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BACKGROUND: Poor sleep quality is associated with higher mortality and lower quality of life in patients with chronic kidney disease-associated pruritus (CKD-aP). Difelikefalin reduces itch in patients with CKD-aP undergoing haemodialysis (HD). This post hoc analysis of the Phase 3 difelikefalin studies (Study 3105 and the pooled dataset from KALM-1 and KALM-2) evaluated whether itch reduction in individuals with CKD-aP improved sleep quality. METHODS: Itch intensity was assessed in patients undergoing HD who had moderate-to-severe CKD-aP treated with intravenous difelikefalin (0.5 µg/kg, three times weekly) (N = 222, Study 3105; N = 426, KALM-1 and -2) or placebo (N = 425, KALM-1 and -2) for 12 weeks, using the Worst Itch Intensity Numerical Rating Scale (WI-NRS). Sleep quality was assessed using the sleep disability question of the 5-D Itch Scale (5-D SDQ) in all studies and, in Study 3105, with the Sleep Quality Numeric Rating Scale (SQ-NRS). RESULTS: Greater improvements in sleep quality were observed in patients with ≥3-point versus

Background: Lebrikizumab improved itch, interference of itch on sleep, and quality of life (QoL) in patients with moderate-to-severe atopic dermatitis (AD), in two Phase 3 trials at 16weeks compared to placebo. Objectives: We assess improvements in itch and sleep interference due to itch and their impact on QoL measurements after treatment. Methods: Data were analyzed from ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967) in patients with moderate-to-severe AD. QoL was evaluated using Dermatology Life Quality Index (DLQI) at Week 16 in patients (>16years of age) who were itch responders/non-responders (defined as ≥4-point improvement in Pruritus Numeric Rating Scale) or Sleep-Loss Scale responders/non-responders (defined as ≥2-point improvement in itch interference on sleep). Results: In ADvocate1 and ADvocate2, significantly greater proportions of itch responders had a clinically meaningful improvement in measures related to QoL (DLQI scores (0/1), ≤5 DLQI total score and ≥4-point DLQI improvement) compared to itch non-responders. In both studies, a significantly greater proportion of Sleep-Loss Scale responders, reported a DLQI score of (0/1), DLQI total score of ≤5 and DLQI improvement of ≥4 points compared to Sleep-Loss Scale non-responders. Conclusions: Improvement in itch and sleep interference due to itch is associated with improvement in the QoL of patients after treatment with lebrikizumab for moderate-to-severe AD. ClinicalTrials.gov registration NCT04146363 (ADvocate1) and NCT04178967 (ADvocate2). [ABSTRACT FROM AUTHOR]

Background: Though Janus kinase inhibitors such as upadacitinib rapidly relieve itch in atopic dermatitis (AD) patients, how early itch relief impacts later skin clearance is not examined. Objectives: This study aims to determine if early itch relief by upadacitinib could predict complete skin clearance in later phases. Methods: This retrospective study involved 105 patients with moderate-to-severe AD treated with upadacitinib 15mg/day. Eczema area and severity index (EASI), atopic dermatitis control tool, and achievement rate of EASI 100 were evaluated at weeks 4, 12, and 24. The threshold of early peak pruritus-numerical rating scale (PP-NRS) predicting later skin clearance was assessed by area under the receiver-operating characteristic curve, and predictors for EASI 100 achievement were determined by logistic regression analysis. Results: The rate of achieving EASI 100 at week 24 was extremely higher in patients who achieved week 2 PP-NRS ≤ 1 (42.9%) than in non-achievers (1.4%). The logistic regression analysis showed that the achievement of week 2 PP-NRS ≤ 1 and low body mass index were associated with achievement of EASI 100 at weeks 12 and 24. Conclusions: The achievement of week 2 PP-NRS ≤ 1 may predict later skin clearance in upadacitinib treatment. [ABSTRACT FROM AUTHOR]

Despite remarkable progress in understanding the fundamental bases of itching, its cortical mechanisms remain poorly understood. Herein, the causal contributions of defined anterior cingulate cortex (ACC) neuronal populations to acute itch modulation in mice are established. Using cell type‐specific manipulations, the opposing functions of ACC glutamatergic and GABAergic neurons in regulating acute itching are demonstrated. Photometry studies indicated that ACC glutamatergic neurons are activated during scratching induced by both histamine and chloroquine, whereas the activation pattern of GABAergic neurons is complicated by GABAergic subpopulations and acute itch modalities. By combining cell type‐ and projection‐specific techniques, a thalamocortical circuit is further identified from the mediodorsal thalamus driving the itch‐scratching cycle related to histaminergic and non‐histaminergic itching, which is contingent on the activation of postsynaptic parvalbumin‐expressing neurons in the ACC. These findings reveal a cellular and circuit signature of ACC neurons orchestrating behavioral responses to itching and may provide insights into therapies for itch‐related diseases. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic inflammatory skin disease with multifactorial and unclear pathogenesis. Its development is characterized by two key elements: epigenetic dysregulation of molecular pathways involved in AD pathogenesis and disrupted skin and gut microbiota (dysbiosis) that jointly trigger and maintain chronic inflammation, a core AD characteristic. Current data suggest that failed inflammation resolution is the main pathogenic mechanism underlying AD development. Inflammation resolution is provided by specialized pro-resolving mediators (SPMs) derived from dietary polyunsaturated fatty acids acting through cognate receptors. SPM levels are reduced in AD patients. Administration of SPMs or their stable, small-molecule mimetics and receptor agonists, as well as supplementation with probiotics/prebiotics, demonstrate beneficial effects in AD animal models. Epidrugs, compounds capable of restoring disrupted epigenetic mechanisms associated with the disease, improve impaired skin barrier function in AD models. Based on these findings, we propose a novel, multilevel AD treatment strategy aimed at resolving chronic inflammation by application of SPM mimetics and receptor agonists, probiotics/prebiotics, and epi-drugs. This approach can be used in conjunction with current AD therapy, resulting in AD alleviation. [ABSTRACT FROM AUTHOR]

Itch is one of the most prevalent symptoms experienced by patients with inflammatory skin conditions, yet it is also one of the most debilitating. Patients suffering from chronic itch have been found to have significantly higher stress levels compared with those not experiencing itch. In fact, recent studies have revealed a bidirectional relationship between stress and itch, where each condition worsens the other. This is thought to be driven by the vicious itch–scratch cycle, which is fueled by underlying inflammation. The precise molecular pathways and mediators involved, however, remain unclear. This narrative review discusses the existing research on the relationship between stress and itch and outlines future research directions that will be necessary to advance our understanding and treatment of these conditions. Given that the effective management of both symptoms often requires a combined treatment approach, further investigation into their shared mechanisms is essential for identifying successful therapies and improving patient outcomes. [ABSTRACT FROM AUTHOR]

Melanosomes play a pivotal role in skin color and photoprotection. In contrast to the well-elucidated pathway of melanosome biogenesis, the process of melanosome degradation, referred to as melanophagy, is largely unexplored. Previously, we discovered that 3,4,5-trimethoxycinnamate thymol ester (TCTE) effectively inhibits skin pigmentation by activating melanophagy. In this study, we discovered a new regulatory signaling cascade that controls melanophagy in TCTE-treated melanocytes. ITCH (itchy E3 ubiquitin protein ligase) facilitates ubiquitination of the melanosome membrane protein MLANA (melan-A) during TCTE-induced melanophagy. This ubiquitinated MLANA is then recognized by an autophagy receptor protein, OPTN (optineurin). Additionally, a phospho-kinase antibody array revealed that TCTE activates PTK2 (protein tyrosine kinase 2), which phosphorylates ITCH, enhancing the ubiquitination of MLANA. Furthermore, inhibition of either PTK2 or ITCH disrupts the ubiquitination of MLANA and the MLANA-OPTN interaction in TCTE-treated cells. Taken together, our findings highlight the critical role of the PTK2-ITCH-MLANA-OPTN cascade in orchestrating melanophagy progression.Abbreviations: α-MSH: alpha-melanocyte-stimulating hormone; dichlone: 2,3-dichloro-1,4-naphthoquinone; ITCH: itchy E3 ubiquitin protein ligase; MITF: melanocyte inducing transcription factor; MLANA: melan-A; NBR1: NBR1 autophagy cargo receptor; OPTN: optineurin; PINK1: PTEN induced kinase 1; PTK2: protein tyrosine kinase 2; SQSTM1/p62: sequestosome 1; TCTE: 3,4,5-trimethoxycinnamate thymol ester; TPC2: two pore segment channel 2; VDAC1: voltage dependent anion channel 1. [ABSTRACT FROM AUTHOR]

