The Plight of the Metabolite: Oxidative Stress and Tear Film Destabilisation Evident in Ocular Allergy Sufferers across Seasons in Victoria, Australia.

Ocular allergy (OA) is characterised by ocular surface itchiness, redness, and inflammation in response to allergen exposure. The primary aim of this study was to assess differences in the human tear metabolome and lipidome between OA and healthy controls (HCs) across peak allergy (spring-summer) and off-peak (autumn-winter) seasons in Victoria, Australia. A total of 19 participants (14 OA, 5 HCs) aged 18-45 were recruited and grouped by allergy questionnaire score. Metabolites and lipids from tear samples were analysed using mass spectrometry. Data were analysed using TraceFinder and Metaboanalyst. Metabolomics analysis showed 12 differentially expressed (DE) metabolites between those with OA and the HCs during the peak allergy season, and 24 DE metabolites were found in the off-peak season. The expression of niacinamide was upregulated in OA sufferers vs. HCs across both seasons (p ≤ 0.05). A total of 6 DE lipids were DE between those with OA and the HCs during the peak season, and 24 were DE in the off-peak season. Dysregulated metabolites affected oxidative stress, inflammation, and homeostasis across seasons, suggesting a link between OA-associated itch and ocular surface damage via eye rubbing. Tear lipidome changes were minimal between but suggested tear film destabilisation and thinning. Such metabolipodome findings may pave new and exciting ways for effective diagnostics and therapeutics for OA sufferers in the future.

Comparison of the efficacy among different interventions for radiodermatitis: A Bayesian network meta­analysis of randomized controlled trials.

BACKGROUND: Radiation dermatitis (RD) is a prevalent and difficult-to-manage consequence of radiation therapy (RT). A variety of interventions have been proven effective in preventing and treating RD. However, the optimal approach remains unclear. This network meta-analysis (NMA) conducted a comparison and ranking of the effectiveness and patient-reported outcomes (PROs) of the interventions currently utilized in RD. METHODS: PubMed, Web of Science, Embase, and Cochrane Library were searched to identify pertinent randomized controlled trials (RCTs) focused on the prevention and treatment of RD. The primary outcome measures included the incidence of grade≥2 RD (i.e., percentage of moist desquamation) and RD score. The secondary outcome measures encompassed patients' subjective assessment scores of pains, itching and burning sensations. RESULTS: Our meta-analysis encompassed 42 studies and 4884 participants. Regarding the primary outcomes, photobiomodulation treatment (PBMT) ranked first in surface under curve cumulative ranking area (SUCRA:0.92) for reducing the incidence of grade≥2 RD. It demonstrated a significant difference when compared to Trolamine (OR 0.18,95%CrI 0.09-0.33) and Xonrid® (OR 0.28,95%CrI 0.12-0.66). Mepitelfilm (SUCRA: 0.98) achieved the highest rank in reducing the RD score, demonstrating superiority over StrataXRT® (MD -0.89, 95% CrI -1.49, -0.29). Henna (SUCRA: 0.89) demonstrated the highest effectiveness in providing pain relief, with a significant difference compared to Hydrofilm (MD -0.44, 95% CrI -0.84, -0.04) and Mepitelfilm (MD -0.55, 95% CrI -0.91, -0.19). Hydrofilm (SUCRA: 0.84) exhibited the fewest itching sensations, demonstrating superiority over Mepitelfilm (MD -0.50, 95% CrI -0.84, -0.17). No statistically significant difference was observed among various interventions in the assessment of burning sensations. CONCLUSION: PBMT and Mepitelfilm demonstrated better efficacy in reducing the incidence of grade≥2 RD and RD score, respectively. In terms of PROs, Henna and Hydrofilm had fewer complaints in pain and itching sensations, respectively. However, studies with larger sample size on different interventions are warranted in the future. TRIAL REGISTRATION: PROSPERO registration number CRD42023428598.

Integrated plasma metabolomic and cytokine analysis reveals a distinct immunometabolic signature in atopic dermatitis.

