FGF13 enhances the function of TRPV1 by stabilizing microtubules and regulates acute and chronic itch.

Itching is an aversive somatosensation that triggers the desire to scratch. Transient receptor potential (TRP) channel proteins are key players in acute and chronic itch. However, whether the modulatory effect of fibroblast growth factor 13 (FGF13) on acute and chronic itch is associated with TRP channel proteins is unclear. Here, we demonstrated that conditional knockout of Fgf13 in dorsal root ganglion neurons induced significant impairment in scratching behaviors in response to acute histamine-dependent and chronic dry skin itch models. Furthermore, FGF13 selectively regulated the function of the TRPV1, but not the TRPA1 channel on Ca2+ imaging and electrophysiological recordings, as demonstrated by a significant reduction in neuronal excitability and current density induced by TRPV1 channel activation, whereas TRPA1 channel activation had no effect. Changes in channel currents were also verified in HEK cell lines. Subsequently, we observed that selective modulation of TRPV1 by FGF13 required its microtubule-stabilizing effect. Furthermore, in FGF13 knockout mice, only the overexpression of FGF13 with a tubulin-binding domain could rescue TRP channel function and the impaired itch behavior. Our findings reveal a novel mechanism by which FGF13 is involved in TRPV1-dependent itch transduction and provide valuable clues for alleviating pathological itch syndrome.

Atopic Dermatitis: Managing the Itch.

Atopic dermatitis has a substantial impact on sleep, appearance, psychological well-being, and other qualities of life. The visual appearance of lichenification, cheilitis, hyperpigmentation, ichthyosis, and erythema can be socially stigmatizing, and treatment of these symptoms is challenging. In managing pruritus in patients, practitioners should assess and document pruritus through questionnaires at each routine visit. Initially, practitioners should advise patients to employ nonpharmaceutical treatments such as emollients with wet wraps, elimination of triggers, changing scratching habits, and psychological interventions. If these methods of treatment are not successful or if the disease presentation is severe, pharmacological therapies should be employed. This chapter describes the therapeutic ladder for pruritus in atopic dermatitis and discusses each treatment modality in further detail for practitioners to advise their patients.First-line topical pharmaceutical agents include topical glucocorticoids and topical calcineurin inhibitors. Second-line topical agents include coal tar, menthol, capsaicin, or doxepin. After the use of topical agents has been exhausted, primary systemic agents can be applied. These include sedating antihistamines, nonsedating antihistamines, oral glucocorticoids, or cyclosporine A. Finally, neuromodulating or immunomodulating agents can be attempted, including SSRI/SNRIs, TCAs, immunosuppressants, neural modulators, and opioid receptor modulators. Outside of pharmacological treatments, phototherapy has been shown to provide a dramatic improvement of pruritus in atopic dermatitis and can be used at any stage of treatment including as a first-line agent.

Seladelpar: New hope for patients with primary biliary cholangitis.

The study by Hirschfield et al.1 demonstrated safety profile and clinically significant effectiveness of the peroxisome proliferator-activated receptor delta (PPARδ) agonist seladelpar in patients with primary biliary cholangitis, highlighting its plausible use as a second-line treatment to reduce disease activity and pruritus.

Patient preferences for treatment attributes in moderate-to-severe atopic dermatitis: a discrete choice experiment.

Purpose: Evidence on treatment preferences of patients with moderate-to-severe atopic dermatitis (AD) in the United States (US) is limited and an assessment of treatment preferences in this group is warranted.Materials and methods: An online discrete choice experiment survey was conducted (June 2023) among US adults with self-reported moderate-to-severe AD or experience with systemic therapy who had inadequate response to topical treatments. Preference weights estimated from conditional logistic regression models were used to calculate willingness to trade off and attributes' relative importance (RI).Results: Participants (N = 300; mean age: 45 years; 70% females; 52% systemic therapy experienced) preferred treatments with higher efficacy, lower risk of adverse events (AEs), and less frequent blood tests (p < .05). Treatment attributes, from high to low RI, were itch control (38%), risk of cancer (23%), risk of respiratory infections (18%), risk of heart problems (11%), sustained improvement in skin appearance (5%), blood test frequency (3%), and frequency and mode of administration (2%); together, AE attributes accounted for more than half of the RI.Conclusions: Participants preferred AD treatments that maximize itch control while minimizing AE risks, whereas mode of administration had little impact on preferences. Understanding patients' preferences may help improve shared decision-making, potentially leading to enhanced patient satisfaction with treatment, increased engagement, and better clinical outcomes.