Introduction: Allergic contact dermatitis (ACD), a prevalent skin disorder affecting up to 20% of the population, triggers significant discomfort and health implications. Our research investigates the pivotal role of Vascular Endothelial Growth Factor A (VEGFA) in chronic itching associated with ACD. Methods: Bioinformatics methods were utilized to identify differentially expressed genes (DEGs) between ACD models and patients. In vivo models of chronic pruritus in mice induced by 2,4-dinitrofluorobenzene (DNFB) were employed. Mice were administered subcutaneously with a VEGFA inhibitor, sFlt1, and compared to a control group. Real-time RT-PCR, Western blot, and immunohistochemical staining were performed to evaluate VEGFA expression and the impact of sFlt1 on itching behavior. Results: The analysis revealed that VEGFA is significantly upregulated in ACD skin, primarily expressed by keratinocytes. Administration of the VEGFA inhibitor sFlt1 in the ACD mouse model led to a substantial reduction in scratching behavior, indicating that VEGFA may mediate pruritus through the VEGFA-VEGFR2-PI3K-TRPV1 signaling pathway. Discussion: These findings suggest that VEGFA plays a crucial role in ACD-associated pruritus and may serve as a potential therapeutic target. However, further research is required to validate these findings and to explore additional molecular pathways involved in the pruritic response in ACD. [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis is a chronic inflammatory skin disease that commonly begins during childhood. Most atopic dermatitis patients may experience symptoms that continue into adulthood. Itching is the characteristic symptom of atopic dermatitis. Over time, patients’ itching can lead to sleep disturbances. In fact, every human being requires sleep to maintain the balance of metabolism, calories, temperature, and immunity. If a person often lacks sleep, the risk of obesity, type 2 diabetes mellitus, hypertension, heart disease, stroke, deterioration of mental health, and premature death will increase. Purpose: To analyze the relationship between the severity of atopic dermatitis and sleep quality in Widya Mandala Surabaya Catholic University (WMSCU) teaching hospital patients. Methods: This is an analytic study with a cross-sectional research design. This study used the purposive sampling technique as its sampling method. A dermatologist used the Eczema Area and Severity Index (EASI) instrument, to assess the severity of atopic dermatitis in the samples, and Pittsburgh Sleep Quality Index (PSQI) questionnaire to assess their sleep quality. Result: The Mann-Whitney test showed a p value of 0.348 (p> 0.05). Conclusion: There is no significant relationship between the severity of atopic dermatitis and sleep quality in WMSCU teaching hospital patients.

Abstract Treating psoriasis presents a major clinical challenge because of the limitations associated with traditional topical glucocorticoid therapy. This study introduced a drug delivery system utilizing zinc-doped mesoporous silica nanoparticle (Zn-MSN) and microneedle (MN), designed to enhance drug utilization for prolonged anti-inflammatory and anti-itch effects. The MN system facilitated the transdermal delivery of betamethasone dipropionate (BD), allowing its slow release. The BD@Zn-MSN-MN system promoted the polarization of macrophages towards the anti-inflammatory M2 phenotype, achieving superior anti-inflammatory effects compared to the clinically used BD cream. Additionally, this study demonstrated that BD@Zn-MSN-MN could further alleviate itching in psoriasis-afflicted mice by decreasing the excitability of the transient receptor potential vanilloid V1 (TRPV1) ion channel positive neurons and reducing the release of calcitonin gene-related peptide (CGRP) in the dorsal root ganglion (DRG). These findings offer new insights and effective therapeutic options for the future design of transdermal drug delivery for psoriasis.

Abstract Hailey–Hailey disease (HHD) is a genetic skin disorder, accompanied by lesional pruritus and a relevant impact on quality of life of affected patients. Approved or even successful treatments are still lacking, highlighting the need for further insight in therapeutic options. µ‐opioid receptor antagonists have recently been identified as a potentially successful therapy in HHD‐patients, while already being used successfully in treating chronic pruritus. In our case of a patient with severe HHD and generalization of chronic pruritus, which led to koebnerization of HHD lesions into clinically healthy skin, intravenous naloxone treatment proved extraordinarily beneficial in improving both HHD and concomitant chronic pruritus.

Abstract The experience of itch and its associated chronic conditions (i.e., atopic dermatitis) form a significant burden of disease. Knowledge of how the brain processes itch, that might occur uniquely for chronic itch populations, could be used to guide more effective psychotherapeutic interventions for these groups. To build the evidence base for such approaches, we conducted a series of coordinates-based fMRI analyses, to identify the shared neural mechanisms for itch across the published literature. Upon so doing, we identified a core “itch network” that spans the Basal Ganglia/Thalamus, Claustrum and Insula. Additionally, we found evidence that the Paracentral Lobule and Medial Frontal Gyrus, regions associated with cognitive control and response inhibition, deactivate during itch. Interestingly, a separate analysis for chronic itch populations identified significant recruitment of the Left Paracentral Lobule, potentially suggesting the recruitment of cognitive control mechanisms to resist the urge to scratch. We position these results in light of further integrative studies that could use neuroimaging alongside clinical studies, to explore how transdiagnostic psychological approaches—such as mindfulness and compassion training—might help to improve quality of life for individuals who experience chronic itch.

Weixiong Chen,1,2,* Jianqiang Liang,3,* Shuang He,1,4,5 Qingsong Liang,1,4,5 Wenting Tian,6 Aobo Lu,1 Demin Li,1 Zhicheng Huang,1 Guanyi Wu1,4,5 1College of Basic Medicine, Guangxi University of Chinese Medicine, Nanning, Guangxi, 530299, People’s Republic of China; 2School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, 200093, People’s Republic of China; 3Department of Dermatology, the First People’s Hospital of Yulin, Yulin, Guangxi, 537000, People’s Republic of China; 4Key Laboratory for Complementary and Alternative Medicine Experimental Animal Models of Guangxi, Nanning, Guangxi, 530299, People’s Republic of China; 5Guangxi Key Laboratory of Translational Medicine for Treating High-Incidence Infectious Diseases with Integrative Medicine, Nanning, Guangxi, 530299, People’s Republic of China; 6College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, Guangxi, 530299, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guanyi Wu, College of Basic Medicine, Guangxi University of Chinese Medicine, Nanning, Guangxi, 530299, People’s Republic of China, Email wugy@gxtcmu.edu.cnPurpose: Psoriasis is an immune-related disorder characterized by silver scales, epidermis thickness, and itching. She-Chuang-Si-Wu-Tang (SSWT), a traditional Chinese medicine decoction, has been used clinically for 400 years. Although it benefits psoriasis treatment, the mechanism of action is still unclear. This study explores SSWT’s molecular mechanism in treating psoriasis through network pharmacology analysis and experiments.Methods: We identified relevant SSWT and psoriasis targets using network pharmacology and conducted SSWT quality control with high-performance liquid chromatography (HPLC). A mouse model of psoriasis was established using imiquimod (IMQ), with the drug administered continuously for seven days, spanning an eight-day period. During the experiment, we observed spontaneous scratching behaviors and assessed the Psoriasis Area and Severity Index (PASI) scores. At the conclusion of the experiment, we examined skin tissue pathology under an optical microscope and measured epidermal thickness. Additionally, we used enzyme-linked immunosorbent assay (ELISA) and quantitative reverse transcription polymerase chain reaction (qRT-PCR) to measure interleukin (IL)-23, IL-17A, IL-17F, and interferon (IFN)-γ levels in the mice’s serum and their mRNA expression in the skin. Western blot analysis was conducted to assess protein levels related to signaling pathways.Results: Results indicate that SSWT may target IL-17 signaling pathways and T helper (Th) 17 cell differentiation, as predicted by network pharmacology. SSWT significantly improved the PASI and Baker scores, reduced epidermal thickness, and decreased spontaneous scratching in IMQ-induced mice. Additionally, SSWT treatment significantly lowered the concentrations of inflammatory factors in the serum and skin lesions, as well as mRNA expression levels, compared to the IMQ group. Furthermore, SSWT significantly inhibited the phosphorylation of both the signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase (MAPK) pathways.Conclusion: In summary, this study unveiled the potential anti-psoriatic mechanism of SSWT, offering new evidence for its clinical application. Keywords: She-Chuang-Si-Wu-Tang, psoriasis, inflammation, itch, STAT3, MAPK

