A basophil-neuronal axis promotes itch.

Itch is an evolutionarily conserved sensation that facilitates expulsion of pathogens and noxious stimuli from the skin. However, in organ failure, cancer, and chronic inflammatory disorders such as atopic dermatitis (AD), itch becomes chronic, intractable, and debilitating. In addition to chronic itch, patients often experience intense acute itch exacerbations. Recent discoveries have unearthed the neuroimmune circuitry of itch, leading to the development of anti-itch treatments. However, mechanisms underlying acute itch exacerbations remain overlooked. Herein, we identify that a large proportion of patients with AD harbor allergen-specific immunoglobulin E (IgE) and exhibit a propensity for acute itch flares. In mice, while allergen-provoked acute itch is mediated by the mast cell-histamine axis in steady state, AD-associated inflammation renders this pathway dispensable. Instead, a previously unrecognized basophil-leukotriene (LT) axis emerges as critical for acute itch flares. By probing fundamental itch mechanisms, our study highlights a basophil-neuronal circuit that may underlie a variety of neuroimmune processes.

Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch.

Mammals have evolved neurophysiologic reflexes, such as coughing and scratching, to expel invading pathogens and noxious environmental stimuli. It is well established that these responses are also associated with chronic inflammatory diseases, including asthma and atopic dermatitis. However, the mechanisms by which inflammatory pathways promote sensations such as itch remain poorly understood. Here, we show that type 2 cytokines directly activate sensory neurons in both mice and humans. Further, we demonstrate that chronic itch is dependent on neuronal IL-4Rα and JAK1 signaling. We also observe that patients with recalcitrant chronic itch that failed other immunosuppressive therapies markedly improve when treated with JAK inhibitors. Thus, signaling mechanisms previously ascribed to the immune system may represent novel therapeutic targets within the nervous system. Collectively, this study reveals an evolutionarily conserved paradigm in which the sensory nervous system employs classical immune signaling pathways to influence mammalian behavior.

Neural Mechanisms of Itch.

Itch is a unique sensation that helps organisms scratch away external threats; scratching itself induces an immune response that can contribute to more itchiness. Itch is induced chemically in the peripheral nervous system via a wide array of receptors. Given the superficial localization of itch neuron terminals, cells that dwell close to the skin contribute significantly to itch. Certain mechanical stimuli mediated by recently discovered circuits also contribute to the itch sensation. Ultimately, in the spinal cord, and likely in the brain, circuits that mediate touch, pain, and itch engage in cross modulation. Much of itch perception is still a mystery, but we present in this review the known ligands and receptors associated with itch. We also describe experiments and findings from investigations into the spinal and supraspinal circuitry responsible for the sensation of itch.

Activation of Mast-Cell-Expressed Mas-Related G-Protein-Coupled Receptors Drives Non-histaminergic Itch.

Classical itch studies have focused on immunoglobulin E (IgE)-mediated mast cell activation and histamine release. Recently, members of the Mas-related G-protein-coupled receptor (Mrgpr) family have been identified as mast cell receptors, but their role in itch is unclear. Here, we report that mast cell activation via Mrgprb2 evoked non-histaminergic itch in mice independently of the IgE-Fc epsilon RI (FcεRI)-histamine axis. Compared with IgE-FcεRI stimulation, Mrgprb2 activation of mast cells was distinct in both released substances (histamine, serotonin, and tryptase) and the pattern of activated itch-sensory neurons. Mrgprb2 deficiency decreased itch in multiple preclinical models of allergic contact dermatitis (ACD), a pruritic inflammatory skin disorder, and both mast cell number and PAMP1-20 concentrations (agonist of the human Mrgprb2 homolog, MRGPRX2) were increased in human ACD skin. These findings suggest that this pathway may represent a therapeutic target for treating ACD and mast-cell-associated itch disorders in which antihistamines are ineffective.

Physiology and Pathophysiology of Itch.