Clinical Presentation of Atopic Dermatitis.

Atopic dermatitis, commonly known as eczema, is a chronic inflammatory dermatosis that can affect individuals from infancy to adulthood. Also referred to as "the itch that rashes," atopic dermatitis is classically associated with significant pruritus that is accompanied by characteristic cutaneous and other clinical findings. The diagnosis of atopic dermatitis can be challenging due to the wide range of clinical presentations based on patient factors such as age, skin type, ethnicity, and other comorbid conditions. This chapter reviews the classical findings as well as the less common manifestations of atopic dermatitis.

Rapid and sustained improvements in itch and quality of life with upadacitinib plus topical corticosteroids in adults and adolescents with atopic dermatitis: 52-week outcomes from the phase 3 AD Up study.

Purpose: Atopic dermatitis (AD) adversely impacts quality of life (QoL). We evaluated the effect of upadacitinib, an oral selective Janus kinase inhibitor approved for moderate-to-severe AD, plus topical corticosteroids (+TCS) on patient-reported outcomes (PROs) over 52 weeks.Materials and methods: In the phase 3 AD Up study (NCT03568318), adults and adolescents with moderate-to-severe AD were randomized 1:1:1 to once-daily upadacitinib 15 mg, 30 mg, or placebo + TCS. Itch, skin pain/symptoms, sleep, QoL, daily activities, emotional state, mental health, and patient impressions of disease severity/improvement/treatment satisfaction were assessed.Results: This analysis included 901 patients. Within 1-2 weeks, PRO improvements were greater with both upadacitinib doses than with placebo (p <.05). Improvements increased through weeks 4-8; rates were generally maintained through week 52. At week 52, the proportion of patients with clinically meaningful improvements in itch (Worst Pruritus Numerical Rating Scale improvement ≥4), skin pain (AD Symptom Scale Skin Pain improvement ≥4), sleep (AD Impact Scale [ADerm-IS] Sleep improvement ≥12), daily activities (ADerm-IS Daily Activities improvement ≥14), and emotional state (ADerm-IS Emotional State improvement ≥11) ranged from 62.1%-77.7% with upadacitinib 15 mg + TCS and 71.3%-83.6% with upadacitinib 30 mg + TCS.Conclusions: Upadacitinib + TCS results in rapid, sustained improvements in burdensome AD symptoms and QoL.

A systematic review of procedural modalities in the treatment of notalgia paresthetica.

BACKGROUND: Notalgia paresthetica (NP) is a rare condition characterized by localized pain and pruritus of the upper back, associated with a distinct area of hyperpigmentation. Given the lack of standardized treatment and the uncertain efficacy of available options, applying procedural methods is of growing interest in treating NP. AIMS: We sought to comprehensively evaluate the role of procedural treatments for NP. METHODS: We systematically searched PubMed/Medline, Ovid Embase, and Web of Science until November 14th, 2023. We also performed a citation search to detect all relevant studies. Original clinical studies published in the English language were included. RESULTS: Out of 243 articles, sixteen studies have reported various procedural modalities, with or without pharmacological components, in treating NP. Pharmacological procedures, including injections of botulinum toxin, lidocaine, and corticosteroids, led to a level of improvement in case reports and case series. However, botulinum toxin did not show acceptable results in a clinical trial. Moreover, non-pharmacological procedures were as follows: physical therapy, exercise therapy, kinesiotherapy, acupuncture and dry needling, electrical muscle stimulation, surgical decompression, and phototherapy. These treatments result in significant symptom control in refractory cases. Physical therapy can be considered a first-line choice or an alternative in refractory cases. CONCLUSION: Procedural modalities are critical in the multidisciplinary approach to NP, especially for patients who are refractory to topical and oral treatments. Procedural modalities include a spectrum of options that can be applied based on the disease's symptoms and severity.

MRGPRX4 mediates phospho-drug-associated pruritus in a humanized mouse model.