Abstract Background Chronic hand dermatitis (CHD) has suboptimal treatments and a negative impact on quality of life (QoL). Topical ruxolitinib, a JAK1/JAK2 inhibitor, is approved for vitiligo and mild‐to‐moderate atopic dermatitis, but has not previously been studied specifically for CHD. Objectives Evaluate the impact of ruxolitinib in CHD. Methods A 12‐week, investigator‐initiated, open‐label trial evaluated ruxolitinib 1.5% in 15 adults with recalcitrant moderate‐to‐severe CHD. Primary outcomes included the proportion of patients: (1) achieving an Investigator Global Assessment (IGA) treatment success (0 or 1 score with a two‐step improvement) (2) a Hand Eczema Severity Index (HECSI)‐75 improvement at 12 weeks. Additional outcomes: clinical improvement at 4 and 8 weeks, improvement in itch (Numerical Rating Scale [NRS]) and QoL outcomes (i.e., Dermatology Life Quality Index [DLQI] and Skindex‐Mini). Results At 12 weeks, 13/15 participants (86%) achieved a HECSI‐75, 12/15 participants (80%) had a two‐point reduction in IGA and 8/15 participants (53%) achieved an IGA treatment success. Both atopic dermatitis (AD; n = 7) and non‐AD (n = 8) CHD participants had clinical improvement in HECSI at 12 weeks (p

Abstract Background Lebrikizumab demonstrated significant improvement versus placebo for measures of skin clearance and patient-reported outcomes at weeks 16 and 52 in patients with moderate-to-severe atopic dermatitis (AD). We report the sustained impact of lebrikizumab monotherapy, over 52 weeks and between visits, on the frequency of itch and sleep loss symptoms, as assessed by Patient-Oriented Eczema Measure (POEM), in patients with moderate-to-severe AD. Methods In ADvocate1 and ADvocate2, Week-16 lebrikizumab responders (EASI75 or IGA 0/1 with ≥ 2-point improvement and without rescue medication) were randomized to lebrikizumab every 2 weeks (Q2W), every 4 weeks (Q4W), or placebo for 36 weeks. This pooled analysis reports improvement from Week 16 to 52 in patients achieving POEM response 0 (no days) or 1 (1–2 days) for Items 1 (itch) and 2 (sleep disturbance) for the lebrikizumab Q2W and Q4W treatment arms. Observed (excluding data collected after treatment discontinuation, rescue medication use, or patient transfer to escape arm) results were reported. Results At Week 16, for lebrikizumab Q2W and Q4W, 35.9% (n = 37/103) and 39.3% (n = 42/107) of patients responded 0 or 1 to Item 1 of POEM (Itch) and 12.6% (n = 13/103) and 12.1% (n = 13/107) responded 0. A total of 66.0% (n = 68/103) and 72.6% (n = 77/106) of patients responded 0 or 1 to Item 2 of POEM (Sleep) and 37.9% (n = 39/103) and 44.3% (n = 47/106) responded 0, respectively. By Week 52, for lebrikizumab Q2W and Q4W, 44.6% (n = 29/65) and 48.0% (n = 36/75) responded 0 or 1 to Item 1 of POEM (Itch), and 21.5% (n = 14/65) and 18.7% (n = 14/75) of patients responded 0. A total of 83.1% (n = 54/65) and 78.4% (n = 58/74) responded 0 or 1 to Item 2 of POEM (Sleep), and 67.7% (n = 44/65) and 59.5% (n = 44/74) responded 0, respectively. Conclusion Weekly POEM responses for itch and sleep disturbance remained stable between doses and visits, and continued to improve from Week 16 through 52, in lebrikizumab-treated patients, demonstrating consistent improvement over time for key AD symptoms. Trial Registration Numbers ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967).

Abstract Background Sleep loss is a key factor contributing to disease burden in people with atopic dermatitis (AD). Mitigating itch to improve sleep is an important outcome of AD treatment. This study explored the content validity and measurement properties of the Sleep-Loss Scale, a single-item rating scale for assessing itch interference with sleep in clinical trials of AD treatments. Methods Concept elicitation and cognitive debriefing interviews were conducted with 21 adults and adolescents (12–17 years of age) with moderate-to-severe AD to develop a conceptual model of patient experience in AD and explore the content validity of the scale. Data collected from adults with moderate-to-severe AD enrolled in a phase 2b study (NCT03443024) were used to assess Sleep-Loss Scale’s psychometric performance, including reliability, construct validity, and ability to detect change. Meaningful within-patient change (MWPC) thresholds were also determined using anchor-based methods. Results Qualitative findings from concept elicitation highlighted the importance of sleep-loss related to itch in AD. Debriefing analysis of the Sleep-Loss Scale indicated that the scale was relevant, appropriate, and interpreted as intended. Trial data supported good reliability, construct validity and ability to detect improvement. MWPC was defined as a 1-point improvement using trial data, a finding supported by qualitative data. Conclusions The Sleep-Loss Scale provides a valid and reliable patient-reported measure of the impact of itch on sleep in patients with AD, and can detect change, indicating it is fit-for-purpose to evaluate the efficacy of AD treatments in moderate-to-severe patients.

Introduction Psoriasis is a chronic skin disease affecting quality of life and causing pruritus. The factors influencing itch and its impact on the quality of life in Thai psoriasis patients are unknown. We aimed to identify these factors and their effect on quality of life. Methods In this questionnaire-based cross-sectional study, we included patients with psoriasis who received treatment at Chulabhorn Hospital in Thailand from January 2019 to July 2021. Interviewer is the non-dermatologist practician. The patient’s information was collected, including demographic data, Itch Numeric Rating Scale (Itch NRS) score, factors affecting itch, and score on the Thai version of the Dermatology Life Quality Index (DLQI). We performed descriptive statistics and logistic regression analysis. Results Of 100 participants, most (99%) experienced itching, with a moderate degree of pruritus (mean Itch NRS score 6.5 ± 2.6) and a moderate effect on quality of life (mean DLQI score 9.4 ± 6.2). Factors associated with itch aggravation were dry skin (p-value = 0.003) and heat and humidity (p-value = 0.042). The results of binary logistic regression revealed that factors associated with moderate-to-extremely large DLQI scores were itch intensity (no-to-mild vs. moderate-to-severe itch: odds ratio [OR] = 13.33; 95% confidence interval [CI] = 2.72–65.32, p < 0.001; and adjusted odds ratio [AOR] = 31.17; 95% CI = 4.55–213.36; p < 0.001. Conclusions Our findings revealed that the quality of life among patients with psoriasis is their greatest concern. Eliminating the itch intensity that affects their quality of life is crucial but remains challenging in Thailand.