Itch is a topic to which everyone can relate. The physiological roles of itch are increasingly understood and appreciated. The pathophysiological consequences of itch impact quality of life as much as pain. These dynamics have led to increasingly deep dives into the mechanisms that underlie and contribute to the sensation of itch. When the prior review on the physiology of itching was published in this journal in 1941, itch was a black box of interest to a small number of neuroscientists and dermatologists. Itch is now appreciated as a complex and colorful Rubik's cube. Acute and chronic itch are being carefully scratched apart and reassembled by puzzle solvers across the biomedical spectrum. New mediators are being identified. Mechanisms blur boundaries of the circuitry that blend neuroscience and immunology. Measures involve psychophysics and behavioral psychology. The efforts associated with these approaches are positively impacting the care of itchy patients. There is now the potential to markedly alleviate chronic itch, a condition that does not end life, but often ruins it. We review the itch field and provide a current understanding of the pathophysiology of itch. Itch is a disease, not only a symptom of disease.

Mas-Related G Protein-Coupled Receptors and the Biology of Itch Sensation.

Chronic, persistent itch is a devastating symptom that causes much suffering. In recent years, there has been great progress made in understanding the molecules, cells, and circuits underlying itch sensation. Once thought to be carried by pain-sensing neurons, itch is now believed to be capable of being transmitted by dedicated sensory labeled lines. Members of the Mas-related G protein-coupled receptor (Mrgpr) family demarcate an itch-specific labeled line in the peripheral nervous system. In the spinal cord, the expression of other proteins identifies additional populations of itch-dedicated sensory neurons. However, as evidence for labeled-line coding has mounted, studies promoting alternative itch-coding strategies have emerged, complicating our understanding of the neural basis of itch. In this review, we cover the molecules, cells, and circuits related to understanding the neural basis of itch, with a focus on the role of Mrgprs in mediating itch sensation.

Blockade of OSMRß signaling ameliorates skin lesions in a mouse model of human atopic dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by severe pruritus and eczematous skin lesions. Although IL-31, a type 2 helper T (Th2)-derived cytokine, is important to the development of pruritus and skin lesions in AD, the blockade of IL-31 signaling does not improve the skin lesions in AD. Oncostatin M (OSM), a member of IL-6 family of cytokines, plays important roles in the regulation of various inflammatory responses through OSM receptor ß subunit (OSMRß), a common receptor subunit for OSM and IL-31. However, the effects of OSM on the pathogenesis of AD remain to be elucidated. When AD model mice were treated with OSM, skin lesions were exacerbated and IL-4 production was increased in the lymph nodes. Next, we investigated the effects of the monoclonal antibody (mAb) against OSMRß on the pathogenesis of AD. Treatment with the anti-OSMRß mAb (7D2) reduced skin severity score in AD model mice. In addition to skin lesions, scratching behavior was decreased by 7D2 mAb with the reduction in the number of OSMRß-positive neurons in the dorsal root ganglia of AD model mice. 7D2 mAb also reduced the serum concentration of IL-4, IL-13, and IgE as well as the gene expressions of IL-4 and IL-13 in the lymph nodes of AD model mice. Blockade of both IL-31 and OSM signaling is suggested to suppress both pruritus and Th2 responses, resulting in the improvement of skin lesions in AD. The anti-OSMRß mAb may be a new therapeutic candidate for the treatment of AD.

Systemic inflammation and its relationship with pruritus in early-stage mycosis fungoides.

The underlying mechanisms mycosis fungoides (MF)-related pruritus remain unclear, and the link between pruritus and systemic inflammation in MF is unexplored. We aimed to investigate systemic inflammation in MF patients and its potential connection to pruritus. In this retrospective study, demographic characteristics, MF stage, clinical and laboratory findings, and neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-lymphocyte ratio (MLR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI) and pan-immune inflammation value (PIV) were assessed for all participants. Additionally, mSWAT scores, Dermatology Life Quality Index (DLQI), and pruritus presence and intensity via Visual Analogue Scale (VAS) scoring were recorded for MF patients. A total of 81 patients with early-stage MF and 50 controls were enrolled. Itching was present in 41 patients (50.6%). NLR, PLR, SII, SIRI and CRP values in the MF group were significantly higher. CRP, NLR, mSWAT and DLQI score were significantly higher in MF patients with pruritus than those without. Pruritus was positively correlated with DLQI, mSWAT, CRP, NLR, MLR and SIRI. VAS score was positively correlated with eosinophil count and DLQI. In the multivariate logistic regression model, only NLR was an independent and significant associate of pruritus in patients with MF. This study provides evidence of enhanced systemic inflammation in early-stage MF patients. Additionally, the correlation between pruritus with mSWAT scores and systemic inflammation parameters suggests a potential link between pruritus and the inflammatory milieu in MF.

