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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]

Background and Purpose Experimental Approach Key Results Conclusion and Implications While pain and itch are both commonly associated with chronic dermatitis (CD), the molecular mechanisms underlying these debilitating symptoms is not well understood. This study aims to identify novel, endogenous compounds that mediate CD‐associated pain and itch.Lesional skin of CD model mice was examined using unbiased metabolomic analysis to identify candidate pain or itch inducing compounds in CD. Sphingosine‐1‐phosphate (S1P) concentration in CD model skin was analysed using UPLC/MS/MS. Behaviour, calcium imaging and immunofluorescence staining were used to determine the pain and itch effects and mechanisms of the identified CD‐related compounds.In the lesional skin of CD model mice, 136 compounds were significantly changed. These compounds are predominately associated with the sphingolipids metabolism pathway. S1P is significantly increased in the lesional skin . The TRPV4 channel was critical for S1P induced itch and pain. Sphingosine kinase 2 (SPHK2), the key enzyme controlling S1P synthesis, was significantly increased in lesional skin. ABC294640, a SPHK2 inhibitor, significantly decreased S1P concentration in lesional CD model skin, as well as in model associated epidermal hyperplasia and chronic pain and itch. In CD patients, SPHK2 expression and S1P concentration were significantly elevated compared to healthy control skin.Our results indicate that, in CD, increased S1P induces chronic pain and itch partly through TRPV4. Inhibition of S1P synthesis or the S1P/S1P receptor‐TRPV4 pathway are promising treatment strategies for CD‐associated pain and itch. [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]

Caring for patients with hard-to-heal (chronic) wounds requires a multifaceted approach that addresses their diverse needs, which can contribute to the complexity of care. Wound care providers must have a comprehensive understanding of the patient's comorbid conditions and psychosocial issues to provide personalised and effective treatment. Key quality indicators for effective wound care involves not only selecting appropriate local wound care products, such as foam dressings, but also addressing individual patient experiences of wound-related pain, odour, itch, excessive wound drainage, and self-care needs. The purpose of this review is to inculcate the wound care practice community, research scientists and healthcare industry with a sense of accountability in order to work collaboratively in addressing these unmet care needs. [ABSTRACT FROM AUTHOR]

Background: Itch terminology is ambiguous. How itch was described in online materials and how terminology influenced the readability of these materials was previously unknown. Materials and methods: Two groups of search terms, itch and prurigo, were translated into five of the most prevalent European Union (EU) languages. The itch group consisted of "itch" and "pruritus." The prurigo group consisted of "prurigo," "prurigo nodularis," and "chronic prurigo". Then, a search of the terms in each language was queried in the Google search engine in the private mode of the Internet browser. The first 50 results generated were assessed for suitability. Patient education was the primary objective of the materials provided, with no barriers or advertisements included. In cases where the terms yielded identical outcomes, any duplicated materials were omitted from the analysis. When translating search terms within a group led to just one shared transcription, the results were attributed to the search term with the most similar syntax. The Lix score was utilized to assess readability. Results: 314 articles in English, German, Italian, French, and Spanish were evaluated. The term "pruritus" was the most commonly used description for the sensation of itching, with 142 (45%) articles included. Overall, the mean Lix score was 54 ± 9, classifying all articles as hard to comprehend. Articles in the itch group had significantly (P < 0.001) lower mean Lix score (52 ± 9) than materials in the prurigo group (56 ± 10). Conclusions: Despite being more accessible to conceptualize, skin conditions such as prurigo had lower readability compared to information about the itch itself. The distinction between "itch" and "pruritus" was unclear. [ABSTRACT FROM AUTHOR]

Itch is a common symptom of dermatologic diseases associated with significant impairment of health-related quality of life (QoL). This study reveals disparities in itch symptom experience and itch impact on QoL. A retrospective study of patient-reported outcome measure (PRO) data (ItchyQoL, Itch NRS, Pain Interference, Anxiety) for 387 outpatient dermatology visits to characterize the impact of itch on patients' QoL and itch symptom experience based on skin color in patients with dermatologic disease. Most patients were Caucasian females (67%) with mean age of 48 years. Correlative analyses showed mild itch associated with emotional impacts on QoL (p < 0.01), while severe itch associated with functional and emotional impacts on QoL (p < 0.01). African American (AA) patients reported more "severe-range" answers for 15 (68%) ItchyQoL items and had higher ItchyQoL mean scores (p = 0.001). ItchyQoL demonstrated an emotional impact on QoL by mild itch, but a functional and emotional impact on QoL by severe itch. Further, AAs suffered from greater itch-related impairment in QoL than Caucasian patients, especially due to scarring and sleeplessness. [ABSTRACT FROM AUTHOR]

Purpose: 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. [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]

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]

Lympho-epithelial Kazal-type-related inhibitor (LEKTI) is a serine protease inhibitor consisting of multiple domains. A loss of function mutation is described in Netherton patients that show severe symptoms of atopic lesions and itch. LEKTI domain 6 (LD6) has shown strong serine protease-inhibitory action in in vitro assays and thus it was tested in vitro and in vivo for potential anti-inflammatory action in models of atopic skin disease. Human skin equivalents were treated with LD6 and an inflammatory reaction was challenged by kallikrein-related endopeptidase 5 (KLK5). Furthermore, LD6 was tested on dorsal root ganglia cells stimulated with KLK5, SLIGRL and histamine by calcium imaging. The effect of topically administered LD6 (0.4–0.8%) in lipoderm was compared to a topical formulation of betamethasone-diproprionate (0.1%) in a therapeutic setting on atopic dermatitis-like lesions in NC/Nga mice sensitized to house dust mite antigen. Endpoints were clinical scoring of the mice as well as determination of scratching behaviour. KLK5 induced an upregulation of CXCL-8, CCL20 and IL-6 in skin equivalents. This upregulation was reduced by pre-incubation with LD6. KLK5 as well as histamine induced calcium influx in a population of neurons. LD6 significantly reduced the calcium response to both stimuli. When administered onto lesional skin of NC/Nga mice, both LD6 and betamethasone-dipropionate significantly reduced the inflammatory reaction. The effect on itch behaviour was less pronounced. Topical administration of LD6 might be a new therapeutic option for treatment of lesional atopic skin. • LEKTI domain 6 reduces activation of sensory neurons provoked by proteases. • LEKTI domain 6 reduces activation of sensory neurons provoked by histamine. • LEKTI domain 6 reduces the inflammatory response in skin constructs. • LEKTI domain 6 reduces the inflammatory response in a murine atopic dermatitis model. [ABSTRACT FROM AUTHOR]