The phosphate modification of drugs is a common chemical strategy to increase solubility and allow for parenteral administration. Unfortunately, phosphate modifications often elicit treatment- or dose-limiting pruritus through an unknown mechanism. Using unbiased high-throughput drug screens, we identified the Mas-related G protein-coupled receptor X4 (MRGPRX4), a primate-specific, sensory neuron receptor previously implicated in itch, as a potential target for phosphate-modified compounds. Using both Gq-mediated calcium mobilization and G protein-independent GPCR assays, we found that phosphate-modified compounds potently activate MRGPRX4. Furthermore, a humanized mouse model expressing MRGPRX4 in sensory neurons exhibited robust phosphomonoester prodrug-evoked itch. To characterize and confirm this interaction, we further determined the structure of MRGPRX4 in complex with a phosphate-modified drug through single-particle cryo-electron microscopy (cryo-EM) and identified critical amino acid residues responsible for the binding of the phosphate group. Together, these findings explain how phosphorylated drugs can elicit treatment-limiting itch and identify MRGPRX4 as a potential therapeutic target to suppress itch and to guide future drug design.

Successful use of tralokinumab for the treatment of atopic dermatitis on the genitals.

BACKGROUND: Genital involvement in atopic dermatitis(AD) can have a significant impact on the patient's quality of life. However, inspection of genital areas is not usually conducted during routine examination and patients may be reluctant to inform the clinician or show this area. OBJECTIVE: to evaluate the efficacy of tralokinumab in AD patients with genital involvement. METHODS: Adult patients with moderate/severe AD and genital involvement receiving tralokinumab have been analyzed. Primary endpoints were EASI, DLQI, PP-NRS, genital-IGA (g-IGA) and genital itching (GI) at week 16. RESULTS: out of 48 patients with moderate/severe AD under treatment with tralokinumab, 12 patients (25%) showed a genital involvement. Seven patients reported itching in the genital area (58%), while none reported a positive history of genital infections. Median scores at T0 were EASI 17.5, PP-NRS 8 and DLQI 14. After 16 weeks of treatment, we observed a median EASI of 3, a median PP-NRS of 1 and a median DLQI of 1. Finally, concerning the genital response, after 16 weeks of treatment, we observed a statistically significant decrease in mean GI and g-IGA scores. CONCLUSION: despite the small size of our sample, tralokinumab can be considered as a valid treatment option for AD with genital involvement.

The relationship between fatigue, pruritus, and thirst distress with quality of life among patients receiving hemodialysis: a mediator model to test concept of treatment adherence.

Hemodialysis is a conservative treatment for end-stage renal disease. It has various complications which negatively affect quality of life (QOL). This study aimed to examine the relationship between fatigue, pruritus, and thirst distress (TD) with QOL of patients receiving hemodialysis, while also considering the mediating role of treatment adherence (TA). This cross-sectional study was carried out in 2023 on 411 patients receiving hemodialysis. Participants were consecutively recruited from several dialysis centers in Iran. Data were collected using a demographic information form, the Fatigue Assessment Scale, the Thirst Distress Scale, the Pruritus Severity Scale, the 12-Item Short Form Health Survey, and the modified version of the Greek Simplified Medication Adherence Questionnaire for Hemodialysis Patients. Covariance-based structural equation modeling was used for data analysis. The structural model and hypothesis testing results showed that all hypotheses were supported in this study. QOL had a significant inverse association with fatigue, pruritus, and TD and a significant positive association with TA. TA partially mediated the association of QOL with fatigue, pruritus, and TD, denoting that it helped counteract the negative association of these complications on QOL. This model explained 68.5% of the total variance of QOL. Fatigue, pruritus, and TD have a negative association with QOL among patients receiving hemodialysis, while TA reduces these negative associations. Therefore, TA is greatly important to manage the associations of these complications and improve patient outcomes. Healthcare providers need to assign high priority to TA improvement among these patients to reduce their fatigue, pruritus, and TD and improve their QOL. Further studies are necessary to determine the most effective strategies for improving TA and reducing the burden of complications in this patient population.

A phytosphingosine derivative mYG-II-6 inhibits histamine-mediated TRPV1 activation and MRGPRX2-dependent mast cell degranulation.