Dendritic cells under allergic condition enhance the activation of pruritogen-responsive neurons via inducing itch receptors in a co-culture study.

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.

Mast cells in type 2 skin inflammation: Maintenance and function.

Mast cells (MCs) are immune cells residing in tissues and playing indispensable roles in maintaining homeostasis and inflammatory states. Skin lesions associated with atopic dermatitis (AD) and type 2 skin inflammation display an increment in MCs, which have both pro- and anti-inflammatory effects. The direct and indirect activations of skin MCs by environmental factors such as Staphylococcus aureus can instigate type 2 skin inflammation in AD with poorly understood mechanisms. Furthermore, both IgE-dependent and -independent degranulation of MCs contribute to pruritus in AD. Conversely, MCs suppress type 2 skin inflammation by promoting Treg expansion through IL-2 secretion in the spleen. Moreover, skin MCs can upregulate gene expression involved in skin barrier function, thus mitigating AD-like inflammation. These functional variances of MCs in AD could stem from differences in experimental systems, their localization, and origins. In this review, we will focus on how MCs are maintained in the skin under homeostatic and inflammatory conditions, and how they are involved in the pathogenesis of type 2 skin inflammation.

Pruritus related to trastuzumab and pertuzumab in HER2 + breast cancer patients.

PURPOSE: The combination of trastuzumab and pertuzumab (HP) as part of a taxane-based regimen has shown benefit in the adjuvant and metastatic HER2 + breast cancer setting. In the CLEOPATRA trial, pruritus was reported in 11-17.6% of patients. The clinical phenotype and potential treatment strategies for this event have not been reported. METHODS: A retrospective review of 2583 patients receiving trastuzumab and pertuzumab for the treatment of HER2 + breast cancer from 11/23/2011 to 6/21/2021 was performed at Memorial Sloan Kettering Cancer Center (MSKCC). Patient demographics, pruritus characteristics, and treatments as documented in the electronic medical record (EMR) were included in this analysis. RESULTS: Of 2583 pts treated with HP, 122 (4.72%) with pruritus were identified. On average, patients experienced pruritus 319.0 days (8-3171) after initiation of HP. The upper extremities (67.4%), back (29.3%), lower extremities (17.4%), and shoulders (14.1%) were the most commonly affected regions. Grade 1/2 pruritus (97.6%) occurred in most cases. Patients responded primarily to treatment with topical steroids (52.2%), antihistamines (29.9%), emollients (20.9%), and gabapentinoids (16.4%). Of those with pruritus, 4 patients (3.3%) required treatment interruption or discontinuation. CONCLUSIONS: Pruritus is uncommon in patients on trastuzumab and pertuzumab, generally a chronic condition, with gabapentinoids or antihistamines representing effective therapies.

IL-4 and IL-13 are not involved in IL-31-induced itch-associated scratching behaviour in mice.

Itchy skin or pruritus is a common cutaneous symptom that causes an urge to scratch, and the role of interleukins (IL) in itchy skin has been widely studied. IL-4 and IL-13 are known to induce chronic itch. Similarly, the direct role of IL-31 in inducing itch has been demonstrated in clinical situations such as atopic dermatitis and prurigo nodularis. Moreover, IL-4 receptor α antibodies (dupilumab) and IL-31 receptor A antibodies (nemolizumab) inhibit pruritus. However, the interplay between these ILs in pruritus remains unclear. Therefore, we investigated the reciprocal effects of these cytokines on pruritus in mice. The intradermal administration of IL-31 induced itch-associated scratching behaviour in a dose-dependent manner. Interestingly, the amount of IL-31 and IL-4/IL-13, co-administration or 30 min pre-administration of IL-4/IL-13 and intradermal or intravenous pre-administration of IL-4 did not affect IL-31-induced itch-associated scratching behaviour when it was observed for 30 min, 2 h, 24 h or 48 h. Pre-administration of neutralising antibodies against IL-4 and IL-13 also did not affect IL-31-induced itch-associated scratching behaviour. These results suggest that IL-31 can induce itching independently of IL-4 and IL-13 in vivo.

Eosinophils in hidradenitis suppurativa patients exhibit pro-inflammatory traits, implicating a potential pathogenic role in the disease.

