RESUMEN
In defying conventional views that dismissed itch as trivial, I persisted in studying basophils and ILC2s in human skin and atopic dermatitis. My research on JAK inhibitors for itch ultimately led to FDA-approved drugs. This is my story of disregarding categories and definitions-a story about an unconventional path in science that emphasizes innovation over conformity.
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Dermatitis Atópica , Modelos Animales de Enfermedad , Prurito , Humanos , Animales , Ratones , Dermatitis Atópica/patología , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/inmunología , Historia del Siglo XX , Historia del Siglo XXI , Basófilos/metabolismo , Inhibidores de las Cinasas Janus/uso terapéutico , Inhibidores de las Cinasas Janus/farmacología , Piel/patología , Piel/metabolismoRESUMEN
INTRODUCTION: Reports regarding the correlation and effect size of change of the full spectrum of quality of life and disease severity measures applied in-person to patients with atopic dermatitis are scarce. OBJECTIVES: To assess quality-of-life with 3 different instruments and to evaluate disease severity indices and to determine their correlation and effect size of change between two measurements. MATERIALS AND METHODS: Patient-level data were obtained through two in-person visits. Sociodemographic information and data related to disease distribution, severity (through the BSA, EASI, SCORAD, POEM, and itching scales), and the impact of atopic dermatitis on quality of life using the DLQI and Skindex-29, and EQ-5D, were assessed. The correlation between change in quality-of-life scores and disease severity scores in addition to the standardized effect size were also evaluated. RESULTS: Only 139 out of 212 patients completed the follow-up visit. BSA highly correlated with SCORAD and EASI, and the lowest correlation was found with POEM. The best correlation of pruritus VAS was found with sleep disturbance. The SCORAD score highly correlated with EASI, and the lowest correlation was found with POEM. The magnitude of the effect at initiation of the study vs follow-up was in average moderate to important. CONCLUSIONS: Patients with atopic dermatitis experience a substantial burden on quality of life. Disease activity correlates better with quality-of-life measurements when the disease is less severe after starting therapy. POEM and Skindex-29 seem to be optimal to determine disease severity and quality of life in adults with atopic dermatitis.
Introducción: La información publicada sobre la correlación entre la magnitud del efecto de todo el espectro de la calidad de vida y la gravedad de la enfermedad en pacientes con dermatitis atópica es escasa. Objetivos: Evaluar la calidad de vida con tres instrumentos diferentes y los índices de gravedad de la enfermedad en pacientes con dermatitis atópica para determinar su correlación y el tamaño del efecto del cambio. Materiales y métodos: Los datos de los pacientes se obtuvieron a partir de dos visitas. Se evaluó la información sociodemográfica y los datos relacionados con la distribución y la gravedad de la enfermedad (mediante de las escalas BSA, EASI, SCORAD, POEM, prurito) y el impacto de la dermatitis atópica en la calidad de vida utilizando el Dermatology Life Quality Index, Skindex-29 y EQ-5D. También se evaluó la correlación entre el cambio en las puntuaciones de calidad de vida y las de gravedad de la enfermedad, además del tamaño del efecto estandarizado. Resultados: Solo 139 de los 212 pacientes completaron la visita de seguimiento. El área de superficie corporal se correlacionó fuertemente con el SCORAD y el EASI, y la correlación más débil fue con el POEM. La mejor correlación del prurito medido con la escala visual análoga se halló con la alteración del sueño. El puntaje SCORAD se correlacionó altamente con el EASI mientras que la correlación más baja se encontró con el POEM. La magnitud del efecto al inicio del estudio respecto al seguimiento fue en promedio de moderada a importante. Conclusiones: Los pacientes con dermatitis atópica experimentan una carga sustancial en la calidad de vida. La actividad de la enfermedad se correlaciona mejor con las mediciones de calidad de vida cuando esta es menos grave, después de comenzar la terapia. Los índices POEM y Skindex-29 parecen ser óptimos para determinar la gravedad de la enfermedad y la calidad de vida en adultos con dermatitis atópica.
