understudied. OBJECTIVE: To understand how daily skin care with a mild cleanser and moisturizer impacts skin health and patients' QoL, in dry skin population. METHODS: A randomized, investigator-blinded study of 52 participants with moderate to severe dry skin. The treatment group (n = 39) used mild cleanser and moisturizer twice daily for two weeks whereas the control group (n = 13) used mild cleanser without moisturizer. Total Clinical Score (TCS; erythema, scale and fissures), Visual Dryness Score (VDS) and subjective itch-related quality of life (ItchyQoL) were collected. RESULTS: The treatment group showed significantly more improvement in TCS and VDS compared to the control group after two weeks. Among the three components of the ItchyQoL (symptoms, functioning, and emotions), symptom showed significantly greater improvement in the treatment compared to the control group. Over 80% of participants in the treatment group agreed that the regimen led to decrease in dryness/pruritus and improved skin texture. CONCLUSIONS: A consistent skin care regimen should be an integral component of management of dry skin.

The association between urinary polycyclic aromatic hydrocarbon metabolites and atopic triad by age and body weight in the US population.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are generated during the incomplete combustion of coal/oil/gas and waste. The role of PAH exposure in the atopic triad remains poorly understood. Due to their lipophilic nature, PAHs deposit in adipocytes, potentially placing elderly and those who are overweight at higher risk. OBJECTIVE: To investigate the association between urinary PAHs and symptoms of atopic triad (chronic pruritus, sneezing, and wheezing). METHODS: Binary multivariable logistic regression was performed to estimate the association of nine urinary PAHs and atopic diseases followed by subgroup analyses by age (children 6-17, adults 18-49, elderly ≥50 years) and body mass index (BMI) (normal: BMI <25, overweight: BMI ≥ 25 kg/m2) among 2,242 participants of National Health and Nutrition Examination Survey 2005-2006 dataset. RESULTS: 1-hydroxynaphthalene (1-NAP) and hydroxyfluorenes (FLUs) were positively associated with wheezing. When stratified by age, positive associations were found between 1-NAP with wheezing in children/adults and 2-/3-FLU with wheezing in adults/elderly. 3-hydroxyphenanthrene (3-PHE) and 1-hydroxypyrene were positively associated with chronic pruritus in elderly. When stratified by BMI, positive associations were found between 2-PHE with chronic pruritus, 1-NAP and FLUs with wheezing in overweight. CONCLUSION: Urinary PAH levels were positively associated with atopic triad and this connection was influenced by age and BMI.