Dry skin is common to many pruritic diseases and is difficult to improve with oral traditional antihistamines. Recently, increasing evidence indicated that histamine H4 receptor (H4R) plays an important role in the occurrence and development of pruritus. Extracellular signal‐regulated kinase (ERK) phosphorylation activation in the spinal cord mediates histamine‐induced acute and choric itch. However, whether the histamine H4 receptor regulates ERK activation in the dry skin itch remains unclear. In the study, we explore the role of the histamine H4 receptor and p‐ERK in the spinal cord in a dry skin mouse model induced by acetone–ether–water (AEW). q‐PCR, Western blot, pharmacology and immunofluorescence were applied in the study. We established a dry skin itch model by repeated application of AEW on the nape of neck in mice. The AEW mice showed typically dry skin histological change and persistent spontaneous scratching behaviour. Histamine H4 receptor, instead of histamine H1 receptor, mediated spontaneous scratching behaviour in AEW mice. Moreover, c‐Fos and p‐ERK expression in the spinal cord neurons were increased and co‐labelled with GRPR‐positive neurons in AEW mice. Furthermore, H4R agonist 4‐methyhistamine dihydrochloride (4‐MH)induced itch. Both 4‐MH‐induced itch and the spontaneous itch in AEW mice were blocked by p‐ERK inhibitor U0126. Finally, intrathecal H4R receptor antagonist JNJ7777120 inhibited spinal p‐ERK expression in AEW mice. Our results indicated that spinal H4R mediates itch via ERK activation in the AEW‐induced dry skin mice. [ABSTRACT FROM AUTHOR]

ABSTRACT Background & Methods Results Conclusion Through the identification of 22 803 cases of chronic pruritus, with a control group comprising 91 212 participants from a national database, we performed a comparative analysis revealing that patients with chronic pruritus had a significantly higher prevalence of liver disease compared to controls.Upon reverse analysis, we similarly found patients with liver disease had a significantly higher prevalence of chronic pruritus. Subsequent multivariate logistic regression highlighted increased odds for several liver diseases in the pruritus cohort, including metabolic dysfunction‐associated steatotic liver disease (aOR 1.65, 95% CI 1.53–1.78) and alcohol‐related liver disease (aOR 1.69, 95% CI 1.43–1.98). The increased odds were most pronounced for hepatitis B (aOR 2.01, 95% CI 1.67–2.42) and cholangitis + primary sclerosing cholangitis + primary biliary cholangitis (aOR 1.81, 95% CI 1.65–1.99).Our results reveal a strong correlation between pruritus in hepatic pathologies different than commonly reported cholestatic diseases. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is still a demanding challenge in clinical practice. Type 2 inflammation is the most common inflammatory pathway in children and adolescents with AD. Anti‐inflammatory drugs, mainly corticosteroids (CS) and immunomodulant agents are the primary therapeutic approach to dampening type 2 inflammation. However, AD patients may require long‐term high CS doses or drug combinations with possibly significant adverse effects to achieve and maintain disease control. In this regard, the advent of biologics constituted a breakthrough in managing this condition. Dupilumab is a monoclonal antibody directed against the IL‐4 receptor α‐subunit (IL‐4Rα), antagonizing both IL‐4 and IL‐13 and is approved for pediatric severe AD. This review presents and discusses the most recent published studies on dupilumab in children and adolescents with AD. There is convincing evidence that dupilumab is safe and effective in managing AD. It can reduce skin lesions and associated itching, reduce the need for additional medications, and improve disease control and quality of life. However, a thorough diagnostic pathway is mandatory, especially considering the different AD phenotypes. The ideal eligible candidate is a child or adolescent with AD requiring systemic treatment because of severe clinical manifestations and impaired quality of life. [ABSTRACT FROM AUTHOR]

Prurigo nodularis (PN) is a chronic inflammatory skin condition that presents with intensely pruritic, hyperkeratotic nodules. The pathophysiology underlying PN is not entirely clear, making treatment challenging. Patients often require a multimodal approach, although many of the available therapies have low efficacy or adverse effects. In this review, we discuss the use of nemolizumab for the treatment of PN in adults. Nemolizumab is a biological therapy that reduces type 2 cytokines and the neuroimmune response implicated in the pathophysiology of PN. It also helps maintain skin barrier integrity, which may be damaged during the vicious itch-scratch cycle. Nemolizumab has demonstrated great efficacy in improving itch and clearing lesions in recent clinical trials with respectable tolerance. Nemolizumab is a promising drug for PN that seems comparable to the recently approved dupilumab in terms of its therapeutic effect and excellent safety profile, although nemolizumab may work more rapidly on itch. JAK inhibitors are also emerging as competitors of biologics for PN, however, their safety profile in this population may differ. Trials evaluating these drugs are needed to assess which is preferable. Additional data on the durability and longevity of nemolizumab for PN treatment is highly anticipated. [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]

