Mind and skin: Exploring the links between inflammation, sleep disturbance and neurocognitive function in patients with atopic dermatitis.

Atopic dermatitis (AD) is a chronic, pruritic and inflammatory, dry skin condition with many known comorbidities. These include airway disease, food allergies, atopic eye disease and autoimmune conditions. Furthermore, there is often significant sleep disturbance as well as increased psychological distress and mental health problems. Severe AD therefore often has a significant impact on the quality of life of both patients and their families. In this review we discuss recent findings on the putative links between AD, its association with itch, sleep disturbance and neuropsychiatric morbidity, including the role of inflammation in these conditions. Itch was thought to predominantly drive sleep disruption in AD. We now understand changes in sleep influence immune cell distribution and the associated inflammatory cytokines, which suggests a bidirectional relationship between AD and sleep. We also increasingly recognize inflammation as a key driver in psychological symptoms and disorders. The link between cutaneous, systemic and possible brain inflammation could at least in part be driven by the sleep deprivation and itch-driven neuronal proliferation seen in AD.

Burden of atopic dermatitis in Europe: A population-centred approach leveraging web search data in 21 European countries.

BACKGROUND: The complexity, high prevalence, and substantial personal and socioeconomic burden collectively render atopic dermatitis (AD) a major public health concern. Using crowdsourced Internet data has the potential to provide unique insights into this concern, as demonstrated by several previous studies. However, a comprehensive comparison across European countries remains lacking. OBJECTIVES: The study aimed to investigate AD-related web searches across Europe to assess spatiotemporal variations and associations between disease-related and external factors. METHODS: AD-related web search data were extracted for 21 European countries between February 2019 and January 2023. Descriptive analysis and autocorrelation functions were performed to examine spatiotemporal patterns. Correlations (r) were used to evaluate the associations between web searches and disease-related, socioeconomic and meteorological data. RESULTS: Over 241 million AD-related web searches were identified, with search volume varying substantially among European countries (p < 0.001) and correlating with AD prevalence and disease burden (both r = 0.51, p = 0.019). Search volume increased between 2019 and 2023 in all countries and seasonally peaked in January and March. Negative correlations with median population age (r = -0.46, p = 0.039), number of general practitioners (r = -0.29, p = 0.226) and specialists (r = -0.27, p = 0.270) were observed. Moderate to strong correlations were found between search volume and cold, humid and windy weather with fewer sunshine hours, while higher online interest typically occurred 1-3 months after such weather conditions. CONCLUSION: The study highlights the great potential of online crowdsourced data analysis, for example, to investigate the impact of climate change or to identify unmet needs at a population level. Furthermore, the growing online interest in AD and the corresponding seasonal peaks emphasize the necessity of adapting treatment plans, intensifying public health campaigns, and disseminating reliable online information by governments and healthcare providers, especially during these periods.

Adverse reactions after oral provocation with aluminium in children with vaccination granulomas and aluminium contact allergy.

BACKGROUND: According to their parents, some children with aluminium contact allergy and vaccination granulomas may react to aluminium-containing foods by developing dermatitis, granuloma itch and subjective symptoms. OBJECTIVES: The objective of this study is to determine whether oral intake of aluminium-containing pancakes can cause adverse events and/or systemic contact dermatitis (SCD) in children with vaccination granulomas and aluminium contact allergy. PATIENTS/METHODS: A total of 15 children aged 3-9 years (mean age, 5 years) with vaccination granulomas and positive patch-test results to aluminium chloride hexahydrate 2%/10% pet. completed a 3-week blinded randomized controlled crossover oral aluminium/placebo provocation study with pancakes. Granuloma itch and other subjective symptoms were evaluated daily on a visual analogue scale (VAS). Dermatitis was evaluated by the primary investigator, and sleep patterns were tracked with an electronic device. Aluminium bioavailability was assessed by measuring aluminium excretion in the urine. The children served as their own controls with the placebo provocations. RESULTS: All 15 children completed the study. The mean VAS scores were slightly higher during aluminium provocations compared with placebo for granuloma itch (mean VAS, 1.5 vs. 1.4, p = 0.6) but identical for other subjective symptoms (0.6 vs. 0.6, p = 1). There were no differences in sleep patterns and no significant correlation between urinary aluminium excretion and symptom severity. Three children developed a symmetrical rash on the face or buttocks on day 4 of the aluminium provocations, but not during placebo provocations. CONCLUSIONS: No difference was found between oral aluminium intake and the occurrence of subjective symptoms and granuloma itch, but on a case-basis oral aluminium may be associated with the development of systemic contact dermatitis.