Importance: Disease models for atopic dermatitis (AD) have primarily focused on understanding underlying environmental, immunologic, and genetic etiologies. However, the role of metabolic mechanisms in AD remains understudied. Objective: To investigate the circulating blood metabolomic and cytokine profile of AD as compared to healthy control patients. Design: This study collected plasma from 20 atopic dermatitis with moderate-to-severe itch (score of ≥5 on the itch Numeric Rating Scale and IGA score ≥3) and 24 healthy control patients. Mass-spectrometry based metabolite data were compared between AD and healthy controls. Unsupervised and supervised machine learning algorithms and univariate analysis analyzed metabolic concentrations. Metabolite enrichment and pathway analyses were performed on metabolites with significant fold change between AD and healthy control patients. To investigate the correlation between metabolites levels and cytokines, Spearman's rank correlation coefficients were calculated between metabolites and cytokines. Setting: Patients were recruited from the Johns Hopkins Itch Center and dermatology outpatient clinics in the Johns Hopkins Outpatient Center. Participants: The study included 20 atopic dermatitis patients and 24 healthy control patients. Main outcomes and measures: Fold changes of metabolites in AD vs healthy control plasma. Results: In patients with AD, amino acids isoleucine, tyrosine, threonine, tryptophan, valine, methionine, and phenylalanine, the amino acid derivatives creatinine, indole-3-acrylic acid, acetyl-L-carnitine, L-carnitine, 2-hydroxycinnamic acid, N-acetylaspartic acid, and the fatty amide oleamide had greater than 2-fold decrease (all P-values<0.0001) compared to healthy controls. Enriched metabolites were involved in branched-chain amino acid (valine, leucine, and isoleucine) degradation, catecholamine biosynthesis, thyroid hormone synthesis, threonine metabolism, and branched and long-chain fatty acid metabolism. Dysregulated metabolites in AD were positively correlated cytokines TARC and MCP-4 and negatively correlated with IL-1a and CCL20. Conclusions and relevance: Our study characterized novel dysregulated circulating plasma metabolites and metabolic pathways that may be involved in the pathogenesis of AD. These metabolic pathways serve as potential future biomarkers and therapeutic targets in the treatment of AD.

Effects of Psychological Stress on Spontaneous Itch and Mechanical Alloknesis of Atopic Dermatitis.

Atopic dermatitis (AD), a chronic inflammatory skin disease, manifests as an intractable itch. Psychological stress has been suggested to play a role in the onset and worsening of AD symptoms. However, the pathophysiological relationships between psychological stressors and cutaneous manifestations remain unclear. To elucidate the mechanisms underlying the stress-related exacerbation of itch, we investigated the effects of water stress, restraint stress and repeated social defeat stress on itch-related scratching behaviour, mechanical alloknesis and dermatitis in male NC/Nga mice with AD-like symptoms induced by the repeated application of ointment containing Dermatophagoides farina body. NC/Nga mice with AD-like symptoms were subjected to water stress, restraint stress and repeated social defeat stress, and their scratching behaviour, sensitivity to mechanical stimuli (mechanical alloknesis) and severity of  dermatitis were evaluated. Social defeat stress+ Dermatophagoides farina body-treated mice exposed to stress showed slower improvements in or the exacerbation of AD-like symptoms, including dermatitis and itch. In the mechanical alloknesis assay, the mechanical alloknesis scores of social defeat stress+ Dermatophagoides farina body-treated mice exposed to stress were significantly higher than those of non-exposed social defeat stress+ Dermatophagoides farina body- and social defeat stress-treated mice. These results suggest that psychological stress delays improvements in dermatitis by exacerbating itch hypersensitivity in AD.

A Qualitative Tool to Guide in the Interpretation of the Numerical Rating Scale for Pruritus Intensity in Patients with Atopic Dermatitis.

Atopic dermatitis is a cutaneous inflammatory disease characterized by intense pruritus, which is often underestimated despite its direct impact on patients' health-related quality of life and the high burden it poses. The authors' goal was to design a qualitative tool to guide patients and healthcare professionals in their assessment and interpretation of pruritus intensity using a numerical rating scale. The draft of this tool, henceforth "guideline", was developed based on a systematic literature review and focus groups comprising patients and a scientific committee. This draft was validated with an independent group of patients and the final version was designed following their feedback. According to the results of the systematic review, pruritus impacts 6 health-related quality of life domains: sleep quality; emotional status; overall health-related quality of life; physical function; social/sexual activity; productivity, particularly affecting sleep quality and the emotional domain. Patients considered that physical function was the most strongly affected domain, followed by sleep quality and emotional well-being, establishing that a minimum pruritus intensity of 4 and 7 points impacts moderately and severely, respectively, on the different domains of patients' health- related quality of life. The guideline may help patients and healthcare professionals to interpret and assess pruritus intensity using a numerical rating scale and to understand the impact of pruritus on patients' health-related quality of life.