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Dermatitis Atópica , Calidad de Vida , Índice de Severidad de la Enfermedad , Humanos , Dermatitis Atópica/psicología , Adulto , Masculino , Femenino , Persona de Mediana Edad , Prurito/etiología , Adulto JovenRESUMEN
BACKGROUND: Progressive familial intrahepatic cholestasis is an autosomal recessive genetic disorder that manifests primarily with jaundice and pruritus and can progresses from persistent cholestasis to cirrhosis and late childhood liver failure. Classically, progressive familial intrahepatic cholestasis is classified into three subtypes: 1, 2, and 3 and results from a defect in a biliary protein responsible for bile formation and circulation in the liver. In the last decade and with the increased use of genetic testing, more types have been known. CASE PRESENTATION: A 6-month-old Afrocentric boy presented with progressive jaundice and pruritus that started since the age of 2 months. He was thoroughly investigated to be finally diagnosed as progressive familial intrahepatic cholestasis type 4. A low-fat diet, ursodeoxycholic acid, fat-soluble vitamins, and cholestyramine were started. He showed initial improvement then had refractory pruritus and impaired quality of life. He underwent surgical biliary diversion at the age of 1 year with marked improvement of manifestations. CONCLUSION: Owing to the increased technology of genetic testing, more clinical subtypes of progressive familial intrahepatic cholestasis were diagnosed other than the classical three types. Surgical management using biliary diversion could be beneficial and delays or may even obviate the need for liver transplantation.
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Colestasis Intrahepática , Prurito , Ácido Ursodesoxicólico , Humanos , Masculino , Colestasis Intrahepática/genética , Colestasis Intrahepática/diagnóstico , Prurito/etiología , Lactante , Ácido Ursodesoxicólico/uso terapéutico , Dieta con Restricción de Grasas , Ictericia/etiología , Resina de Colestiramina/uso terapéutico , Colagogos y Coleréticos/uso terapéutico , Vitaminas/uso terapéutico , Resultado del Tratamiento , Calidad de VidaRESUMEN
The experience of itch and its associated chronic conditions (i.e., atopic dermatitis) form a significant burden of disease. Knowledge of how the brain processes itch, that might occur uniquely for chronic itch populations, could be used to guide more effective psychotherapeutic interventions for these groups. To build the evidence base for such approaches, we conducted a series of coordinates-based fMRI analyses, to identify the shared neural mechanisms for itch across the published literature. Upon so doing, we identified a core "itch network" that spans the Basal Ganglia/Thalamus, Claustrum and Insula. Additionally, we found evidence that the Paracentral Lobule and Medial Frontal Gyrus, regions associated with cognitive control and response inhibition, deactivate during itch. Interestingly, a separate analysis for chronic itch populations identified significant recruitment of the Left Paracentral Lobule, potentially suggesting the recruitment of cognitive control mechanisms to resist the urge to scratch. We position these results in light of further integrative studies that could use neuroimaging alongside clinical studies, to explore how transdiagnostic psychological approaches-such as mindfulness and compassion training-might help to improve quality of life for individuals who experience chronic itch.
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Encéfalo , Imagen por Resonancia Magnética , Prurito , Prurito/psicología , Prurito/fisiopatología , Humanos , Encéfalo/fisiopatología , Encéfalo/diagnóstico por imagen , Mapeo Encefálico/métodos , Masculino , Femenino , Adulto , Dermatitis Atópica/psicología , Dermatitis Atópica/fisiopatología , Dermatitis Atópica/terapiaRESUMEN
To observe the efficacy of topical antipruritic spray (TAS) in the treatment of epidermal growth factor receptor (EGFR) tyrosine kinase-related rashes, and to evaluate its efficacy and safety. 120 malignant tumor patients with confirmed pathological diagnosis and rash after EGFR application were selected and randomly divided into an experimental group of 60 cases and a control group of 60 cases. The 2 groups were intervened with self-made antipruritic spray and erythromycin ointment for 14 consecutive days. To observe the changes in rash, itching degree, and quality of life index of skin diseases in both groups of patients before and after treatment. The decrease in the number of itching cases in the experimental group reached 53.84%, and after 7 weeks of intervention, the total effective rate of rash treatment in this group of patients (91.67%) was significantly better than that in the control group (36.67%); The symptoms of the dermatology life quality index (DLQI) scale in the experimental group patient table after intervention showed significant changes compared to before intervention. After statistical testing, there was a significant difference between the groups and outside the group (Râ <â 0.05). And the comprehensive effect of the experimental patients with external spray after 14 weeks of intervention reached 93.16%. The self-made antipruritic spray has significant effect on improving EGFR rash and itching, and there is no obvious adverse reaction.