A nationwide 104 weeks real-world study of dupilumab in adults with atopic dermatitis: Ineffectiveness in head-and-neck dermatitis.

BACKGROUND: Evaluation of effectiveness and safety of new systemic treatments for atopic dermatitis (AD) after approval is important. There are few published data exceeding 52-week therapy with dupilumab. OBJECTIVES: To examine the safety, effectiveness and drug survival of dupilumab in a Danish nationwide cohort with moderate-to-severe AD up to 104 weeks exposure. METHODS: We included 347 adult patients with AD who were treated with dupilumab and registered in the SCRATCH registry during 2017-2022. RESULTS: At all visits, we observed improvement in AD severity measured by Eczema Area and Severity Index (EASI) [median (IQR)]. EASI score at baseline was 18.0 (10.6-25.2), at week 4: 6.5 (3.5-11.6), at week 16: 3.7 (1.2-6.2), at week 52: 2.0 (0.8-3.6), at week 104: 1.7 (0.8-3.8). While drug survival was high (week 52: 90%; week 104: 86%), AD in the head-and-neck area remained present in most patients at high levels; proportion with head-and-neck AD at baseline was 76% and 68% at week 104. 35% of patients reported any AE. Conjunctivitis was the most frequent (25% of all patients) and median time to first registration of conjunctivitis was 201 days. CONCLUSIONS: While 2-year drug survival was 86%, dupilumab was unable to effectively treat AD in the head-and-neck area, and conjunctivitis was found in 25% of patients.

Evaluation of itch and pain induced by bovine adrenal medulla (BAM)8-22, a new human model of non-histaminergic itch.

Chronic itch is a socioeconomic burden with limited management options. Non-histaminergic itch, involved in problematic pathological itch conditions, is transmitted by a subgroup of polymodal C-fibres. Cowhage is traditionally used for studying experimentally induced non-histaminergic itch in humans but encounters some limitations. The present study, therefore, aims to design a new human, experimental model of non-histaminergic itch based on the application of bovine adrenal medulla (BAM)8-22, an endogenous peptide that activates the MrgprX1 receptor. Twenty-two healthy subjects were recruited. Different concentrations (0.5, 1 and 2 mg/ml) of BAM8-22 solution and vehicle, applied by a single skin prick test (SPT), were tested in the first session. In the second session, the BAM8-22 solution (1 mg/ml) was applied by different number of SPTs (1, 5 and 25) and by heat-inactivated cowhage spicules coated with BAM8-22. Provoked itch and pain intensities were monitored for 9 min, followed by the measurement of superficial blood perfusion (SBP) and mechanical and thermal sensitivities. BAM8-22 induced itch at the concentration of 1, 2 mg/ml (p < 0.05) and with the significantly highest intensity when applied through BAM8-22 spicules (p < 0.001). No concomitant pain sensation or increased SBP was observed. SBP increased only in the 25 SPTs area probably due to microtrauma from the multiple skin penetrations. Mechanical and thermal sensitivities were not affected by any of the applications. BAM8-22 applied through heat-inactivated spicules was the most efficient method to induce itch (without pain or changes in SBP and mechanical and thermal sensitivities) suggesting BAM8-22 as a novel non-histaminergic, human, experimental itch model.

Severe and ChRonic Atopic dermatitis Treatment CoHort (SCRATCH): A Danish Real-world Evidence Atopic Dermatitis Treatment Registry.

Data from real-world use of new systemic treatments in atopic dermatitis (AD) is important for assessing safety and efficacy. The aim of this study is to describe the baseline characteristics of adult patients with moderate-to-severe AD enrolled in the Danish nationwide Severe and ChRonic Atopic dermatitis Treatment CoHort (SCRATCH) database, between October 2017 and August 2021. A total of 282 adult patients were included. Most (62%) were men, the median age at baseline was 43 years (interquartile range (IQR) 29-54 years), and median age at onset of AD was 1 year (IQR 0-6 years). The median Eczema Area and Severity Index at treatment initiation was 19.1 (IQR 11.9-25.7); median Patient Oriented Eczema Measure 21.0 (IQR 16.0-25.0); median Dermatology Life Quality Index 13.0 (IQR 7.0-19.0); and median itch and sleep numerical rating scale scores 8.0 (IQR 6.0-9.0) and 6.0 (IQR 4.0-8.0). Differences were found between the sexes. This registry will provide a source for future efficacy and safety studies.