Hidradenitis suppurativa (HS) is an inflammatory skin disease characterized by painful nodules, abscesses and purulent secretions in intertriginous regions. Intense pruritus frequently accompanies HS lesions, adding further discomfort for patients. While Th17 pathway activation is implicated in HS pathogenesis, disease mechanisms are still not fully understood, and therapeutics are lacking. Previous reports raise a potential role for eosinophils in HS, showing a strong association of eosinophil levels with disease severity. To investigate eosinophils in HS, we recruited patients and matched healthy controls and then performed flow-cytometry studies, eosinophil stimulation assays, and lesional skin staining for eosinophils. We found that HS patients reported similar levels of pain and itch. Compared to matched controls, HS blood exhibited decreased mature eosinophils and increased numbers of immature eosinophils, coupled with a significant increase in dermal eosinophilic infiltrates. Additionally, IL-17RA+ eosinophils were highly and significantly correlated with multiple HS-related clinical scores. In both stimulated and unstimulated conditions, HS eosinophils showed an inflammatory phenotype versus controls, including an increase in costimulatory T- and B-cell markers (e.g. CD5 and CD40) following all stimulations (TNFα/IL-17A/IL-17F). These findings highlight the significance of pruritus in HS and suggest a higher turnover of eosinophils in HS blood, potentially due to the consumption of eosinophils in skin lesions. Our data delineate the features and functions of eosinophils in HS and suggest that eosinophils participate in disease pathogenesis, advancing Th17-related inflammation. Further studies are needed to investigate eosinophils' response to current HS treatments and their potential as a therapeutic target in the disease.

Intrapatient comparison of atopic dermatitis skin transcriptome shows differences between tape-strips and biopsies.

BACKGROUND: Our knowledge of etiopathogenesis of atopic dermatitis (AD) is largely derived from skin biopsies, which are associated with pain, scarring and infection. In contrast, tape-stripping is a minimally invasive, nonscarring technique to collect skin samples. METHODS: To construct a global AD skin transcriptomic profile comparing tape-strips to whole-skin biopsies, we performed RNA-seq on tape-strips and biopsies taken from the lesional skin of 20 moderate-to-severe AD patients and the skin of 20 controls. Differentially expressed genes (DEGs) were defined by fold-change (FCH) ≥2.0 and false discovery rate <0.05. RESULTS: We detected 4104 (2513 Up; 1591 Down) and 1273 (546 Up; 727 Down) DEGs in AD versus controls, in tape-strips and biopsies, respectively. Although both techniques captured dysregulation of key immune genes, tape-strips showed higher FCHs for innate immunity (IL-1B, IL-8), dendritic cell (ITGAX/CD11C, FCER1A), Th2 (IL-13, CCL17, TNFRSF4/OX40), and Th17 (CCL20, CXCL1) products, while biopsies showed higher upregulation of Th22 associated genes (IL-22, S100As) and dermal cytokines (IFN-γ, CCL26). Itch-related genes (IL-31, TRPV3) were preferentially captured by tape-strips. Epidermal barrier abnormalities were detected in both techniques, with terminal differentiation defects (FLG2, PSORS1C2) better represented by tape-strips and epidermal hyperplasia changes (KRT16, MKI67) better detected by biopsies. CONCLUSIONS: Tape-strips and biopsies capture overlapping but distinct features of the AD molecular signature, suggesting their respective utility for monitoring specific AD-related immune, itch, and barrier abnormalities in clinical trials and longitudinal studies.

Difelikefalin in Black/African American Hemodialysis Patients with Moderate-to-Severe Pruritus: Post hoc Analysis of KALM-1 and KALM-2.