Atopic dermatitis (AD) is a chronic inflammatory skin disease with a complex pathophysiology characterized by intense pruritus, often associated with psychological stress and atopic and non-atopic comorbidities that significantly reduce quality of life. The psychological aspects of AD and the interaction between the mind and body via the skin–brain axis have led to an interest in mind–body therapies (MBT). The aim of this article is, therefore, to reinforce the importance of psychodermatological care in AD. We performed a focused literature review on holistic practices or integrative MBT in AD, including education, cognitive behavioral therapy, habit reversal, meditation, mindfulness, hypnotherapy, eye movement desensitization and reprocessing, biofeedback, progressive muscle relaxation, autonomous sensory meridian response, music therapy, massage, and touch therapy. A multidisciplinary holistic approach with MBT, in addition to conventional pharmacologic antipruritic therapies, to break the itch–scratch cycle may improve AD outcomes and psychological well-being. Although there is a paucity of rigorously designed trials, evidence shows the potential benefits of an integrative approach on pruritus, pain, psychological stress, anxiety, depressive symptoms, and sleep quality. Relaxation and various behavioral interventions, such as habit reversal therapy for replacing harmful scratching with massaging with emollient 'plus', may reduce the urge to scratch, while education may improve adherence to conventional therapies. [ABSTRACT FROM AUTHOR]

The experience of itch and its associated chronic conditions (i.e., atopic dermatitis) form a significant burden of disease. Knowledge of how the brain processes itch, that might occur uniquely for chronic itch populations, could be used to guide more effective psychotherapeutic interventions for these groups. To build the evidence base for such approaches, we conducted a series of coordinates-based fMRI analyses, to identify the shared neural mechanisms for itch across the published literature. Upon so doing, we identified a core "itch network" that spans the Basal Ganglia/Thalamus, Claustrum and Insula. Additionally, we found evidence that the Paracentral Lobule and Medial Frontal Gyrus, regions associated with cognitive control and response inhibition, deactivate during itch. Interestingly, a separate analysis for chronic itch populations identified significant recruitment of the Left Paracentral Lobule, potentially suggesting the recruitment of cognitive control mechanisms to resist the urge to scratch. We position these results in light of further integrative studies that could use neuroimaging alongside clinical studies, to explore how transdiagnostic psychological approaches—such as mindfulness and compassion training—might help to improve quality of life for individuals who experience chronic itch. [ABSTRACT FROM AUTHOR]

Cisplatin-induced renal tubular injury largely restricts the wide-spread usage of cisplatin in the treatment of malignancies. Identifying the key signaling pathways that regulate cisplatin-induced renal tubular injury is thus clinically important. PARVB, a focal adhesion protein, plays a crucial role in tumorigenesis. However, the function of PARVB in kidney disease is largely unknown. To investigate whether and how PARVB contributes to cisplatin-induced renal tubular injury, a mouse model (PARVB cKO) was generated in which PARVB gene was specifically deleted from proximal tubular epithelial cells using the Cre-LoxP system. In this study, we found depletion of PARVB in proximal tubular epithelial cells significantly attenuates cisplatin-induced renal tubular injury, including tubular cell death and inflammation. Mechanistically, PARVB associates with transforming growth factor-β-activated kinase 1 (TAK1), a central regulator of cell survival and inflammation that is critically involved in mediating cisplatin-induced renal tubular injury. Depletion of PARVB promotes cisplatin-induced TAK1 degradation, inhibits TAK1 downstream signaling, and ultimately alleviates cisplatin-induced tubular cell damage. Restoration of PARVB or TAK1 in PARVB-deficient cells aggravates cisplatin-induced tubular cell injury. Finally, we demonstrated that PARVB regulates TAK1 protein expression through an E3 ligase ITCH-dependent pathway. PARVB prevents ITCH association with TAK1 to block its ubiquitination. Our study reveals that PARVB deficiency protects against cisplatin-induced tubular injury through regulation of TAK1 signaling and indicates targeting this pathway may provide a novel therapeutic strategy to alleviate cisplatin-induced kidney damage. [ABSTRACT FROM AUTHOR]

Introduction: Psoriasis is one of the most common autoimmune, psychosomatic skin diseases that is accompanied by vulnerability to stress, emotional disorders, and difficulty expressing negative feelings. The role of psychological factors such as emotional experiences and especially emotional ataxia in the clinical course of many skin diseases has been confirmed. The aim of the present study was to investigate the role of emotional ataxia and psychological distress in predicting the degree of itching and the severity of the disease in people with psoriasis. Methodology: The statistical population of the research was psoriasis sufferers in Tehran in 1401. For this purpose, with the available sampling method, 187 people with psoriasis who were members of the Iranian Psoriasis Association participated in the research online. Toronto Ataxia Questionnaire (TAS), Kessler's Psychological Distress Scale, Psoriasis Level and Severity Index (PASI) and self-report itch intensity measurement were completed. Results: The results of the correlation analysis showed that there is a positive and significant correlation between emotional dyslexia, psychological distress, the severity of itching and the severity of the disease. Stepwise regression was used to investigate the moderating role of alexithymia between psychological distress and itching intensity. Conclusion: The findings show that the beta related to the interaction of emotional ataxia and psychological distress is significant in predicting 34% of itching in psoriasis. But these results were not significant for predicting the severity of the disease by emotional ataxia and psychological distress. [ABSTRACT FROM AUTHOR]

Itch is a unique sensory experience that is responded to by scratching. How pruritogens, which are mechanical and chemical stimuli with the potential to cause itch, engage specific pathways in the peripheral and central nervous system has been a topic of intense investigation over the last few years. Studies employing recently developed molecular, physiological, and behavioral techniques have delineated the dedicated mechanisms that transmit itch information to the brain. This review outlines the genetically defined and evolutionary conserved circuits for itch ranging from the skin-innervating peripheral neurons to the cortical neurons that drive scratching. Moreover, scratch suppression of itch is attributed to the concurrent activation of pain and itch pathways. Hence, we discuss the similarities between circuits driving pain and itch. [ABSTRACT FROM AUTHOR]

Background: Lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA) are the most common causes of lymphocytic scarring alopecia. Itching of the scalp is a common accompanying symptom. The aim of the study was the clinical assessment of pruritus and its correlation with dermoscopic features. Methods: Sixty-one patients with scarring alopecia were analyzed (LPP = 16; FFA = 33; coexisting LPP-FFA = 12). Each patient underwent a trichoscopic examination. Itch severity and characteristics were assessed using a Visual Analogue Scale (VAS), 4-item Itch Questionnaire and 12-item Descriptive Pruritus Assessment Questionnaire. Results: Itching of the scalp occurred in 73.8% of the patients (mean maximal VAS 5.3 ± 3.1 points). Pruritus was most frequently accompanied by tingling (19.7%) or burning (14.8%) sensations. The following factors most frequently increased the severity of pruritus: sweating, heat, stress and hot water. On the other hand, cold water and cold air often relieved symptoms. There was a significant relationship between itch and perifollicular scaling (p = 0.011), hair diameter diversity (p = 0.008) and white halo (p = 0.016). Conclusions: Pruritus was the main subjective complaint reported by patients suffering from LPP and FFA. A better understanding of pruritic features may help in the selection of an effective therapeutic strategy. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic and fluctuating disease. Optimal management of AD and related comorbidities requires seamless coordination across multiple layers of the healthcare system. The objective of this survey was to explore patients' experiences with current management of AD. Out of 251 responders to this anonymous survey, 76% reported to have moderate or severe AD. Sixty-nine percent with moderate and 45% with severe AD were followed up at primary care level only. Use of advanced systemic treatment options was rare, and the majority experienced itch (97%), dry skin, rash, negative impact on self-esteem and comorbidities despite ongoing treatment. Only 36% received a treatment plan, more often in secondary (78.3%) than primary care (25.0%). Forty-three percent did not know who was responsible for their follow-up and 54% felt no one was responsible. Treatment options were commonly not known or understood. The survey results demonstrate undertreatment, lack of a holistic approach for management of AD. A national pathway including clear referral criteria and timelines can streamline management of AD across multiple levels of the healthcare system. [ABSTRACT FROM AUTHOR]