Background: Itch is the most common symptom of atopic dermatitis (AD) and significantly decreases the quality of life. Skin microbiome is involved in AD pathogenesis, whereas its role in the regulation of itch remains elusive. In this study, we aimed to investigate the effects of skin microbial metabolite propionate on acute and chronic pruritus and to explore the mechanism. Methods: Using various mouse models of itch, the roles of propionate were explored by behavioral tests and histopathology/immunofluorescent analysis. Primary‐cultured dorsal root ganglion neurons and HEK293 cells expressing recombinant human TRP channels were utilized for in vitro calcium imaging/in vivo miniature two‐photon imaging in combination with electrophysiology and molecular docking approaches for investigation of the mechanism. Results: Propionate significantly alleviated itch and alloknesis in various mouse models of pruritus and AD and decreased the density of intraepidermal nerve fibers. Propionate reduced the responsiveness of dorsal root ganglion neurons to pruritogens in vitro, attenuated the hyper‐excitability in sensory neurons in MC903‐induced AD model, and inhibited capsaicin‐evoked hTRPV1 currents (IC50 = 20.08 ± 1.11 μM) via interacting with the vanilloid binding site. Propionate also decreased the secretion of calcitonin gene‐related peptide by nerves in MC903‐induced AD mouse model, which further attenuated itch and skin inflammation. Conclusion: Our study revealed a protective effect of propionate against persistent itch through direct modulation of sensory TRP channels and neuropeptide production in neurons. Regulation of itch via the skin microbiome might be a novel strategy for the treatment of AD. [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]

Pruritus, particularly in its chronic form, often imposes significant suffering and reductions in patients' quality of life. The pathophysiology of itch is varied depending on disease context, creating opportunities for unique drug development and multimodal therapy. The purpose of this article is to provide an update of the literature regarding current and emerging therapeutics in itch. We review the multitudes of drug targets available and corresponding drugs that have shown efficacy in clinical trials, with a particular emphasis on phase 2 and 3 trials and beyond. Broadly, these targets include therapies directed against type 2 inflammation (i.e. Th2 cytokines, JAK/STAT, lipid mediators, T-cell mediators, and other enzymes and receptors) and neural receptors and targets (i.e. PARs, TRP channels, opioid receptors, MRGPRs, GABA receptors, and cannabinoid receptors). Therapeutics for itch are emerging at a remarkable pace, and we are entering an era with more and more specialized therapies. Increasingly, these treatments are able to relieve itch beyond their effect on inflammation by directly targeting the neurosensory system. [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]

Aims: Itch, a common uncomfortable sensory experience, occurs frequently in inflammatory or allergic disorders. In recent years, with the discovery of itch‐specific pathways in the peripheral and central nervous system, the association between immunology and neural pathways has gradually emerged as the main mechanism of itch. Although many studies have been conducted on itch, no bibliometric analysis study focusing on this topic has been conducted. This study aimed to explore the research hotspots and trends in the itch field from a bibliometric perspective. Methods: Publications relevant to itch, published from 2003 to 2022, were retrieved from the Science Citation Index‐Expanded of Web of Science Core Collection. Publications were critically reviewed and analyzed with CiteSpace software, Vosviewer, and the bibliometric online analysis platform. Visual maps were conducted in terms of annual production, collaborating countries or institutions, productive authors, core journals, co‐cited references, and keyword bursts. Results: 2395 articles on itch that met our criteria were identified and the quantity of publications has been increasing rapidly since 2012. The USA was the most influential country. University Hospital Münster was the institution with the most publications. Gil Yosipovitch was the most prolific author. Atopic dermatitis (AD), intradermal serotonin, chronic pruritus, mechanical itch, gastrin‐releasing peptide, substance p, interleukin‐31 receptor, histamine‐induced itch, bile acid, scratching behavior, and h‐4 receptor were the top 11 clusters in co‐citation cluster analysis. Keyword burst analysis suggested that treatment, inflammation, and AD are current research hotspots. Conclusion: Global publications on itch research have increased steadily and rapidly over the past 20 years. Inflammation and AD are current research hotspots. The neuroimmunological and neuroinflammatory mechanisms of itch, as well as clinical assessment methods and therapeutic targets, will be novel research directions in the future. This study provides guidance for further itch research. [ABSTRACT FROM AUTHOR]

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

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

Post-burn pruritus is one of the most common complaints reported by patients with limited evidence for a gold-standard treatment. To review the literature and assess the efficacy of various interventions in treating post-burn pruritus. PubMed, MEDLINE, CINAHL, Web of Sciences, Ovid Databases, and ClinicalTrials.Gov were searched. The articles were scored by two assessors for inclusion with a third independent assessor resolving conflicting scores. The present systematic review and meta-analysis synthesised findings from a total of nine studies, representing a pool of 323 patients. The standardized mean effect size for the various categories of interventions was: naltrexone at 1.47 (95 % CI of 0.75–2.20, p < 0.0000), coverings at 0.94 (95 % CI of 0.40–1.48, p = 0.006), topical ozonated oil at 2.64 (95 % CI of 1.94–3.34, p < 0.00001), lasers at 2.34 (95 % CI of 1.60–3.09, p < 0.00001), current stimulation at 1.03 (95 % CI of −0.04 to 2.10, p = 0.06), and lemon balm tea at 0.54 (95% CI of 0.12–0.96, p = 0.01). Current evidence suggests that current modalities have a statistically significant, but not clinically significant, reduction in pruritus. This review highlights the limited quality of evidence in the literature and the poor quality of reporting among excluded studies. • Post-burn pruritus affects up to 93 % of patients with burn injuries by day of discharge. • Current treatment modalities do not achieve clinically significant reduction of symptoms. • Future studies in post-burn pruritus are warranted in both quantity and quality of data reporting. [ABSTRACT FROM AUTHOR]