Atopic Dermatitis in Children.

Atopic dermatitis (AD) is extremely common in the pediatric population, and most children with AD will first present to their primary care provider (PCP). The PCP can recognize AD by its clinical features, including itch, a chronic relapsing course, and the characteristic eruption. The cornerstone of AD therapy is dry skin care, typically a short daily bath/shower followed by an emollient applied to all skin. Most children with AD will also require topical medications, such as topical corticosteroids and/or topical nonsteroidal therapies. For children with more severe disease, systemic agents, including several novel therapies, may be required. In managing AD, the clinician must monitor for side effects of medications as well as complications of the AD itself, the most common of which is secondary infection. An understanding of the pathogenesis, treatments, and complications of AD is essential for the PCP, as untreated (or undertreated) AD has a significant impact on the quality of life of affected children and their caregivers. [Pediatr Ann. 2024;53(4):e121-e128.].

Evaluation of linear dermatoses by reflectance confocal microscopy in children.

Lichen striatus (LS), linear psoriasis (LPs), linear cutaneous lupus erythematosus (LCLE) and linear lichen planus (LLP) often have similar clinical manifestations, which makes clinical diagnosis with the naked eye difficult; therefore, they are easily misdiagnosed. The purpose of this study was to determine whether reflectance confocal microscopy (RCM) is helpful in differentiating between these four linear dermatoses in children. This retrospective study included 14 patients with LS, nine with LPs, eight with LCLE and 12 with LLP. All patients were analysed using RCM, and biopsies were collected from lesions previously imaged by RCM. For LS, the dermal papillary rings were partially absent, but when present, manifested with small, homogeneously round, bright cells and occasionally highly refractive plump cellular structures, aggregated in clusters. LPs exhibited dark cyst-like structures with small, bright, round cells aggregated at the epidermal level; at the dermal-epidermal junction, homogeneously distributed, enlarged, faint dermal papillary rings and numerous enlarged low-refractive canalicular structures were observed in the superficial dermis. LCLE and LLP exhibited similar manifestations, including epidermal disarray, almost total absence of dermal papillary rings, and various sized refractive structures densely distributed in the dermis. The key distinguishing features of LCLE were the different sized structures mainly clustered around hair follicles, while LLP demonstrated dense structures with a scattered distribution. RCM may be used to distinguish between the key features of LS, LPs, LCLE and LLP in children.

Pain type and neuropathic pain components in acute herpes zoster.

OBJECTIVES: The aim of this study was to investigate the pain type (nociceptive or neuropathic) and neuropathic pain components in patients with acute herpes zoster (HZ). METHODS: Patients with acute HZ referred to the outpatient Dermatology and Venereology clinic between January 2021 and January 2022 were retrospectively detected. The demographic data including gender and age, rash localization, pain severity, and neuropathic pain components were recorded. Pain severity and neuropathic pain components were evaluated using a Visual Analog Scale (VAS) and Douleur Neuropathique 4 (DN4), respectively. RESULTS: The study included a total of 58 patients, comprising 33 females and 25 males. Of these patients, 35 (60.3%) were found to have neuropathic pain. Itching, burning, pins and needles, and tingling were the most frequently reported neuropathic pain signs and symptoms. The proportion of female patients with neuropathic pain was found to be significantly higher than that of male patients (p=0.021). No significant differences were observed in the distribution of pain across different body sites or in the age of patients with neuropathic pain (p>0.05). Itching was significantly more common in younger patients (p=0.02). CONCLUSION: In conclusion, the study found that over half of the patients with acute HZ experienced neuropathic pain, and this was more frequently observed in female patients. Analysis of different components of neuropathic pain showed significant differences in age, gender, and site distribution. The findings of this study may have important implications for the manage-ment and treatment of acute HZ.

Allergic Rhinitis: A Review.