Cadaverine is an endogenous metabolite produced by the gut microbiome with various activity in physiological and pathological conditions. However, whether cadaverine regulates pain or itch remains unclear. In this study, we first found that cadaverine may bind to histamine 4 receptor (H4R) with higher docking energy score using molecular docking simulations, suggesting cadaverine may act as an endogenous ligand for H4R. We subsequently found intradermal injection of cadaverine into the nape or cheek of mice induces a dose-dependent scratching response in mice, which was suppressed by a selective H4R antagonist JNJ-7777120, transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine and PLC inhibitor U73122, but not H1R antagonist or TRPA1 antagonist or TRPV4 antagonist. Consistently, cadaverine-induced itch was abolished in Trpv1 −/− but not Trpa1 −/− mice. Pharmacological analysis indicated that mast cells and opioid receptors were also involved in cadaverine-induced itch in mice. scRNA-Seq data analysis showed that H4R and TRPV1 are mainly co-expressed on NP2, NP3 and PEP1 DRG neurons. Calcium imaging analysis showed that cadaverine perfusion enhanced calcium influx in the dissociated dorsal root ganglion (DRG) neurons, which was suppressed by JNJ-7777120 and capsazepine, as well as in the DRG neurons from Trpv1 −/− mice. Patch-clamp recordings found that cadaverine perfusion significantly increased the excitability of small diameter DRG neurons, and JNJ-7777120 abolished this effect, indicating involvement of H4R. Together, these results provide evidences that cadaverine is a novel endogenous pruritogens, which activates H4R/TRPV1 signaling pathways in the primary sensory neurons. [ABSTRACT FROM AUTHOR]

Lysophosphatidic acids (LPAs) evoke nociception and itch in mice and humans. In this study, we assessed the signaling paths. Hydroxychloroquine was injected intradermally to evoke itch in mice, which evoked an increase of LPAs in the skin and in the thalamus, suggesting that peripheral and central LPA receptors (LPARs) were involved in HCQ-evoked pruriception. To unravel the signaling paths, we assessed the localization of candidate genes and itching behavior in knockout models addressing LPAR5, LPAR2, autotaxin/ENPP2 and the lysophospholipid phosphatases, as well as the plasticity-related genes Prg1/LPPR4 and Prg2/LPPR3. LacZ reporter studies and RNAscope revealed LPAR5 in neurons of the dorsal root ganglia (DRGs) and in skin keratinocytes, LPAR2 in cortical and thalamic neurons, and Prg1 in neuronal structures of the dorsal horn, thalamus and SSC. HCQ-evoked scratching behavior was reduced in sensory neuron-specific Advillin-LPAR5−/− mice (peripheral) but increased in LPAR2−/− and Prg1−/− mice (central), and it was not affected by deficiency of glial autotaxin (GFAP-ENPP2−/−) or Prg2 (PRG2−/−). Heat and mechanical nociception were not affected by any of the genotypes. The behavior suggested that HCQ-mediated itch involves the activation of peripheral LPAR5, which was supported by reduced itch upon treatment with an LPAR5 antagonist and autotaxin inhibitor. Further, HCQ-evoked calcium fluxes were reduced in primary sensory neurons of Advillin-LPAR5−/− mice. The results suggest that LPA-mediated itch is primarily mediated via peripheral LPAR5, suggesting that a topical LPAR5 blocker might suppress "non-histaminergic" itch. [ABSTRACT FROM AUTHOR]

Background: Lebrikizumab demonstrated significant improvement versus placebo for measures of skin clearance and patient-reported outcomes at weeks 16 and 52 in patients with moderate-to-severe atopic dermatitis (AD). We report the sustained impact of lebrikizumab monotherapy, over 52 weeks and between visits, on the frequency of itch and sleep loss symptoms, as assessed by Patient-Oriented Eczema Measure (POEM), in patients with moderate-to-severe AD. Methods: In ADvocate1 and ADvocate2, Week-16 lebrikizumab responders (EASI75 or IGA 0/1 with ≥ 2-point improvement and without rescue medication) were randomized to lebrikizumab every 2 weeks (Q2W), every 4 weeks (Q4W), or placebo for 36 weeks. This pooled analysis reports improvement from Week 16 to 52 in patients achieving POEM response 0 (no days) or 1 (1–2 days) for Items 1 (itch) and 2 (sleep disturbance) for the lebrikizumab Q2W and Q4W treatment arms. Observed (excluding data collected after treatment discontinuation, rescue medication use, or patient transfer to escape arm) results were reported. Results: At Week 16, for lebrikizumab Q2W and Q4W, 35.9% (n = 37/103) and 39.3% (n = 42/107) of patients responded 0 or 1 to Item 1 of POEM (Itch) and 12.6% (n = 13/103) and 12.1% (n = 13/107) responded 0. A total of 66.0% (n = 68/103) and 72.6% (n = 77/106) of patients responded 0 or 1 to Item 2 of POEM (Sleep) and 37.9% (n = 39/103) and 44.3% (n = 47/106) responded 0, respectively. By Week 52, for lebrikizumab Q2W and Q4W, 44.6% (n = 29/65) and 48.0% (n = 36/75) responded 0 or 1 to Item 1 of POEM (Itch), and 21.5% (n = 14/65) and 18.7% (n = 14/75) of patients responded 0. A total of 83.1% (n = 54/65) and 78.4% (n = 58/74) responded 0 or 1 to Item 2 of POEM (Sleep), and 67.7% (n = 44/65) and 59.5% (n = 44/74) responded 0, respectively. Conclusion: Weekly POEM responses for itch and sleep disturbance remained stable between doses and visits, and continued to improve from Week 16 through 52, in lebrikizumab-treated patients, demonstrating consistent improvement over time for key AD symptoms. Trial Registration Numbers: ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967). [ABSTRACT FROM AUTHOR]

Background: Sleep loss is a key factor contributing to disease burden in people with atopic dermatitis (AD). Mitigating itch to improve sleep is an important outcome of AD treatment. This study explored the content validity and measurement properties of the Sleep-Loss Scale, a single-item rating scale for assessing itch interference with sleep in clinical trials of AD treatments. Methods: Concept elicitation and cognitive debriefing interviews were conducted with 21 adults and adolescents (12–17 years of age) with moderate-to-severe AD to develop a conceptual model of patient experience in AD and explore the content validity of the scale. Data collected from adults with moderate-to-severe AD enrolled in a phase 2b study (NCT03443024) were used to assess Sleep-Loss Scale's psychometric performance, including reliability, construct validity, and ability to detect change. Meaningful within-patient change (MWPC) thresholds were also determined using anchor-based methods. Results: Qualitative findings from concept elicitation highlighted the importance of sleep-loss related to itch in AD. Debriefing analysis of the Sleep-Loss Scale indicated that the scale was relevant, appropriate, and interpreted as intended. Trial data supported good reliability, construct validity and ability to detect improvement. MWPC was defined as a 1-point improvement using trial data, a finding supported by qualitative data. Conclusions: The Sleep-Loss Scale provides a valid and reliable patient-reported measure of the impact of itch on sleep in patients with AD, and can detect change, indicating it is fit-for-purpose to evaluate the efficacy of AD treatments in moderate-to-severe patients. Key summary points: • The Sleep-Loss Scale is a novel rating scale for assessing the impact of itch on sleep in atopic dermatitis (AD). • A mixed-methods approach was used to explore the content validity and psychometric properties of the Sleep-Loss Scale. • Qualitative results supported sleep loss as a common experience in AD and indicated that the Sleep-Loss Scale was relevant, appropriate, and interpreted as intended. • Quantitative results demonstrated the Sleep-Loss Scale is valid, reliable, and able to detect change. • The Sleep-Loss Scale was found to be fit-for-purpose for use in clinical trials of AD treatments among moderate-to-severe patients. [ABSTRACT FROM AUTHOR]