INTRODUCTION: Black and African American (AA) people are over-represented in the kidney failure population; therefore, the safety and efficacy of difelikefalin in Black/AA patients was evaluated. METHODS: This was a post hoc, pooled exploratory subgroup analysis of the Phase 3 KALM-1 and -2 studies. Patients undergoing hemodialysis (HD) who had moderate-to-severe chronic kidney disease-associated pruritus (CKD-aP) at enrollment were stratified into self-reported Black/AA or White subgroups. Patients were randomized (1:1) to receive intravenous (IV) difelikefalin 0.5 µg/kg or placebo for 12 weeks. Difelikefalin efficacy was assessed with validated patient-reported outcome questionnaires: 24-h Worst Itch Numerical Rating Scale (WI-NRS), 5-D itch, and Skindex­10. RESULTS: There were 249 (29.3%) patients from the KALM studies that self-identified as Black/AA (n = 135 difelikefalin; n = 114 placebo). Clinically meaningful (≥3-point) reduction in WI-NRS score was achieved by 47.9% of Black/AA patients with difelikefalin versus 24.6% with placebo (p < 0.001). More Black/AA patients achieved a ≥5-point 5-D itch total improvement (54.9% vs. 35.7%; p = 0.013) and a ≥15-point Skindex-10 score improvement with difelikefalin versus placebo (49.0% vs. 28.9%; p = 0.006) compared with White patients. Incidence of treatment-emergent adverse events (TEAEs) was higher for Black/AA patients (difelikefalin: 78.5%; placebo: 70.8%) versus White patients (difelikefalin: 64.8%; placebo: 61.8%). CONCLUSION: In this post hoc analysis, difelikefalin was efficacious in the Black/AA population and had an acceptable safety profile.

Blockade of HMGB1 Reduces Inflammation and Pruritus in Atopic Dermatitis by Inhibiting Skin Fibroblasts Activation.

INTRODUCTION: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by relapsed eczema and serious pruritus. High-mobility group box 1 protein (HMGB1) is a nuclear-binding protein and serves as an alarmin to promote inflammatory responses. METHODS: In this study, we established an AD mouse model by topical use of MC903 on ears and then used a specific HMGB1-binding peptide cIY8 and a HMGB1 inhibitor of glycyrrhizin to investigate HMGB1 on fibroblast activation in the pathogenesis of AD-like symptoms. RESULTS: Topical use of cIY8 and oral use of glycyrrhizin significantly improved the MC903-induced AD-like symptoms and pathological changes of the ears and scratching behavior in an AD mouse model; cIY8 treatment inhibited the higher mRNAs of IL-1α, IL-4, IL-5, IL-13, and IL-31 in the ears. In human fibroblasts, HMGB1 caused nuclear translocation of NF-kB, and the nuclear translocation could be inhibited by pre-treatment of HMGB1 with cIY8, suggesting that NF-κB signaling pathway participates in the HMGB1-induced inflammation of AD in fibroblasts and that cIY8 effectively impedes the function of HMGB1. Glycyrrhizin inhibited the Ca2+ signaling induced by ionomycin in mouse primary fibroblasts. The fibroblast-related proteins of α-SMA, Hsp47, and vimentin and the pruritus-related proteins of IL-33 and periostin were increased in the ears of the AD mouse model, the ratio of EdU incorporation became higher in mouse fibroblasts treated with MC903, and the higher proliferation and inflammatory responses of the fibroblasts could be reversed by glycyrrhizin treatment. CONCLUSIONS: Fibroblast activation by HMGB1 is one of the critical processes in the development of inflammation and pruritus in the AD mouse model. The specific HMGB1-binding peptide cIY8 and the HMGB1 inhibitor glycyrrhizin inactivate skin fibroblasts to alleviate the inflammation and pruritus in the AD mouse model. Peptide cIY8 may be topically used to treat AD patients in the future.

Inhibition of cutaneous heat-sensitive Ca2+ -permeable transient receptor potential vanilloid 3 channels alleviates UVB-induced skin lesions in mice.

Ultraviolet B (UVB) radiation causes skin injury by trigging excessive calcium influx and signaling cascades in the skin keratinocytes. The heat-sensitive Ca2+ -permeable transient receptor potential vanilloid 3 (TRPV3) channels robustly expressed in the keratinocytes play an important role in skin barrier formation and wound healing. Here, we report that inhibition of cutaneous TRPV3 alleviates UVB radiation-induced skin lesions. In mouse models of ear swelling and dorsal skin injury induced by a single exposure of weak UVB radiation, TRPV3 genes and proteins were upregulated in quantitative real-time PCR and Western blot assays. In accompany with TRPV3 upregulations, the expressions of proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were also increased. Knockout of the TRPV3 gene alleviates UVB-induced ear swelling and dorsal skin inflammation. Furthermore, topical applications of two selective TRPV3 inhibitors, osthole and verbascoside, resulted in a dose-dependent attenuation of skin inflammation and lesions. Taken together, our findings demonstrate the causative role of overactive TRPV3 channel function in the development of UVB-induced skin injury. Therefore, topical inhibition of TRPV3 may hold potential therapy or prevention of UVB radiation-induced skin injury.