Importance: Allergic rhinitis affects an estimated 15% of the US population (approximately 50 million individuals) and is associated with the presence of asthma, eczema, chronic or recurrent sinusitis, cough, and both tension and migraine headaches. Observations: Allergic rhinitis occurs when disruption of the epithelial barrier allows allergens to penetrate the mucosal epithelium of nasal passages, inducing a T-helper type 2 inflammatory response and production of allergen-specific IgE. Allergic rhinitis typically presents with symptoms of nasal congestion, rhinorrhea, postnasal drainage, sneezing, and itching of the eyes, nose, and throat. In an international study, the most common symptoms of allergic rhinitis were rhinorrhea (90.38%) and nasal congestion (94.23%). Patients with nonallergic rhinitis present primarily with nasal congestion and postnasal drainage frequently associated with sinus pressure, ear plugging, muffled sounds and pain, and eustachian tube dysfunction that is less responsive to nasal corticosteroids. Patients with seasonal allergic rhinitis typically have physical examination findings of edematous and pale turbinates. Patients with perennial allergic rhinitis typically have erythematous and inflamed turbinates with serous secretions that appear similar to other forms of chronic rhinitis at physical examination. Patients with nonallergic rhinitis have negative test results for specific IgE aeroallergens. Intermittent allergic rhinitis is defined as symptoms occurring less than 4 consecutive days/week or less than 4 consecutive weeks/year. Persistent allergic rhinitis is defined as symptoms occurring more often than 4 consecutive days/week and for more than 4 consecutive weeks/year. Patients with allergic rhinitis should avoid inciting allergens. In addition, first-line treatment for mild intermittent or mild persistent allergic rhinitis may include a second-generation H1 antihistamine (eg, cetirizine, fexofenadine, desloratadine, loratadine) or an intranasal antihistamine (eg, azelastine, olopatadine), whereas patients with persistent moderate to severe allergic rhinitis should be treated initially with an intranasal corticosteroid (eg, fluticasone, triamcinolone, budesonide, mometasone) either alone or in combination with an intranasal antihistamine. In contrast, first-line therapy for patients with nonallergic rhinitis consists of an intranasal antihistamine as monotherapy or in combination with an intranasal corticosteroid. Conclusions and Relevance: Allergic rhinitis is associated with symptoms of nasal congestion, sneezing, and itching of the eyes, nose, and throat. Patients with allergic rhinitis should be instructed to avoid inciting allergens. Therapies include second-generation H1 antihistamines (eg, cetirizine, fexofenadine, desloratadine, loratadine), intranasal antihistamines (eg, azelastine, olopatadine), and intranasal corticosteroids (eg, fluticasone, triamcinolone, budesonide, mometasone) and should be selected based on the severity and frequency of symptoms and patient preference.

Polarizing itch.

An itch-associated GPCR on neutrophils controls their activation during bacterial infection.

Role of gut-derived bacterial lipopolysaccharide and peripheral TLR4 in immobilization stress-induced itch aggravation in a mouse model of atopic dermatitis.

Psychological stress and intestinal leakage are key factors in atopic dermatitis (AD) recurrence and exacerbation. Here, we demonstrate the mechanism underlying bacterial translocation across intestinal epithelial barrier damaged due to stress and further aggravation of trimellitic anhydride (TMA)-induced itch, which remain unclear, in AD mice. Immobilization (IMO) stress exacerbated scratching bouts and colon histological damage, and increased serum corticosterone and lipopolysaccharide (LPS). Orally administered fluorescein isothiocyanate (FITC)-dextran and surgically injected (into the colon) Cy5.5-conjugated LPS were detected in the serum and skin after IMO stress, respectively. The relative abundance of aerobic or facultative anaerobic bacteria was increased in the colon mucus layer, and Lactobacillus murinus, E. coli, Staphylococcus nepalensis, and several strains of Bacillus sp. were isolated from the spleens and mesenteric lymph nodes. Oral antibiotics or intestinal permeability blockers, such as lubiprostone (Lu), 2,4,6-triaminopyrimidine (TAP) and ML-7, inhibited IMO stress-associated itch; however, it was reinduced through intradermal or i.p. injection of LPS without IMO stress. I.p. injection of TAK-242 (resatorvid), a TLR4 inhibitor, abrogated IMO stress-associated itch, which was also confirmed in TLR4-KO mice. IMO stress alone did not cause itch in naïve mice. IMO stress-induced itch aggravation in TMA-treated AD mice might be attributed to the translocation of gut-derived bacterial cells and LPS, which activates peripheral TLR4 signaling.