BACKGROUND: Phytosphingosine and its derivative are known for their skin-protective properties. While mYG-II-6, a phytosphingosine derivative, has shown anti-inflammatory and antipsoriatic effects, its potential antipruritic qualities have yet to be explored. This study aimed to investigate mYG-II-6's antipruritic properties. METHODS: The calcium imaging technique was employed to investigate the activity of ion channels and receptors. Mast cell degranulation was confirmed through the ß-hexosaminidase assay. Additionally, in silico molecular docking and an in vivo mouse scratching behavior test were utilized. RESULTS: Using HEK293T cells transfected with H1R and TRPV1, we examined the impact of mYG-II-6 on histamine-induced intracellular calcium rise, a key signal in itch-mediating sensory neurons. Pretreatment with mYG-II-6 significantly reduced histamine-induced calcium levels and inhibited TRPV1 activity, suggesting its role in blocking the calcium influx channel. Additionally, mYG-II-6 suppressed histamine-induced calcium increase in primary cultures of mouse dorsal root ganglia, indicating its potential antipruritic effect mediated by histamine. Interestingly, mYG-II-6 exhibited inhibitory effects on human MRGPRX2, a G protein-coupled receptor involved in IgE-independent mast cell degranulation. However, it did not inhibit mouse MrgprB2, the ortholog of human MRGPRX2. Molecular docking analysis revealed that mYG-II-6 selectively interacts with the binding pocket of MRGPRX2. Importantly, mYG-II-6 suppressed histamine-induced scratching behaviors in mice. CONCLUSIONS: Our findings show that mYG-II-6 can alleviate histamine-induced itch sensation through dual mechanisms. This underscores its potential as a versatile treatment for various pruritic conditions.

The regulation of the PD-1/PD-L1 pathway in imiquimod-induced chronic psoriasis itch and itch sensitization in mouse.

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.

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

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

Fire acupuncture for plaque psoriasis case series.

OBJECTIVE: To investigate the clinical efficacy of fire acupuncture (FA) on plaque psoriasis (PP), exploring its suitable syndrome types, in order to achieve better therapeutic effects, accelerate the possibility of psoriasis skin lesion recovery, and provide assistance for clinical treatment. METHODS: A total of 8 patients with PP aged between 18 and 60 years were recruited and treated with FA once a week, and the lesion area and severity index (PASI), visual analog scale and pruritus were measured before, 2, 4 and 8 weeks after treatment and at the follow-up period (week 12), respectively. Visual analog scale, and dermoscopy were used for assessment. RESULTS: All patients showed improvement in pruritus after 1 FA treatment, and lesions were reduced to varying degrees after 2 weeks. Except for patients 5 and 8, who only achieved effective results due to severe disease, all other patients with psoriasis achieved significant results at 8 weeks after treatment. CONCLUSION: FA can significantly control the development of lesions, reduce the symptoms of PP lesions and pruritus, and help prevent psoriasis recurrence.

Hyperdiluted Botulinum Toxin and Intense Pulsed Light Treatment: A Case Series to Illustrate a Novel Protocol for Hypertrophic Scar Reduction.

Hypertrophic scars can have significant and far-reaching effects on patients that range from itching to creating difficulty with mobility, all of which can negatively impact the individual's quality of life. A recent study showed that many patients with recent scars report pain, burning, pruritus, erythema, in combination with psychological difficulties that impact bodily movement, choice of clothing, and participation in leisure activities. Botulinum toxin Type A (BoNTA) and intense pulsed light (IPL) have shown promise in treating such scars. We propose a novel treatment protocol involving a 4-week intervention with hyperdiluted BoNTA injections and supplemental treatment with IPL for erythema, and a 6-month scar scale assessment and photographic documentation that occurs before and 6 months after treatment. We report four cases where using hyperdiluted BoNTA, either alone or in conjunction with IPL, substantially reduced scar size, improved overall scar appearance, and diminished erythema in areas on the face and the breasts. Although this report suggests that a schedule of alternating treatments with BoNTA and IPL may be beneficial in reducing scar size and enhancing appearance, further research is necessary to better understand the most effective dosages, the relationship between BoNTA and IPL, and the optimal management of scarring.