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Receptores ErbB , Calidad de Vida , Humanos , Masculino , Femenino , Persona de Mediana Edad , Receptores ErbB/antagonistas & inhibidores , Anciano , Adulto , Antipruriginosos/administración & dosificación , Antipruriginosos/uso terapéutico , Prurito/tratamiento farmacológico , Prurito/etiología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Resultado del Tratamiento , Eritromicina/administración & dosificación , Eritromicina/uso terapéutico , Dermatitis/tratamiento farmacológico , Dermatitis/etiología , Administración Tópica , Administración CutáneaRESUMEN
Psossibility and appropriate timing of discontinuation of dupilumab for atopic dermatitis (AD) remain unclear. We explored the possibility of patients, who could maintain remission with topical therapy alone after withdrawing dupilumab in the real world. Furthermore, we identified their characteristics. All adult AD patients who initiated dupilumab from June 2018 to July 2022 and were treated with dupilumab for more than 3 months at our hospital were included in this study. The observation period was from June 2018 to July 2023. In 138 patients, 58 (42.0%) discontinued dupilumab at least once. Among them, 18 (13.0%) discontinued dupilumab but reinitiated dupilumab later due to exacerbation. Only seven patients (5.1%) could maintain remission with topical therapy alone after discontinuation of dupilumab, with characteristics of lower POEM, VAS of pruritus, serum levels of TARC and LDH, and neutrophil counts at baseline, and those of longer duration of dupilumab until its discontinuation (24.0 ± 13.3 vs. 12.8 ± 7.3 months) and lower EASI and affected BSA at the discontinuation of dupilumab. In 118 patients treated with dupilumab for at least 1 year, 38 patients (32.2%) discontinued at least once. Only four patients (3.4%) could maintain remission with topical therapy alone after discontinuation of dupilumab, with characteristics of lower POEM at baseline and lower EASI at the discontinuation of dupilumab. In conclusion, maintaining remission after withdrawing dupilumab is challenging. Discontinuation of dupilumab may be considered in patients with low baseline POEM, after more than 2 years of dupilumab treatment, with a substantial decrease in EASI.
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Anticuerpos Monoclonales Humanizados , Dermatitis Atópica , Humanos , Dermatitis Atópica/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Adulto , Femenino , Masculino , Persona de Mediana Edad , Inducción de Remisión , Japón , Estudios Retrospectivos , Privación de Tratamiento , Prurito/tratamiento farmacológico , Administración Cutánea , Adulto Joven , Administración Tópica , Índice de Severidad de la Enfermedad , Pueblos del Este de AsiaRESUMEN
OBJECTIVE: To compare oral pregabalin with oral sertraline for treatment of uraemic pruritus. STUDY DESIGN: Randomised controlled trial. Place and Duration of the Study: Department of Nephrology, Pak Emirates Military Hospital Rawalpindi, Pakistan, from October 2023 to January 2024. METHODOLOGY: Patients with end-stage renal disease having pruritus for at least 6 weeks were included. Exclusion criteria comprised other dermatological or systemic diseases associated with pruritus, mental health issues, thrice-a-week haemodialysis schedule, and use of other treatments for uraemic pruritus. They were randomised to receive either pregabalin 75mg daily or sertraline 50mg daily for six weeks using computer-generated sequences. The Urdu version of the 5-D Itch scale was used to document the severity of pruritus at the baseline and at the end of therapy. Side effects to the treatment were also monitored. RESULTS: There were 8 (16.67%) females and 40 (83.33%) males, with a mean age of 52.19 ± 12.19 years. The baseline 5-D Itch scale scores were equal in both groups. Mean improvement in 5-D Itch scale scores was 3.75 ± 1.26 and 2.08 ± 1.18 with pregabalin and sertraline, respectively (p <0.001). Side effects were reported by 2 (8.33%) patients on pregabalin and none using sertraline (p = 0.489). CONCLUSION: Pregabalin was found to be more effective than sertraline in treating uraemic pruritus, though with a statistically insignificant trend towards a higher frequency of side effects. KEY WORDS: Chronic renal failure, Pruritus, Renal dialysis, Selective serotonin reuptake inhibitors, Uraemia.