Prurigo nodularis (PN) is a chronic inflammatory skin condition that presents with pruritus and hyperkeratotic nodules. These symptoms impact patients' quality of life and mental health. Treating prurigo nodularis is challenging, and many of the available topical and systemic therapies have limited efficacy and a myriad of adverse effects. In this article, we discuss the use of dupilumab for adult patients with prurigo nodularis. Dupilumab is a biologic that inhibits Th2-mediated inflammation and has been successfully used to treat a variety of dermatologic disorders. Dupilumab has revolutionized the management of PN, with recent clinical trials showing its efficacy in treating both pruritus and prurigo nodules, as well as improving quality of life. It has a favorable safety profile and is well tolerated. Other novel treatments are also currently under investigation for the treatment of PN, with early studies reporting promising results. Dupilumab is becoming the drug of choice for the treatment of PN and may also be effective in treating patients with systemic underlying causes of their PN, although more studies are needed to assess this. Trials evaluating the long-term efficacy and durability of dupilumab in PN are also of interest. [ABSTRACT FROM AUTHOR]

Background: Itch sensitization has been reported in patients with chronic allergic skin diseases and observed in a mouse model of allergic contact dermatitis (ACD). There is evidence suggesting that neuroimmune interactions may contribute to itch sensitization, as an increase in dendritic cells (DCs) within ganglia has been observed during allergic conditions. However, how DCs interact with sensory neurons in ganglia during allergic conditions is still not known. This study aims to investigate the role of DCs in dorsal root ganglion (DRG) under ACD conditions, specifically focusing on itch sensitization within the DRG. The tolylene-2,4-diisocyanate (TDI) mouse model for ACD and the co-culture model of DCs and DRG neurons was employed in this study. Results: We successfully induced ACD by TDI, as evidenced by the development of edema, elevated total serum IgE levels, and an observed itch reaction in TDI-sensitized mice. Calcium imaging and RT-qPCR analysis revealed that TDI-sensitized mice exhibited signs of peripheral sensitization, including a higher percentage of neurons responding to pruritogens and increased activation and expression of itch receptors in excised DRG of TDI-sensitized mice. Immunofluorescence and flow cytometric analysis displayed an increase of MHCII+ cells, which serves as a marker for DCs, within DRG during ACD. The co-culture study revealed that when DRG neurons were cultured with DCs, there was an increase in the number of neurons responsive to pruritogens and activation of itch receptors such as TRPA1, TRPV1, H1R, and TRPV4. In addition, the immunofluorescence and RT-qPCR study confirmed an upregulation of TRPV4. Conclusions: Our findings indicate that there is an increase of MHCII+ cells and itch peripheral sensitization in DRG under TDI-induced ACD condition. It has been found that MHCII+ cells in DRG might contribute to the itch peripheral sensitization by activating itch receptors, as shown through co-culture studies between DRG neurons and DCs. Further studies are required to identify the specific mediator(s) responsible for peripheral sensitization induced by activated DCs. [ABSTRACT FROM AUTHOR]

Introduction: Prevalence and severity of pruritus among US patients with chronic hepatitis B and C (HBV, HCV) are not well-documented. Chronic Hepatitis Cohort Study (CHeCS) patients were surveyed to examine pruritus prevalence and impact on quality of life (QoL). Methods: Patients who reported experiencing pruritus ≥3 on a Numeric Rating Scale (NRS) within the past 30 days were invited to participate in a 6-month study using the SF-36 questionnaire. General regression (univariate followed by multivariable modelling) was used to analyse pruritus intensity and eight QoL dimensions. Results: Among 1654 patients (HBV = 358, HCV = 1296, HBV/HCV = 6), pruritus prevalence was significantly higher among patients with HCV than those with HBV (44% vs. 35%; p < .05). One hundred and twenty-three patients (21 HBV and 102 HCV) participated in the QoL study (72% ≥60 years; 50% men; 25% Black; 37% with cirrhosis; 66% had BMI > 25). Mean NRS was 4.9--5.3. QoL responses for social functioning and emotional well-being were higher (70--72 points) than responses for energy/fatigue (50--51). Antiviral treatment rates were higher in HCV (92%, SVR 99%) than HBV (71% ever, 43% ongoing). Multivariable analyses showed no significant effect of hepatitis type or antiviral treatments on itch. Antihistamines were associated with severe itch. Higher NRS was associated with significantly reduced QoL. Each unit increase in NRS was associated with a 2--3 unit decline in emotional well-being, general health, physical function, energy/fatigue, social functioning and emotional health. Conclusion: Pruritus negatively affects many viral hepatitis patients, regardless of antiviral treatment status. Improved treatment options are needed to address its impact on QoL. [ABSTRACT FROM AUTHOR]

Aims: Itch is an unpleasant sensation that severely impacts the patient's quality of life. Recent studies revealed that the G protein‐coupled estrogen receptor (GPER) may play a crucial role in the regulation of pain and itch perception. However, the contribution of the GPER in primary sensory neurons to the regulation of itch perception remains elusive. This study aimed to investigate whether and how the GPER participates in the regulation of itch perception in the trigeminal ganglion (TG). Methods and Results: Immunofluorescence staining results showed that GPER‐positive (GPER+) neurons of the TG were activated in both acute and chronic itch. Behavioral data indicated that the chemogenetic activation of GPER+ neurons of the TG of Gper‐Cre mice abrogated scratching behaviors evoked by acute and chronic itch. Conversely, the chemogenetic inhibition of GPER+ neurons resulted in increased itch responses. Furthermore, the GPER expression and function were both upregulated in the TG of the dry skin‐induced chronic itch mouse model. Pharmacological inhibition of GPER (or Gper deficiency) markedly increased acute and chronic itch‐related scratching behaviors in mouse. Calcium imaging assays further revealed that Gper deficiency in TG neurons led to a marked increase in the calcium responses evoked by agonists of the transient receptor potential ankyrin A1 (TRPA1) and transient receptor potential vanilloid V1 (TRPV1). Conclusion: Our findings demonstrated that the GPER of TG neurons is involved in the regulation of acute and chronic itch perception, by modulating the function of TRPA1 and TRPV1. This study provides new insights into peripheral itch sensory signal processing mechanisms and offers new targets for future clinical antipruritic therapy. [ABSTRACT FROM AUTHOR]