Irritant contact dermatitis (ICD) is a nonspecific skin inflammation caused by irritants, leading to itch and pain. We tested whether differential responses to histamine-dependent and -independent pruritogens can be evoked in ICD induced by sodium lauryl sulfate (SLS). An ICD mouse model was established with 5% SLS in acetone versus a vehicle topically applied for 24 h to the cheek. Site-directed itch- and pain-like behaviors, occurring spontaneously and in response to mechanical, thermal, and chemical stimuli (histamine, ß-alanine, BAM8-22, and bradykinin) applied to the cheek, were recorded before (day 0) and after irritant removal (days 1, 2, 3, and 4). Skin inflammation was assessed through visual scoring, ultrasound, and measurements of skin thickness. SLS-treated mice exhibited hyperalgesia-like behavior in response to mechanical and heat stimuli on day 1 compared to the controls. SLS mice exhibited more spontaneous wipes (pain) but not scratching bouts (itch) on day 1. Pruritogen injections caused more scratching but not wiping in SLS-treated mice compared to the controls. Only bradykinin increased wiping behavior compared to saline. SLS-treated mice developed noticeable erythema, scaling, and increased skin thickness on days 1 and 2. SLS induced cutaneous inflammation and behavioral signs of spontaneous pain and itching, hyperalgesia to mechanical and heat stimuli and a chemical algogen, and enhanced itch response to pruritogens. These sensory reactions preceded the inflammation peak and lasted up to two days. [ABSTRACT FROM AUTHOR]

Most reports agree that aging negatively impacts pain processing and that the prevalence of chronic pain increases significantly with age. To improve current therapies, it is critical that aged animals be included in preclinical studies. Here we compared sensitivities to pain and itch-provoking stimuli in naïve and injured young and aged mice. Surprisingly, we found that in the absence of injury, aged male and female mice are significantly less responsive to mechanical stimuli and, in females, also to noxious thermal (heat) stimuli. In both older male and female mice, compared to younger (6 month-old mice), we also recorded reduced pruritogen-evoked scratching. On the other hand, after nerve injury, aged mice nevertheless developed significant mechanical hypersensitivity. Interestingly, however, and in contrast to young mice, aged mice developed both ipsilateral and contralateral post-injury mechanical allodynia. In a parallel immunohistochemical analysis of microglial and astrocyte markers, we found that the ipsilateral to contralateral ratio of nerve injury-induced expression decreased with age. That observation is consistent with our finding of contralateral hypersensitivity after nerve injury in the aged, but not the young mice. We conclude that aging has opposite effects on baseline vs post injury pain and itch processing. PERSPECTIVE: Aged male and female mice (22-24 months) are less sensitive to mechanical, thermal (heat) and itch-provoking stimuli than are younger mice (6 months).

Background: As the available treatments for moderate-to-severe atopic dermatitis (AD) expand, understanding patient and physician preferences becomes crucial for informed decision-making.Objective: To quantify patient and physician preferences for biologics and oral systemic AD treatment attributes.Materials and methods: We conducted a cross-sectional, online discrete choice experiment (DCE) involving 306 AD patients and 206 physicians throughout the United Kingdom and Germany. Qualitative interviews identified the key attributes for inclusion in the DCE. Each choice task comprised two hypothetical patient profiles. Data were analyzed using a random-parameters logit model.Results: Results indicated a significant emphasis on efficacy, with reducing sleep disturbance and itch ranking first and second among patients, and the reverse for physicians. Time to itch relief was the third most important efficacy attribute for both groups, but relatively more important for patients than for physicians. For both groups, the risk of eye problems was the most important safety concern of those included. Mode of administration was not of great importance compared to efficacy and safety attributes.Conclusions: Our findings suggest patients prioritize sleep disturbance, an attribute not captured in prior preference studies in AD, time to itch relief and itch. These findings emphasize the importance of addressing sleep-related issues, whilst also targeting fast itch control, to enhance patients’ well-being.

Purpose The presence of wheals or hives has been viewed as a hallmark symptom of urticaria, a highly debilitating disease. This study explores our experience with omalizumab in patients with apparent mast-cell mediated pruritus in the absence of hives.Materials and Methods This is a retrospective case series examining all patients with mast cell-mediated pruritus in the absence of hives from April 2022 to May 2024 at a tertiary referral clinic at Icahn School of Medicine at Mount Sinai in New York. Peak pruritus-numerical rating scale (PP-NRS) itch score changes over time were recorded and analyzed.Results Six patients (67% women; mean [SD] age, 47.67 [13.52] years) were included in the analysis. The median [IQR] pruritus PP-NRS itch score before omalizumab injection was 9 [6 – 10] and the final median [IQR] PP-NRS itch score was 2.5 [0 – 5]. The mean [SD] reduction in the PP-NRS itch score was 6 [3.16].Conclusions This study suggests that patients with evidence of mast cell-mediated pruritus can be identified based on clinical features and may benefit from omalizumab therapy.

AbstractPurpose Based on a potential shared pathophysiology tied to mast cell activity and neurogenic inflammation that may link pruritus and chronic cough (CC), this study, leveraging the All of Us database, examines the association between the two conditions.Materials and methods A nested case-control comparison was used to examine the association, identifying cases with SNOMED codes 418363000 (pruritus) and 68154008 (CC). Matching was performed on a 1:4 ratio by age, sex, and ethnicity using the MatchIt package in R, followed by maximum likelihood method to estimate odds ratios (ORs) and 95% confidence intervals from 2x2 contingency tables.Results CC patients (n = 2,388) were more than twice as likely to be diagnosed with pruritus (OR: 2.65) and pruritus patients (n = 22,496) were more than twice as likely to be diagnosed with CC (OR: 2.57), than respective matched controls.Conclusions These results highlight the potential bidirectional relationship between CC and pruritus, suggesting possible shared immune and neural pathways. Treatments like difelikefalin and nalbuphine that modulate these pathways, alongside P2X3 targeting agents, are emerging as potential therapeutic approaches for itch and chronic cough given the possible interconnected pathophysiology. This study’s insights into the associations between pruritus and CC may pave the way for targeted therapeutic strategies that address their shared mechanisms.

AbstractBackground Lebrikizumab improved itch, interference of itch on sleep, and quality of life (QoL) in patients with moderate-to-severe atopic dermatitis (AD), in two Phase 3 trials at 16 weeks compared to placebo.Objectives We assess improvements in itch and sleep interference due to itch and their impact on QoL measurements after treatment.Methods Data were analyzed from ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967) in patients with moderate-to-severe AD. QoL was evaluated using Dermatology Life Quality Index (DLQI) at Week 16 in patients (>16 years of age) who were itch responders/non-responders (defined as ≥4-point improvement in Pruritus Numeric Rating Scale) or Sleep-Loss Scale responders/non-responders (defined as ≥2-point improvement in itch interference on sleep).Results In ADvocate1 and ADvocate2, significantly greater proportions of itch responders had a clinically meaningful improvement in measures related to QoL (DLQI scores (0/1), ≤5 DLQI total score and ≥4-point DLQI improvement) compared to itch non-responders. In both studies, a significantly greater proportion of Sleep-Loss Scale responders, reported a DLQI score of (0/1), DLQI total score of ≤5 and DLQI improvement of ≥4 points compared to Sleep-Loss Scale non-responders.Conclusions Improvement in itch and sleep interference due to itch is associated with improvement in the QoL of patients after treatment with lebrikizumab for moderate-to-severe AD.ClinicalTrials.gov registration NCT04146363 (ADvocate1) and NCT04178967 (ADvocate2).

Abstract Despite remarkable progress in understanding the fundamental bases of itching, its cortical mechanisms remain poorly understood. Herein, the causal contributions of defined anterior cingulate cortex (ACC) neuronal populations to acute itch modulation in mice are established. Using cell type‐specific manipulations, the opposing functions of ACC glutamatergic and GABAergic neurons in regulating acute itching are demonstrated. Photometry studies indicated that ACC glutamatergic neurons are activated during scratching induced by both histamine and chloroquine, whereas the activation pattern of GABAergic neurons is complicated by GABAergic subpopulations and acute itch modalities. By combining cell type‐ and projection‐specific techniques, a thalamocortical circuit is further identified from the mediodorsal thalamus driving the itch‐scratching cycle related to histaminergic and non‐histaminergic itching, which is contingent on the activation of postsynaptic parvalbumin‐expressing neurons in the ACC. These findings reveal a cellular and circuit signature of ACC neurons orchestrating behavioral responses to itching and may provide insights into therapies for itch‐related diseases.