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Fallo Renal Crónico , Pregabalina , Prurito , Diálisis Renal , Sertralina , Uremia , Humanos , Sertralina/uso terapéutico , Sertralina/administración & dosificación , Pregabalina/uso terapéutico , Femenino , Prurito/tratamiento farmacológico , Prurito/etiología , Masculino , Persona de Mediana Edad , Fallo Renal Crónico/terapia , Fallo Renal Crónico/complicaciones , Adulto , Uremia/complicaciones , Uremia/terapia , Pakistán , Resultado del Tratamiento , AncianoRESUMEN
Notalgia paresthetica (NP) is a sensory neuropathy characterized by chronic pruritus, skin pain, and other pathologic sensations affecting the mid-to-upper back. NP may be under-recognized and under-diagnosed, with limited data available on its symptom presentation and treatment patterns. NP-DERM was an internet-based survey of dermatologists (n = 650) from 8 different countries on their perspectives on NP symptoms and current treatment practices. Dermatologists typically treated a median of 12 patients with NP per month. Dermatologists reported that itch (pruritus) was the most common symptom for their patients with NP, followed by hyperpigmentation and sensitive skin. The most burdensome NP symptom was pruritus, followed by burning or hot sensation, and painful or raw skin. The most prescribed treatments included non-medicated skin care, topical corticosteroids, oral antihistamines, medicated topicals, and gabapentin or pregabalin. Physicians reported low satisfaction with available treatments. The most common reason for physicians to discontinue patients' therapy was lack of response.
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Dermatólogos , Encuestas de Atención de la Salud , Pautas de la Práctica en Medicina , Prurito , Humanos , Prurito/tratamiento farmacológico , Prurito/diagnóstico , Prurito/terapia , Prurito/etiología , Pautas de la Práctica en Medicina/estadística & datos numéricos , Parestesia/diagnóstico , Femenino , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Carga SintomáticaRESUMEN
A 24-year-old male patient was seen with generalized itch and papules located at the hands. Staining of a papule with a purple medical skin marker, followed by wiping of the ink with an alcohol-gauze revealed an ink-filled burrow. These findings are consistent with a positive burrow ink test, and a clinical diagnosis of scabies was made.
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Prurito , Escabiosis , Humanos , Masculino , Escabiosis/diagnóstico , Escabiosis/tratamiento farmacológico , Escabiosis/patología , Prurito/etiología , Prurito/diagnóstico , Adulto Joven , AdultoRESUMEN
Atopic dermatitis (AD) is a chronic inflammatory skin condition that can be difficult to treat due to a complex etiology and diverse clinical presentations. Itch is the most common symptom associated with AD with profound negative impact on quality of life. Thus, the adjunctive management of itch in patients with AD is needed to control and reduce disease burden. Supplemental treatment options are continuously emerging and undergoing testing in clinical trials. This article summarizes the latest data on topical and systemic adjunctive therapies for AD safety and efficacy in reducing itch.
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Dermatitis Atópica , Prurito , Dermatitis Atópica/complicaciones , Humanos , Prurito/etiología , Prurito/terapia , Prurito/tratamiento farmacológico , Administración Cutánea , Fármacos Dermatológicos/uso terapéutico , Antipruriginosos/uso terapéutico , Terapia Combinada , Calidad de Vida , Emolientes/uso terapéuticoRESUMEN
The use of omega-3 fatty acids (omega-3 FA) in the treatment of atopic dermatitis (AD) is an area of ongoing research. Some studies suggest that dietary supplementation with omega-3 FA can help manage symptoms of AD by reducing lesion severity, skin inflammation, dryness and itching, while others show no significant beneficial effect. The aim of this study was to evaluate the effect of omega-3 FA from fish oil in combination with gamma-linolenic acid (GLA) from blackcurrant seed oil in children with AD. This is a longitudinal, prospective, randomized, triple blind, placebo-controlled parallel clinical trial. The study was conducted during the 2-year period throughout autumn, winter, and spring, avoiding the summer when AD usually improves. Children were randomized to receive the active study product (Mega Kid®) containing a specific blend of omega-3 and omega-6 fatty acids or placebo. The primary outcomes were changes in severity of AD measured using SCORing Atopic Dermatitis (SCORAD), patient-oriented SCORAD (PO-SCORAD) and the difference in topical corticosteroid (TCS) use. The secondary outcomes were changes in itch intensity, sleep quality and Family Dermatology Life Quality Index (FDLQI). Data were analyzed for 52 children (26 in the intervention group and 26 in the placebo group). In children receiving the active product, intention-to-treat analysis showed that after 4 months of treatment, there was a significant decrease in the SCORAD index (from median 42 to 25, p < 0.001) and the use of topical corticosteroids (from median 30 to 10 mg/month, p < 0.001), but also significant improvements in itch, sleep quality, and overall quality of life. Omega-3 fatty acids in combination with GLA and vitamin D may decrease symptoms and were associated with an improvement clinical picture of AD in children. Therefore, we can conclude that supplementation with this specific combination could be considered a safe and effective intervention that may significantly reduce the severity of AD in pediatric patients.