Neuropathic itch is a relatively common yet under-reported cause of systemic pruritus. It is a debilitating condition often associated with pain, which impairs the patient's quality of life. Although much literature exists about renal and hepatic pruritus, there is a dearth of information and awareness about neuropathic itch. The pathogenesis of neuropathic itch is complex and can result from an insult at any point along the itch pathway, ranging from the peripheral receptors and nerves until the brain. There are several causes of neuropathic itch, many of which do not produce any skin lesions and are thus, often missed. A detailed history and clinical examination are necessary for the diagnosis, while laboratory and radiologic investigations may be needed in select cases. Several therapeutic strategies currently exist involving both non-pharmacological and pharmacological measures, the latter including topical, systemic, and invasive options. Further research is ongoing to clarify its pathogenesis and to design newer targeted therapies with minimal adverse effects. This narrative review highlights the current understanding of this condition, focusing on its causes, pathogenesis, diagnosis, and management, along with newer investigational drugs. [ABSTRACT FROM AUTHOR]

Background: Phototherapy is a mainstay to treat itchy conditions. However, only little is known about differences in the antipruritic effect of phototherapy amongst different skin conditions, phototypes and genders. Methods: In this prospective, single‐center study, we analyzed the effect of phototherapy on itch intensity and itch‐related quality of life amongst these subgroups after a treatment duration of 4 weeks, while on‐demand treatment with topical corticosteroids, topical calcineurin inhibitors and/or antihistamines was allowed. Results: Of 102 patients (age 53.0 ± 18.7, 56 females [54.9%]), 72 (78.3%) reported a significant reduction of itch intensity by Δ −2.76 on a 0–10 Numerical Rating Scale (NRS), p = <.001, 95% CI [2.2; 3.3] paralleled by a significant improvement of itch‐related quality of life as measured by the German version of the ItchyQoL by Δ 7.3, p = <.001, 95% CI [4.4; 11.6]. The best improvement of itch intensity and itch‐related QoL was reported by patients with pruritus on non‐diseased skin (ΔNRS −3.5; Δ 9.7 Ger‐ItchyQoL points), followed by patients with atopic dermatitis and psoriasis. We found no statistical differences in the response to phototherapy amongst Fitzpatrick phototypes I–VI. Women had higher itch intensities at baseline but itch‐related quality of life impairment at baseline and phototherapy treatment response did not significantly differ between genders. Conclusion: Phototherapy appears to induce a meaningful itch reduction in various itchy skin conditions, all phototypes and both genders within 4 weeks that directly translates into improvement of itch‐related quality of life. [ABSTRACT FROM AUTHOR]

Patients with chronic kidney disease (CKD) undergoing hemodialysis often experience significant itch secondary to their condition and a subsequent reduction in their overall quality of life. Current treatments are underwhelming, necessitating the search for new, effective therapeutic options to combat itch in this population. The purpose of this review is to explore the available data for the use of intravenous difelikefalin in patients with CKD undergoing hemodialysis. The pathophysiology of CKD-associated itch is multifactorial, with one proposed mechanism involving an imbalance in the endogenous opioid system, favoring upregulation of itch-activating μ-opioid receptors (MORs) and downregulation of itch-inhibiting κ-opioid receptors (KORs). Dysregulation of the immune system is also involved. Difelikefalin is a recent FDA approved treatment that functions as peripherally acting KOR agonist, targeting this imbalance in the endogenous opioid system seen in CKD patients with itch and having an anti-inflammatory effect on immune cells. Clinical data on intravenous difelikefalin is promising regarding its ability to reduce itch in CKD patients on hemodialysis and improve patient quality of life, with few, mild adverse side effects. As intravenous difelikefalin becomes more widely used in the clinical setting, further studies assessing long-term efficacy and safety will be needed. [ABSTRACT FROM AUTHOR]

Primary cutaneous T-cell lymphomas (CTCL), which include mycosis fungoides (MF) and Sézary syndrome (SS), are a group of lymphoproliferative disorders characterized by clonal accumulation of neoplastic T-lymphocytes in the skin. Severe pruritus, one of the most common and distressing symptoms in primary CTCL, can significantly impair emotional well-being, physical functioning, and interpersonal relationships, thus greatly reducing quality of life. Unfortunately, effectively managing pruritus remains challenging in CTCL patients as the underlying mechanisms are, as of yet, not fully understood. Previous studies investigating the mechanisms of itch in CTCL have identified several mediators and their corresponding antagonists used for treatment. However, a comprehensive overview of the mediators and receptors contributing to pruritus in primary CTCL is lacking in the current literature. Here, we summarize and review the mediators and receptors that may contribute to pruritus in primary CTCL to explore the mechanisms of CTCL pruritus and identify effective therapeutic targets using the PubMed and Web of Science databases. Studies were included if they described itch mediators and receptors in MF and SS. Overall, the available data suggest that proteases (mainly tryptase), and neuropeptides (particularly Substance P) may be of greatest interest. At the receptor level, cytokine receptors, MRGPRs, and TRP channels are most likely important. Future drug development efforts should concentrate on targeting these mediators and receptors for the treatment of CTCL pruritus. [ABSTRACT FROM AUTHOR]