Does aluminium in sunscreens cause dermatitis in children with aluminium contact allergy: A repeated open application test study.

BACKGROUND: Parents report that children with aluminium contact allergy and vaccination granulomas may react to aluminium-containing sunscreen following application. OBJECTIVES: To evaluate whether contact dermatitis develops following repeated application of aluminium-containing sunscreens in children with aluminium sensitization and vaccination granulomas. METHODS: Sixteen children aged 2-9 years (mean age 5 years) with vaccination granulomas and a positive patch test reaction to aluminium chloride hexahydrate 2%/10% petrolatum completed a blinded repeated open application test (ROAT) with two daily applications of two sunscreens for 14 days. One cream contained aluminium and the other did not. The children served as their own controls. RESULTS: Sixteen children completed the study. Only one child (6%) had a positive skin reaction during ROAT on day 2 to the sunscreen with aluminium. None reacted to the sunscreen without aluminium. CONCLUSIONS: Use of aluminium-containing sunscreens may on a case basis lead to allergic contact dermatitis in aluminium allergic children.

Intradermal Testing Identifies 1 in 4 Patients with Nonimmediate Penicillin Allergy.

BACKGROUND: Intradermal testing with delayed reading (IDTdr), used routinely in many centers, may identify delayed reactions to penicillins. However, few studies have compared the results of IDTdr with drug provocation test (DPT). The aim of this study was to examine the proportion of provocation-positive patients testing positive on IDTdr. METHODS: Fifty-seven patients with a positive DPT occurring >2 h after intake of penicillin V, dicloxacillin, pivampicillin, or amoxicillin had an IDTdr with penicillin G, amoxicillin, ampicillin, and dicloxacillin. A control group included 18 patients with negative DPTs with the suspected penicillin. RESULTS: In total 25% (n = 14) of provocation-positive patients tested positive on IDTdr. Among patients with positive IDTdr, 9/14 (64%) versus 11/43 (26%) in the IDTdr negative group (p < 0.05) had required oral steroids to treat skin reactions following DPT. No other differences between IDTdr positive and negative groups were found. No controls had a positive IDTdr. CONCLUSION: Investigating with IDTdr would have identified 25% of patients with a DPT-verified allergy with delayed reactions. It is difficult to target subgroups who will test positive on IDTdr. There were more patients who tested positive on IDT who had received oral steroids after DPT, and this may be an indication that skin reaction severity plays a role in skin testing diagnostics. Further potential predictors for positivity of IDTdr, such as duration of skin symptoms, should be assessed in large studies in order to optimize the investigations of nonimmediate drug allergic reactions.

Sensory defunctionalization induced by 8% topical capsaicin treatment in a model of ultraviolet-B-induced cutaneous hyperalgesia.

Subpopulations of primary nociceptors (C- and Aδ-fibers), express the TRPV1 receptor for heat and capsaicin. During cutaneous inflammation, these afferents may become sensitized, leading to primary hyperalgesia. It is known that TRPV1+ nociceptors are involved in heat hyperalgesia; however, their involvement in mechanical hyperalgesia is unclear. This study explored the contribution of capsaicin-sensitive nociceptors in the development of mechanical and heat hyperalgesia in humans following ultraviolet-B (UVB) irradiation. Skin areas in 18 healthy volunteers were randomized to treatment with 8% capsaicin/vehicle patches for 24 h. After patches removal, one capsaicin-treated area and one vehicle area were irradiated with 2xMED (minimal erythema dose) of UVB. 1, 3 and 7 days post-UVB exposure, tests were performed to evaluate the development of UVB-induced cutaneous hyperalgesia: thermal detection and pain thresholds, pain sensitivity to supra-threshold heat stimuli, mechanical pain threshold and sensitivity, touch pleasantness, trans-epidermal water loss (TEWL), inflammatory response, pigmentation and micro-vascular reactivity. Capsaicin pre-treatment, in the UVB-irradiated area (Capsaicin + UVB area), increased heat pain thresholds (P < 0.05), and decreased supra-threshold heat pain sensitivity (P < 0.05) 1, 3 and 7 days post-UVB irradiation, while mechanical hyperalgesia resulted unchanged (P > 0.2). No effects of capsaicin were reported on touch pleasantness (P = 1), TEWL (P = 0.31), inflammatory response and pigmentation (P > 0.3) or micro-vascular reactivity (P > 0.8) in response to the UVB irradiation. 8% capsaicin ablation predominantly defunctionalizes TRPV1+-expressing cutaneous nociceptors responsible for heat pain transduction, suggesting that sensitization of these fibers is required for development of heat hyperalgesia following cutaneous UVB-induced inflammation but they are likely only partially necessary for the establishment of robust primary mechanical hyperalgesia.