Introduction. Anal contact or conduction in the anal canal and rectum is a common condition in the coloproctological field, occurring in 5% of the population that affects this country. Treatment consists of hygiene and the use of topical steroids, antibacterial and antifungal agents. No generally accepted attitude towards a private person has been developed.Aim. To study the effectiveness of using homeopathic ointment in the treatment of patients with anal itching.Material and methods. A prospective comparative randomized study was conducted in a specialized advisory center of the Clinics of Samara State Medical University. The study included 96 patients with anal itching without fungal infection of the perianal skin and concomitant purulent pathology. In the main group (n = 46), treatment was carried out using homeopathic ointment in the perianal area 2–3 times a day for 14 days. In the control group (n = 50), treatment was carried out with topical steroid ointments 2–3 times a day for 14 days.Results and discussion. From the data obtained on the use of homeopathic ointment, it follows that it is not inferior in effectiveness to topical steroid ointments in reducing symptoms of the disease (Student’s t-test = 0.35; p > 0.05 and Student’s t-test = 0.28; p > 0.05), and by the number of relapses (χ2 = 0.535; p > 0.05).Conclusion. The use of homeopathic ointment for topical application appears to be a promising new treatment for patients with anal itching and is as effective as topical steroid ointments.

Abstract Introduction Atopic dermatitis (AD) is characterized by intense itch and other symptoms that negatively impact quality of life (QoL). This study evaluates the effect of upadacitinib (an oral selective Janus kinase inhibitor) monotherapy on patient-reported outcomes (PROs) among adults and adolescents with moderate-to-severe AD over 16 weeks. Methods This integrated analysis of the double-blind, placebo-controlled periods of phase 3 monotherapy clinical trials Measure Up 1 (NCT03569293) and Measure Up 2 (NCT03607422) assessed itch (Worst Pruritus Numerical Rating Scale [WP-NRS] and SCORing Atopic Dermatitis [SCORAD]), skin pain and symptom severity (AD Symptom Scale), symptom frequency (Patient-Oriented Eczema Measure), sleep (AD Impact Scale [ADerm-IS] and SCORAD), daily activities and emotional state (ADerm-IS), QoL (Dermatology Life Quality Index [DLQI] and Children’s DLQI), mental health (Hospital Anxiety and Depression Scale), and patient impressions (Patient Global Impression of Severity, Patient Global Impression of Change, and Patient Global Impression of Treatment). Results Data from 1683 patients (upadacitinib 15 mg, n = 557; upadacitinib 30 mg, n = 567; placebo, n = 559) were analyzed. A greater proportion of patients receiving upadacitinib versus placebo experienced improvements in itch (≥ 4-point improvement on WP-NRS) by week 1 (upadacitinib 15 mg, 11.2%; upadacitinib 30 mg, 17.7%; placebo, 0.5%; P

Abstract The experience of itch often poses a burden on patient quality of life and has the capacity to inflict significant suffering. Topical therapies are a mainstay of treatment for many cutaneous and systemic diseases and afford patients the opportunity to manage their conditions without many of the systemic side effects of non-topical therapies. We review a multitude of new topical medications targeting the skin, immune system, and neural receptors. The list includes Janus kinase inhibitors, tyrosine kinase inhibitors, phosphodiesterase inhibitors, transient receptor vanilloid inhibitors, topical cannabinoids, and topical acetaminophen. Many of the topical therapies reviewed show promising data in phase 2–3 clinical trials, but further research is needed to compare therapies head-to-head and test their efficacy on a broader range of conditions.

As human skin comes into contact with the tiny hairs or setae of the oak processionary caterpillar, Thaumetopoea processionea, a silent yet intense chemical confrontation occurs. The result is a mix of issues: skin rashes and an intense itching that typically lasts days and weeks after the contact. This discomfort poses a significant health threat not only to humans but also to animals. In Western Europe, the alarming increase in outbreaks extends beyond areas near infested trees due to the dispersion of the setae. Predictions indicate a sustained rise in outbreaks, fueled by global changes favoring the caterpillar's survival and distribution. Currently, the absence of an efficient treatment persists due to significant gaps in our comprehension of the pathophysiology associated with this envenomation. Here, we explored the interaction between the venom extract derived from the setae of T. processionea and voltage- and ligand-gated ion channels and receptors. By conducting electrophysiological analyses, we discovered ex vivo evidence highlighting the significant role of TPTX1-Tp1, a peptide toxin from T. processionea, in modulating TRPV1. TPTX1-Tp1 is a secapin-like peptide and demonstrates a unique ability to modulate TRPV1 channels in the presence of capsaicin, leading to cell depolarization, itch and inflammatory responses. This discovery opens new avenues for developing a topical medication, suggesting the incorporation of a TRPV1 blocker as a potential solution for the local effects caused by T. processionea. [ABSTRACT FROM AUTHOR]

Glycinergic neurons regulate nociceptive and pruriceptive signaling in the spinal cord, but the identity and role of the glycineregulated neurons are not fully known. Herein, we have characterized spinal glycine receptor alpha 3 (Glra3) subunit-expressing neurons in Glra3-Cre female and male mice. Glra3-Cre(+) neurons express Glra3, are located mainly in laminae III-VI, and respond to glycine. Chemogenetic activation of spinal Glra3-Cre(+) neurons induced biting/licking, stomping, and guarding behaviors, indicative of both a nociceptive and pruriceptive role for this population. Chemogenetic inhibition did not affect mechanical or thermal responses but reduced behaviors evoked by compound 48/80 and chloroquine, revealing a pruriceptive role for these neurons. Spinal cells activated by compound 48/80 or chloroquine express Glra3, further supporting the phenotype. Retrograde tracing revealed that spinal Glra3-Cre(+) neurons receive input from afferents associated with pain and itch, and dorsal root stimulation validated the monosynaptic input. In conclusion, these results show that spinal Glra3(+) neurons contribute to acute communication of compound 48/80- and chloroquine-induced itch in hairy skin. [ABSTRACT FROM AUTHOR]

Pruritis, the sensation of itch, is produced by multiple substances, exogenous and endogenous, that sensitizes specialized sensory neurons (pruriceptors and pruri-nociceptors). Unfortunately, many patients with acute and chronic pruritis obtain only partial relief when treated with currently available treatment modalities. We recently demonstrated that the topical application of high molecular weight hyaluronan (HMWH), when combined with vehicles containing transdermal transport enhancers, produce potent long-lasting reversal of nociceptor sensitization associated with inflammatory and neuropathic pain. In the present experiments we tested the hypothesis that the topical formulation of HMWH with protamine, a transdermal transport enhancer, can also attenuate pruritis. We report that this topical formulation of HMWH markedly attenuates scratching behavior at the nape of the neck induced by serotonin (5-hydroxytryptamine, 5-HT), in male and female rats. Our results support the hypothesis that topical HMWH in a transdermal transport enhancer vehicle is a strong anti-pruritic. [ABSTRACT FROM AUTHOR]