Studies have demonstrated that bleach baths improve atopic dermatitis (AD) severity; however, the effects on itch, skin barrier, and cutaneous microbial composition are less clear. We examined whether bleach baths reduce itch, normalize skin barrier function, reduce S. aureus absolute abundance, and increase microbial diversity in adults with AD who were colonized with S. aureus on their non-lesional skin. This was an open label, non-randomized, controlled trial performed at a single academic center. Fifteen AD and five non-atopic healthy controls (NA) were instructed to take two bleach baths (0.005% NaClO; 5–10 min duration) per week for a total of 12 weeks as add-on therapy. Adults 18 to 65 years (inclusive) with mild to severe AD were recruited with EASI score > 6.0, S. aureus culture positivity, access to a bathtub, and ability and willingness to maintain current topical or systemic treatments. They were evaluated at baseline (before bleach baths), 6 weeks, and 12 weeks after the intervention of twice-weekly bleach baths. Efficacy measurements included EASI as well as 5-D Pruritus and ItchyQoL™. Transepidermal water loss (TEWL) and stratum corneum (SC) integrity assay were performed to assess the skin barrier. Skin dysbiosis was measured by S. aureus cultivation, S. aureus abundance (qPCR of thermonuclease gene), and V1-V3 16S rRNA gene sequencing on non-lesional and lesional AD skin. After 12 weeks of bleach baths, 8/15 (53.3%) AD subjects achieved an EASI50 and a significant reduction in itch as measured by 5-D pruritus and Itchy QoL. Eighty-seven percent reported improvements in sleep quality. At study entry, AD subjects had higher non-lesional TEWL values than NA subjects, and only AD subjects experienced a reduction with bleach baths (p = 0.006). Similarly, SC integrity improved as early as 6 weeks after bleach baths in AD subjects. Notably, bleach baths had no significant effect on S. aureus culture-positivity, qPCR absolute abundance, or microbial diversity. The addition of twice-weekly bleach baths improves investigator-assessed AD severity, patient-reported pruritus and sleep as well as physiological measures of skin barrier function in adult AD subjects while having no effect on qualitative and quantitative measures of cutaneous S. aureus. Trial Registration: ClinicalTrials.gov Identifier: NCT01996150, Date of registration: November 27th, 2013. [ABSTRACT FROM AUTHOR]

Introduction: Pruritus is a prevalent symptom, described as one of the most bothersome of psoriasis. Specific itch management remains a challenge, for which hydrotherapy could be used as adjunct care to medical treatment. Therefore, we assessed the immediate and longer-term benefit of 3 weeks of Avène thermal spring water hydrotherapy on chronic pruritus in patients in addition to their usual psoriasis and/or pruritus management. Methods: Twenty-six patients suffering from chronic pruritus due to psoriasis were evaluated before and after 3 weeks of hydrotherapy with a 3 and 6 month follow-up. A control group (18 patients) did not undergo hydrotherapy and continued to follow their usual skin management. Pruritus was assessed according to the numeric rating scale (NRS, pruritus intensity), the visual dynamic pruritus score (vDPS, change in pruritus intensity), and the 5-D itch scale (pruritus characteristics). Psoriasis severity was measured using the psoriasis area and severity index (PASI) score. The "itchy quality of life" (ItchQoL) scale was used to assess quality-of-life (QoL) impact related to itch. Pruritus and psoriasis gene and protein biomarkers were measured in lesional and nonlesional skin. Results: Pruritus measurements (NRS, vDPS, and 5-D itch scale) indicated an immediate and long-lasting positive effect of hydrotherapy compared with control patients. The psoriasis area and severity index (PASI) was decreased by 40.0% by hydrotherapy, which was sustained over 6 months. The ItchQoL also improved directly after hydrotherapy, which was still much improved even 6 months later. Analysis of gene and/or protein biomarkers revealed a significant decrease of inflammation biomarkers (IL-8, IL-1α, IL-1RA, and RANTES), of psoriasis biomarkers (PI3, S100A7, and IL-17), and of pruritus biomarkers (IL-31, TRPV1, and CGRP1). Conclusions: These findings demonstrated an immediate and long-lasting improvement of pruritus in patients with psoriasis who underwent Avène thermal spring water hydrotherapy, indicating that this would be a good complementary therapy in the management of this disease. Trial Registration: NCT03023254. [ABSTRACT FROM AUTHOR]

Background and Purpose: Pruritic dermatitis is a disease with a considerable unmet need for treatment and appears to present with not only epidermal but also peripheral neuronal complications. Here, we propose a novel pharmacological modulation targeting both peripheral dorsal root ganglion (DRG) sensory neurons and skin keratinocytes. GPR35 is an orphan G‐protein‐coupled receptor expressed in DRG neurons and has been predicted to downregulate neuronal excitability when activated. Modulator information is currently increasing for GPR35, and pamoic acid (PA), a salt‐forming agent for drugs, has been shown to be an activator solely specific for GPR35. Here, we investigated its effects on dermatitic pathology. Experimental Approach: We confirmed GPR35 expression in peripheral neurons and tissues. The effect of PA treatment was pharmacologically evaluated in cultured cells in vitro and in in vivo animal models for acute and chronic pruritus. Key Results: Local PA application mitigated acute non‐histaminergic itch and, consistently, obstructed DRG neuronal responses. Keratinocyte fragmentation under dermatitic simulation was also dampened following PA incubation. Chronic pruritus in 1‐chloro‐2,4‐dinitrobenzene and psoriasis models were also moderately but significantly reversed by the repeated applications of PA. Dermatitic scores in the 1‐chloro‐2,4‐dinitrobenzene and psoriatic models were also improved by its application, indicating that it is beneficial for mitigating disease pathology. Conclusion and Implications: Our findings suggest that pamoic acid activation of peripheral GPR35 can contribute to the improvement of pruritus and its associated diseases. [ABSTRACT FROM AUTHOR]