Guselkumab in Patients with Scalp Psoriasis: A post hoc Analysis of the VOYAGE 2 Phase III Randomized Clinical Trial.

Scalp psoriasis affects approximately 80% of patients with psoriasis and can negatively impact their quality of life. This post hoc analysis of the VOYAGE 2 Phase III randomized clinical trial evaluated scalp response to guselkumab treatment and its association with skin response and patient-reported outcomes. The study included patients with moderate-to-severe plaque psoriasis and baseline scalp psoriasis who were initially randomized to receive guselkumab. Patients were divided into 3 groups based on their achievement of a Psoriasis Area and Severity Index 90 response at week 28: responder continuation, non-responder continuation and responder withdrawal. In all 3 groups, mean Psoriasis Area and Severity Index head and scalp-specific Investigator's Global Assessment scores improved through week 28. In the responder withdrawal group, these scores worsened after treatment withdrawal at week 28, but remained stable through week 48 in both continuation groups. Trends in Dermatology Life Quality Index and Psoriasis Symptoms and Signs Diary itch scores mirrored those of mean scalp-specific Investigator's Global Assessment scores through week 48. Within-subject correlations were 0.83 between scalp-specific Investigator's Global Assessment and Psoriasis Area and Severity Index head scores and 0.78 between scalp-specific Investigator's Global Assessment and Psoriasis Symptoms and Signs Diary itch scores. Through week 252, Psoriasis Area and Severity Index head scores remained stable in the responder continuation group, improved in the non-responder continuation group and rapidly improved by week 84 in the responder withdrawal group after retreatment.

Orexin neurons play contrasting roles in itch and pain neural processing via projecting to the periaqueductal gray.

Pain and itch are recognized as antagonistically regulated sensations; pain suppresses itch, whilst pain inhibition enhances itch. The neural mechanisms at the central nervous system (CNS) underlying these pain-itch interactions still need to be explored. Here, we revealed the contrasting role of orexin-producing neurons (ORX neurons) in the lateral hypothalamus (LH), which suppresses pain while enhancing itch neural processing, by applying optogenetics to the acute pruritus and pain model. We also revealed that the circuit of ORX neurons from LH to periaqueductal gray regions served in the contrasting modulation of itch and pain processing using optogenetic terminal inhibition techniques. Additionally, by using an atopic dermatitis model, we confirmed the involvement of ORX neurons in regulating chronic itch processing, which could lead to a novel therapeutic target for persistent pruritus in clinical settings. Our findings provide new insight into the mechanism of antagonistic regulation between pain and itch in the CNS.

Yeast-Derived Nucleotides Enhance Fibroblast Migration and Proliferation and Provide Clinical Benefits in Atopic Dermatitis.

Nucleotides, glycosaminoglycans, and omega-3 essential fatty acids (O3s) could be used for improving skin health, although their modes of action, alone or in combination, are not yet fully understood. To gain some insight into these mechanisms, we performed two in vitro tests and one in vivo pilot trial. The effects on human dermal fibroblast proliferation and migration were evaluated with the following compounds and combinations: 0.156 mg/mL O3s, 0.0017 mg/mL hyaluronic acid (HA), 0.0004 mg/mL dermatan sulfate (DS), 0.0818 mg/mL nucleotides, and [O3s + HA + DS] and [O3s + HA + DS + nucleotides] at the same concentrations. In both in vitro assays, adding nucleotides to [O3s + HA + DS] provided significant improvements. The resulting combination [O3s + HA + DS + nucleotides] was then tested in vivo in dogs with atopic dermatitis by oral administration of a supplement providing a daily amount of 40 mg/kg nucleotides, 0.9 mg/kg HA, 0.18 mg/kg DS, 53.4 mg/kg EPA, and 7.6 mg/kg DHA. After 30 days, the pruritus visual analog scale (pVAS) score was significantly reduced, and no adverse effects were observed. In conclusion, the combination of nucleotides plus glycosaminoglycans and O3s could serve as a useful therapeutic alternative in skin health applications.