Role of hydrogen sulfide in dermatological diseases.

Hydrogen sulfide (H2S), together with carbon monoxide (CO) and nitric oxide (NO), is recognized as a vital gasotransmitter. H2S is biosynthesized by enzymatic pathways in the skin and exerts significant physiological effects on a variety of biological processes, such as apoptosis, modulation of inflammation, cellular proliferation, and regulation of vasodilation. As a major health problem, dermatological diseases affect a large proportion of the population every day. It is urgent to design and develop effective drugs to deal with dermatological diseases. Dermatological diseases can arise from a multitude of etiologies, including neoplastic growth, infectious agents, and inflammatory processes. The abnormal metabolism of H2S is associated with many dermatological diseases, such as melanoma, fibrotic diseases, and psoriasis, suggesting its therapeutic potential in the treatment of these diseases. In addition, therapies based on H2S donors that release H2S are being developed to treat some of these conditions. In the review, we discuss recent advances in the function of H2S in normal skin, the role of altering H2S metabolism in dermatological diseases, and the therapeutic potential of diverse H2S donors for the treatment of dermatological diseases.

Serum bile acid change correlates with improvement in pruritus in patients with primary biliary cholangitis receiving linerixibat.

BACKGROUND & AIMS: Total serum bile acid (TSBA) levels are elevated in patients with primary biliary cholangitis (PBC) and may mediate cholestatic pruritus. Linerixibat, an ileal bile acid transporter inhibitor, improved pruritus in patients with PBC. We explored the relationship between linerixibat dose, TSBA concentration, and pruritus. METHODS: Data from Phase 1/2 trials were used to develop a population kinetic-pharmacodynamic model to characterize the linerixibat dose-TSBA relationship. Individual Bayesian parameter estimates for participants in the GLIMMER study were used to derive the area under the TSBA concentration curve over 24 h (AUC0-24). Time-matched post hoc estimates of AUC0-24 were correlated with pruritus reported on a 0-10 numerical rating scale. Baseline TSBA concentration was correlated with change from baseline (ΔBL) in monthly itch score (MIS). ΔBL in model-estimated TSBA AUC0-24 was correlated with time-matched ΔBL in weekly itch score (WIS) or MIS. RESULTS: Linerixibat dose dependently reduced TSBA AUC0-24, reaching steady state after 5 days. Baseline TSBA levels in GLIMMER did not correlate with ΔBL in MIS. ΔBL in TSBA AUC0-24 correlated with improved WIS over 12 weeks of treatment (r = 0.52, p < 0.0001). Of participants with a ≥30% decrease in TSBA AUC0-24, 60% were pruritus responders (≥2-point improvement in WIS from baseline). CONCLUSIONS: Linerixibat treatment leads to rapid, dose-dependent TSBA reductions. Baseline TSBA levels do not correlate with on-treatment pruritus change, suggesting they do not predict linerixibat response. Change in TSBA AUC0-24 correlates significantly with, and can be predictive of, pruritus improvement in patients with PBC.

Molecular and cellular pruritus mechanisms in the host skin.

Pruritus, also known as itching, is a complex sensation that involves the activation of specific physiological and cellular receptors. The skin is innervated with sensory nerves as well as some receptors for various sensations, and its immune system has prominent neurological connections. Sensory neurons have a considerable impact on the sensation of itching. However, immune cells also play a role in this process, as they release pruritogens. Disruption of the dermal barrier activates an immune response, initiating a series of chemical, physical, and cellular reactions. These reactions involve various cell types, including keratinocytes, as well as immune cells involved in innate and adaptive immunity. Collective activation of these immune responses confers protection against potential pathogens. Thus, understanding the molecular and cellular mechanisms that contribute to pruritus in host skin is crucial for the advancement of effective treatment approaches. This review provides a comprehensive analysis of the present knowledge concerning the molecular and cellular mechanisms underlying itching signaling in the skin. Additionally, this review explored the integration of these mechanisms with the broader context of itch mediators and the expression of their receptors in the skin.