Congenital dermal melanocytosis (DM) represents a common birthmark mainly found in children of Asian and darker skin phototype descent, clinically characterized by an oval blue-grey macule or macules, commonly located on the lumbosacral area. In rare DM cases, when presenting with diffuse macules persisting during the first years of life, it could represent a cutaneous feature of mucopolysaccharidoses (MPS). Extensive congenital DM is actually associated with Hurler syndrome (MPS type I) and Hunter syndrome (MPS type II), although several reports also described this association with MPS type VI and other lysosomal storage disorders (LySD), including GM1 gangliosidosis, mucolipidosis, Sandhoff disease, and Niemann–Pick disease. Here, we present the case of a two-year-old boy presenting with extensive dermal melanocytosis, generalized hypertrichosis, and chronic itch, harboring a heterozygous variant of uncertain significance, NM_152419.3: c.493C>T (p.Pro165Ser), in the exon 4 of HGSNAT gene, whose mutations are classically associated with MPS IIIC, also known as Sanfilippo syndrome. This is the first report that highlights the association between extensive congenital DM and MPS type IIIC, as well as a pathogenetic link between heterozygous LySD carrier status and congenital DM. We speculate that some cases of extensive congenital DM could be related to heterozygous LySD carriers, as a manifestation of a mild clinical phenotype. [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by intermittent itchy rash. Type 2 inflammatory cytokines such as interleukin (IL)-4, IL-13, and IL-31 are strongly implicated in AD pathogenesis. Stimulation of IL-31 cognate receptors on C-fiber nerve endings is believed to activate neurons in the dorsal root ganglion (DRG), causing itch. The IL-31 receptor is a heterodimer of OSMRβ and IL31RA subunits, and OSMRβ can also bind oncostatin M (OSM), a pro-inflammatory cytokine released by monocytes/macrophages, dendritic cells, and T lymphocytes. Further, OSM expression is enhanced in the skin lesions of AD and psoriasis vulgaris patients. Objective: The current study aimed to examine the contributions of OSM to AD pathogenesis and symptom expression. Methods: The expression levels of the OSM gene (OSM) and various cytokine receptor genes were measured in human patient skin samples, isolated human monocytes, mouse skin samples, and mouse DRG by RT-qPCR. Itching responses to various pruritogens were measured in mice by counting scratching episodes. Results: We confirmed overexpression of OSM in skin lesions of patients with AD and psoriasis vulgaris. Monocytes isolated from the blood of healthy subjects overexpressed OSM upon stimulation with IL-4 or GM-CSF. Systemic administration of OSM suppressed IL31RA expression in the mouse DRG and IL-31-stimulated scratching behavior. In contrast, systemic administration of OSM increased the expression of IL-4- and IL-13-related receptors in the DRG. Conclusion: These results suggest that OSM is an important cytokine in the regulation of skin monocytes, promoting the actions of IL-4 and IL-13 in the DRG and suppressing the action of IL-31. It is speculated that OSM released from monocytes in skin modulates the sensitivity of DRG neurons to type 2 inflammatory cytokines and thereby the severity of AD-associated skin itch. [ABSTRACT FROM AUTHOR]

Morphine-induced antinociception is partially reduced in interleukin-31 (IL-31) receptor A (IL-31RA)-deficient mice, indicating that IL-31RA is crucial for morphine-induced peripheral antinociception. Herein, we examined the combined effects of IL-31 and morphine on the antinociceptive activity and itch-associated scratching behavior (LLS) in mice and elucidated the regulatory mechanisms. A hot-plate test was used to assess antinociception. LLS was automatically detected and recorded via a computer. IL-31RA mRNA expression was assessed using real-time polymerase chain reaction. Repeated pre-treatment with IL-31 resulted in significant antinociceptive activity. Repeated administration of morphine decreased the morphine-induced antinociceptive activity, LLS counts, and regular dose and inhibited IL-31-induced LLS. These results suggested that the repeated administration of morphine depleted inter-neuronal IL-31RA levels, preventing morphine-induced antinociception. Therefore, IL-31 may be helpful as an adjunct analgesic to morphine. To explore the benefits of IL-31, its influence on morphine-induced antinociceptive tolerance in mice was examined. An IL-31 and morphine combination increased the analgesic action, which increased the expression of DRG neuronal IL-31RA, elucidating the site of peripheral antinociception of morphine. This site may induce exocytosis of IL-31RA in the sensory nervous system. Collectively, the suppressive effect of IL-31 on morphine-induced antinociceptive tolerance may result from IL-31RA supplementation in sensory nerves. [ABSTRACT FROM AUTHOR]

Pruritus is one of the most debilitating symptoms for patients with epidermolysis bullosa (EB). This study aimed to assess the burden of itch and to address its dimensions across patients with EB. Forty-six patients with EB were recruited from the Saudi EB registry to participate. All participants completed the Leuven Itch Scale. The sample included 5 patients with EB simplex (EBS), 3 with junctional EB (JEB), 34 with dystrophic EB (DEB), and 4 patients had unknown type. Overall, 97.8% patients reported itch. In patients with itch, 73.3% reported that it was often or always present, longer than 2h Itch episodes was reported by JEB (66.7%) and recessive DEB (3.2%). Itch, in all its dimensions, was worst in patients with JEB and DEB than EBS. Itch occurred mostly in a hot environment (80%), when sweating (71.1%), in healing wounds (40%), and during dressing change (35.6%) whereas cold environment resulted in itch in only (2.2%). The burden of pruritus increased with increasing age. This study highlights a challenging area in EB care with a need for specific treatments. [ABSTRACT FROM AUTHOR]