Children with vaccination granulomas and aluminum contact allergy: Evaluation of predispositions, avoidance behavior, and quality of life.

BACKGROUND: Aluminum contact allergy is mostly seen in children with vaccination granulomas, following immunization with aluminum-adsorbed childhood vaccines. OBJECTIVES: To characterize a cohort of children with vaccination granulomas and aluminum allergy concerning early life conditions, exacerbating factors, avoidance behavior, treatments, and potential impact on quality of life. METHODS: A questionnaire study was conducted among 177 children aged 0 to 15 years with vaccination granulomas and aluminum allergy, and a reference group of 61 children aged 3 to 14 years with various types of dermatitis undergoing patch testing. RESULTS: All children in the granuloma group were reportedly affected by itch. Infection exacerbated the itch in 59%. Other worsening factors were eating tin-foiled/canned food (31%) and use of aluminum-containing sunscreen (46%). Many parents took precautions to avoid aluminum exposure. Children with granulomas were more likely to be nonadherent to the National Vaccination Program than the reference group (27% vs 2%, P < .001). Parents in the granuloma group reported a decreased life quality for both parents and children compared with the reference group. CONCLUSIONS: Itching vaccination granulomas and aluminum allergy have a considerable negative impact on affected children and their families, causing avoidance behavior, reduced adherence to vaccination programs, and a negative effect on the overall life quality.

UVB- and NGF-induced cutaneous sensitization in humans selectively augments cowhage- and histamine-induced pain and evokes mechanical hyperknesis.

Exaggerated itch responses to pruritic chemical provocations and mechanical stimuli are evident in patients with chronic itch, for example, in atopic dermatitis. Currently used human models of itch do not account for such itch sensitization features, and the mechanisms underlying clinical itch sensitization are unknown. This study utilized two established human models of cutaneous nociceptive sensitization to explore how pre-established inflammatory hyperalgesia (ultraviolet-B-irradiation; "UVB") and non-inflammatory neurotrophic pain sensitization (nerve growth factor; "NGF") alter sensitivity to chemical and mechanically evoked itch. Twenty healthy volunteers participated in the UVB experiment. Six volar forearm areas (2 cm diameter) were UVB irradiated with ≤2 × minimal erythemal dose, and two non-irradiated areas were used as controls. Sixteen healthy volunteers participated in the NGF experiment and had 2 µg intradermally injected (4 × 50 µL in 2 cm diameter areas) into both volar forearms. Isotonic saline was applied as control. Pain sensitivity measurements (mechanical and heat pain thresholds) were conducted to validate the models. Subsequently, itch was evoked using histamine and cowhage spicules in the sensitized skin areas, and itch/pain was rated using visual analogue scales. Mechanical hyperknesis (increased itch to punctuate stimuli) was probed with von Frey filaments before/after each itch provocation. Both UVB- and NGF models induced robust primary mechanical hyperalgesia (P < .01) and hyperknesis (P < .05). Neither of the models augmented itch in response to chemical itch provocations but significant increases specifically for pain ratings were observed for both histamine and cowhage (P < .05). This suggests that these models are of limited value as proxies for itch sensitization to pruritogens observed, e.g., in inflammatory dermatoses.

Antipruritic Effect of Cold-induced and Transient Receptor Potential-agonist-induced Counter-irritation on Histaminergic Itch in Humans.