Introduction: Atopic dermatitis (AD) is characterized by intense itch and other symptoms that negatively impact quality of life (QoL). This study evaluates the effect of upadacitinib (an oral selective Janus kinase inhibitor) monotherapy on patient-reported outcomes (PROs) among adults and adolescents with moderate-to-severe AD over 16 weeks. Methods: This integrated analysis of the double-blind, placebo-controlled periods of phase 3 monotherapy clinical trials Measure Up 1 (NCT03569293) and Measure Up 2 (NCT03607422) assessed itch (Worst Pruritus Numerical Rating Scale [WP-NRS] and SCORing Atopic Dermatitis [SCORAD]), skin pain and symptom severity (AD Symptom Scale), symptom frequency (Patient-Oriented Eczema Measure), sleep (AD Impact Scale [ADerm-IS] and SCORAD), daily activities and emotional state (ADerm-IS), QoL (Dermatology Life Quality Index [DLQI] and Children's DLQI), mental health (Hospital Anxiety and Depression Scale), and patient impressions (Patient Global Impression of Severity, Patient Global Impression of Change, and Patient Global Impression of Treatment). Results: Data from 1683 patients (upadacitinib 15 mg, n = 557; upadacitinib 30 mg, n = 567; placebo, n = 559) were analyzed. A greater proportion of patients receiving upadacitinib versus placebo experienced improvements in itch (≥ 4-point improvement on WP-NRS) by week 1 (upadacitinib 15 mg, 11.2%; upadacitinib 30 mg, 17.7%; placebo, 0.5%; P < 0.001), with response rates sustained through week 16 (upadacitinib 15 mg, 47.1%; upadacitinib 30 mg, 59.8%; placebo, 10.4%; P < 0.001). Improvements were similar for PROs assessing skin pain/symptoms, sleep, daily activities, QoL, emotional state, mental health, and patient impressions of disease severity and treatment. Responses generally improved rapidly (within 1–2 weeks), increased through weeks 4–6, and were maintained through week 16. Conclusions: Once-daily oral upadacitinib monotherapy improved response rates across PROs compared with placebo. Upadacitinib therapy resulted in rapid, sustained improvements in PROs measuring symptom burden and QoL in adults and adolescents with moderate-to-severe AD. Trial Registration: ClinicalTrials.gov identifiers, NCT03569293 and NCT03607422. Plain Language Summary: Atopic dermatitis, or eczema, is characterized by itchy, dry, inflamed skin. These symptoms often make it difficult for patients to get adequate sleep. Patients with atopic dermatitis may also experience anxiety, depression, reduced self-confidence, social isolation, disruption to daily activities like school and work, and decreased quality of life. Many atopic dermatitis symptoms, including itch and psychological impact, are difficult for doctors to assess. Thus, it is important to consider patients' descriptions of their symptoms and quality of life, particularly when assessing treatment benefit. Upadacitinib is an orally administered drug approved to treat moderate-to-severe atopic dermatitis. We investigated how upadacitinib (15 mg or 30 mg) given once daily to adults and adolescents with moderate-to-severe atopic dermatitis in the Measure Up 1 and 2 clinical trials impacts their symptoms and quality of life over a 16-week period. We compared changes in patient-reported itch, pain, sleep, daily activities, emotional state, mental health, and overall quality of life among patients in the clinical trials who received upadacitinib with those in the same studies who received a dummy (placebo) treatment. Upadacitinib improved patient-reported symptoms and quality of life early in the clinical trials, often within the first 1–2 weeks. The extent of the improvements increased through weeks 4–6 of treatment and lasted through week 16. Patients who received upadacitinib reported greater improvements in symptoms and quality of life than did patients who received placebo. Upadacitinib treatment resulted in rapid and lasting improvements in the well-being of patients with atopic dermatitis. [ABSTRACT FROM AUTHOR]

Background: The nature of itch sensation varies depending upon the patient and the disease. However, few studies have focused on verbal expressions describing itch of atopic dermatitis (AD) in quality. Objectives: To investigate itch quality in patients with AD compared with that of urticaria. Methods: We conducted an online questionnaire survey describing itch experiences in June 2021. Participants were Japanese patients who had visited hospitals for their consultations and treatments of AD or urticaria in the last 6 months, and 295 and 290 responses, respectively, to questions using 12 terms describing itch quality were analyzed. Results: The most suitable expression describing intense itch that patients could not help scratching differed between the diseases, where most AD patients selected "muzumuzu" (a mimetic word for creepy-crawly itch) (27%) or "painful itch" (20%), and most urticaria patients selected "muzumuzu" (24%) or "itch like mosquito bites" (22%). The most suitable expressions describing itch that would make patients happiest if improved was "painful itch" (27%) in AD patients, significantly higher than urticaria patients (19%). More AD patients (55%) responded that they sometimes felt itch even after the skin symptoms had subsided than urticaria patients (41%). The most suitable expression of remnant itch selected was "muzumuzu" for AD (58/161 patients, 36%) and urticaria (29/120 patients, 24%). Conclusion: The quality of itch sensations can be classified not only between diseases but also during the clinical course of each disease. Significant expressions that patients with AD use to describe itch sensations could promote more appropriate treatment for itch. [ABSTRACT FROM AUTHOR]

Various disorders are accompanied by histamine‐independent itching, which is often resistant to the currently available therapies. Here, it is reported that the pharmacological activation of Slack (Kcnt1, KNa1.1), a potassium channel highly expressed in itch‐sensitive sensory neurons, has therapeutic potential for the treatment of itching. Based on the Slack‐activating antipsychotic drug, loxapine, a series of new derivatives with improved pharmacodynamic and pharmacokinetic profiles is designed that enables to validate Slack as a pharmacological target in vivo. One of these new Slack activators, compound 6, exhibits negligible dopamine D2 and D3 receptor binding, unlike loxapine. Notably, compound 6 displays potent on‐target antipruritic activity in multiple mouse models of acute histamine‐independent and chronic itch without motor side effects. These properties make compound 6 a lead molecule for the development of new antipruritic therapies targeting Slack. [ABSTRACT FROM AUTHOR]

Few studies have examined pruritus in elderly patients, a common dermatological condition. The study examines pruritus prevalence and characteristics in elderly patients referred to the Dermatology Unit, at Genoa’s Galliera Hospital. The demographic characteristics of all Outpatient Clinic patients with any skin condition were examined, focusing on pruritus patients over 65. Pruritus was present in 36/262 patients (14%; M:F =20:16; mean age: 59.55 years). About 14% of 140 patients aged ≥65 years had pruritus, with 20/262 (8%; M:F =14:6; mean age: 74.6 years) exhibiting it. Visual analog score pruritus did not differ between patients aged ≥65 years (20/36) and <65 years (16/36) statistically. In 89% of patients, itch was related to a dermatological condition, mainly psoriasis. Only extracutaneous diseases resulted more frequently in the patients aged >65. No anamnestic link was found between drug use and pruritus in these patients. We confirm that pruritus is a common skin problem that affects both sexes, young and old, and is almost always caused by an underlying skin condition (mainly psoriasis). It is rarely caused by a new drug. [ABSTRACT FROM AUTHOR]

PD-1/PD-L1 inhibitors have been demonstrated to induce itch in both humans and experimental animals. However, whether the PD-1/PD-L1 pathway is involved in the regulation of chronic psoriatic itch remains unclear. This study aimed to investigate the role of the PD-1/PD-L1 pathway in imiquimod-induced chronic psoriatic itch. The intradermal injection of PD-L1 in the nape of neck significantly alleviated chronic psoriatic itch in imiquimod-treated skin. Additionally, we observed that spontaneous scratching behavior induced by imiquimod disappeared on day 21. Still, intradermal injection of PD-1/PD-L1 inhibitors could induce more spontaneous scratching for over a month, indicating that imiquimod-treated skin remained in an itch sensitization state after the spontaneous scratching behavior disappeared. During this period, there was a significant increase in PD-1 receptor expression in both the imiquimod-treated skin and the spinal dorsal horn in mice, accompanied by significant activation of microglia in the spinal dorsal horn. These findings suggest the potential involvement of the peripheral and central PD-1/PD-L1 pathways in regulating chronic itch and itch sensitization induced by imiquimod. [ABSTRACT FROM AUTHOR]

The experience of itch often poses a burden on patient quality of life and has the capacity to inflict significant suffering. Topical therapies are a mainstay of treatment for many cutaneous and systemic diseases and afford patients the opportunity to manage their conditions without many of the systemic side effects of non-topical therapies. We review a multitude of new topical medications targeting the skin, immune system, and neural receptors. The list includes Janus kinase inhibitors, tyrosine kinase inhibitors, phosphodiesterase inhibitors, transient receptor vanilloid inhibitors, topical cannabinoids, and topical acetaminophen. Many of the topical therapies reviewed show promising data in phase 2–3 clinical trials, but further research is needed to compare therapies head-to-head and test their efficacy on a broader range of conditions. [ABSTRACT FROM AUTHOR]