Introduction: Chronic pruritus (CP) is a common symptom defined as a sensation that provokes the desire to scratch and which lasts for at least 6 weeks. CP remains a problem for up to 21.3% of renal transplant recipients (RTRs). Our research aimed to establish the possible association between serum levels of neurotrophin-4 (NT-4) and brain-derived neurotrophic factor (BDNF) and the presence and intensity of CP in RTR. Methods: The study was performed on a group of 129 RTRs, who were divided according to the presence or absence of pruritus in the previous 3 days. The assessment of pruritus was performed with the use of a numeric rating scale (NRS), 4-Item Itch Questionnaire (4IIQ), and Itchy Quality of Life (Itchy QoL). A total of 129 blood samples with a volume of 9 ml were drawn from RTRs during the monthly routine control. Serum levels (pg/mL) of NT-4 and BDNF were measured by the ELISA. Results: Pruritic RTRs have statistically significantly higher serum concentrations of NT-4 serum level compared to non-pruritic RTRs (229.17 ± 143.86 pg/mL and 153.08 ± 78.19 pg/mL [p = 0.024], respectively). Moreover, a statistically significant difference between pruritic and non-pruritic RTRs with healthy controls was shown (p < 0.001 and p < 0.001, respectively). Although there was a numerically higher serum concentration of BDNF in pruritic RTRs (32.18 ± 7.31 pg/mL vs. 31.58 ± 10.84 pg/mL), the difference did not reach statistical significance. No statistically significant difference was also seen in BDNF serum levels between RTRs and healthy controls. Furthermore, there was a statistically significant, positive correlation between serum concentration of NT-4 and NRS score (p = 0.008, r = 0.357). Conclusions: The results indicate higher NT-4 serum concentration in RTRs with pruritus compared to RTRs without pruritus. Furthermore, the study revealed a statistically significant, positive correlation between the serum concentration of NT-4 and NRS score. [ABSTRACT FROM AUTHOR]

Purpose: Dupilumab, a fully human monoclonal antibody that inhibits the signaling pathways of interleukin (IL)-4 and IL-13, has demonstrated remarkable efficacy in the treatment of atopic dermatitis (AD). Dupilumab has been reported to attenuate itch and reduce several serum markers, including blood lactate dehydrogenase (LDH), blood eosinophil count, and serum total immunoglobulin E (IgE).Patients and Methods: The present study investigated retrospectively changes in clinical scores and serum biomarker from 175 adults with moderate-to-severe AD treated with dupilumab. Clinical manifestations were assessed using eczema area and severity index (EASI) and visual analogue scale (VAS) for itch at baseline and subsequently at 16-week intervals up to a duration of 48 weeks. Total IgE, LDH and blood eosinophil count were also collected.Results: The dupilumab treatment significantly improved EASI and VAS scores and decreased serum levels of IgE, LDH, and total eosinophil count. The EASI scores were positively correlated with VAS for itch at all recorded time points, whereas serum biomarkers did not exhibit a strong correlation with EASI scores.Conclusion: These findings highlight the close relationship between the extent and severity of eczema and the intensity of itch experienced by patients and suggest that factors beyond the measured serum biomarkers play a significant role in the clinical manifestations of AD, emphasizing the complex nature of the disease. [ABSTRACT FROM AUTHOR]

Background: Pain and itch are impactful and burdensome symptoms of hidradenitis suppurativa (HS). Elucidating factors associated with pain and itch severity may identify groups disproportionally affected by HS-related pain and itch and further our understanding of how pain and itch impact quality of life (QoL) in patients with HS. Objective: The objective of the study was to determine factors associated with pain severity, itch severity, and reduced QoL in patients with HS. Methods: This is a retrospective cross-sectional study of 257 adults with HS who received care in an HS Specialty Clinic from January 2019 to August 2021. Multivariable mixed-effects linear regression was used to determine the relationships between clinical and demographic patient factors and the outcomes of pain severity, itch severity, and skin-specific QoL. Results: Factors associated with reduced QoL were Hurley stage II (β = 19.66, 95% CI: 1.40–37.93) and III (β = 21.98, 95% CI: 1.57–42.39) disease as well as severity of pain (β = 13.74, 95% CI: 11.93–15.55), itch (β = 4.57, 95% CI: 2.59–6.55), anxiety (β = 2.55 95% CI: 1.29–3.81), and depression (β = 1.43, 95% CI: 0.30–2.56). Increasing HS pain severity was associated with Hurley stage III disease (β = 2.04, 95% Cl: 0.99–3.09), black race (β = 1.23, 95% Cl: 0.40, 2.06), depression severity (β = 0.08, 95% Cl: 0.02, 0.14), and anxiety severity (β = 0.10 95% Cl: 0.04, 0.17). Factors associated with HS itch severity were Hurley stage III disease (β = 2.23, 95% Cl: 1.19, 3.27), black race (β = 0.92, 95% Cl: 0.07, 1.78), depression severity (β = 0.09, 95% Cl: 0.04, 0.14), and anxiety severity (β = 0.07, 95% Cl: 0.01, 0.13). Conclusion: Pain is one of the largest contributors to QoL in patients with HS; on a 0–10 numeric rating scale, a 2-point increase in HS pain had a similar independent effect on QoL as having Hurley stage III disease compared to Hurley stage I. [ABSTRACT FROM AUTHOR]