A frequent empirical observation is that cold-induced counter-irritation may attenuate itch. The aim of this randomized, single-blinded, exploratory study was to evaluate the counter-irritation effects of cold-stimulation and topical application of transient receptor potential TRPA1/M8-agonists (trans-cinnamaldehyde/L-menthol, respectively), on histamine-induced itch, wheals and neurogenic inflammation in 13 healthy volunteers. Histamine 1% was applied to the volar forearms using skin prick-test lancets. Recorded outcome-parameters were itch intensity, wheal reactions, and neurogenic inflammation (measured by laser-speckle perfusion-imaging). Homotopic thermal counter-irritation was performed with 6 temperatures, ranging from 4°C to 37°C, using a 3 × 3-cm thermal stimulator. Chemical "cold-like" counter-irritation was conducted with 40% L-menthol and 10% trans-cinnamaldehyde, while 5% doxepin was used as a positive antipruritic control/comparator. Cold counter-irritation stimuli from 4°C to 22°C inhibited itch in a stimulus-intensity-dependent manner (p < 0.05) and, to a lesser extent, also wheal reactions and neurogenic inflammation. Chemical "cold-like" counter-irritation with both L-menthol and trans-cinnamaldehyde had antipruritic efficacy similar to doxepin (p < 0.05). Cold-induced counter-irritation had an inhibitory effect on histaminergic itch, suggesting that agonists of cold transduction receptors could be of potential antipruritic value.

A Test-Retest Reliability Study of Human Experimental Models of Histaminergic and Non-histaminergic Itch.

Numerous exploratory, proof-of-concept and interventional studies have used histaminergic and non-histaminergic human models of itch. However, no reliability studies for such surrogate models have been conducted. This study investigated the test-retest reliability for the response to histamine- and cowhage- (5, 15, 25 spiculae) induced itch in healthy volunteers. Cowhage spiculae were individually applied with tweezers and 1% histamine was applied with a skin prick test (SPT) lancet, both on the volar forearm. The intensity of itch was recorded on a visual analogue scale and self-reported area of itch was assessed 5 and 10 min after itch provocation. Reliability of the evoked itch (area under the curve and peak intensity) was assessed by the coefficient of variation (CV), intra-class correlation coefficient (ICC), and sample size estimation for parallel and cross-over designs. Cowhage (ICC = 0.57-0.77, CVbetween = 97%, CVwithin = 41%) and histamine: (ICC = 0.83-0.93, CVbetween = 97%, CVwithin = 20%) exhibited moderate-to-excellent intra-individual reliability and moderate inter-individual reliability for the itch intensity. For a test-retest observation period of one week, SPT-delivered histamine and application of cowhage-spiculae are reproducible human models of itch. The high inter-individual and low intra-individual variability suggests cross-over designed studies when applicable.

A randomised, placebo-controlled trial of transcranial pulsed electromagnetic fields in patients with multiple chemical sensitivity.

OBJECTIVE: To evaluate the efficacy of transcranially applied pulsed electromagnetic fields (PEMF) on functional impairments and symptom severity in multiple chemical sensitivity (MCS) patients. METHODS: The study was conducted as a nationwide trial in Denmark using a randomised, parallel-group, double-blind and placebo-controlled design. Sample size was estimated at 40 participants. Eligibility criteria were age 18-75 years and fulfilment of the MCS case criteria. Participants received either PEMF or placebo PEMF (no stimulation) applied transcranially for 6 weeks. The primary outcome was the Life Impact Scale (LIS) of the Quick Environmental Exposure and Sensitivity Inventory (QEESI). Secondary outcomes were the Symptom Severity Scale (SSS) and the Chemical Intolerance Scale of QEESI. RESULTS: A total of 39 participants were randomised to PEMF or placebo treatment. No significant difference was observed on QEESI LIS between groups with a mean change score of -5.9 in the PEMF group compared with -1.5 in the placebo group (p=0.35, effect size=-0.31). However, a significant decrease was detected on QEESI SSS within and between groups with a mean change score of -11.3 in the PEMF group compared with -3.2 in the placebo group (p=0.03, effect size=-0.60). CONCLUSION: PEMF treatment of 6 weeks showed no effect on functional impairments in MCS. However, a significant decrease in symptom severity was observed.