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Dermatitis Atópica , Suplementos Dietéticos , Ácidos Grasos Omega-3 , Calidad de Vida , Ácido gammalinolénico , Humanos , Dermatitis Atópica/tratamiento farmacológico , Femenino , Masculino , Ácidos Grasos Omega-3/administración & dosificación , Niño , Preescolar , Resultado del Tratamiento , Estudios Prospectivos , Ácido gammalinolénico/administración & dosificación , Ácido gammalinolénico/uso terapéutico , Índice de Severidad de la Enfermedad , Estudios Longitudinales , Prurito/tratamiento farmacológicoRESUMEN
Ursolic acid (UA), a pentacyclic triterpene, exhibits diverse pharmacological effects, including potential treatment for allergic diseases. It downregulates thymic stromal lymphopoietin (TSLP) and disrupts mast cell signaling pathways. However, the exact molecular mechanism by which UA interferes with mast cell action remains unclear. Therefore, the current study aimed to uncover molecular entities underlying the effect of UA on mast cells and its potential antipruritic effect, specifically investigating its modulation of key molecules such as TRPV4, PAR2, and MRGPRX2, which are involved in TSLP regulation and sensation. Calcium imaging experiments revealed that UA pretreatment significantly suppressed MRGPRX2 activation (and its mouse orthologue MrgprB2), a G protein-coupled receptor predominantly expressed in mast cells. Molecular docking predictions suggested potential interactions between UA and MRGPRX2/MrgprB2. UA pretreatment also reduced mast cell degranulation through MRGPRX2 and MrgprB2-dependent mechanisms. In a dry skin mouse model, UA administration decreased tryptase and TSLP production in the skin, and diminished TSLP response in the sensory neurons. While PAR2 and TRPV4 activation enhances TSLP production, UA did not inhibit their activity. Notably, UA attenuated compound 48/80-induced scratching behaviors in mice and suppressed spontaneous scratching in a dry skin model. The present study confirms the effective inhibition of UA on MRGPRX2/MrgprB2, leading to reduced mast cell degranulation and suppressed scratching behaviors. These findings highlight the potential of UA as an antipruritic agent for managing various allergy- or itch-related conditions.
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Degranulación de la Célula , Citocinas , Mastocitos , Receptores Acoplados a Proteínas G , Linfopoyetina del Estroma Tímico , Triterpenos , Ácido Ursólico , Animales , Mastocitos/efectos de los fármacos , Mastocitos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Degranulación de la Célula/efectos de los fármacos , Citocinas/metabolismo , Ratones , Triterpenos/farmacología , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/genética , Canales Catiónicos TRPV/metabolismo , Prurito/tratamiento farmacológico , Prurito/metabolismo , Simulación del Acoplamiento Molecular , Receptores de Neuropéptido/metabolismo , Masculino , Piel/efectos de los fármacos , Piel/metabolismoRESUMEN
Background: Notalgia paresthetica (NP) is a form of neuropathic itch characterized by recurrent itch in the mid back. Much about NP remains unclear, especially the patient experience.Objectives: The Neuropathic Itch Patient Survey (NIRVE) was a global, online survey conducted to better characterize the symptom burden of neuropathic itch from the patient perspective.Patients and methods: This report focuses on the symptom burden of the subpopulation of NIRVE participants with a self-reported diagnosis of NP (N = 91). Respondents reported visiting a median of 2 healthcare providers (HCPs) for their symptoms before receiving an accurate diagnosis of NP.Results: The most common cutaneous symptoms ever experienced were itch/pruritus, sensitive skin, painful or raw skin, numbness, and tingling. The symptoms reported by the most respondents as currently being experienced included itch/pruritus, numbness, painful or raw skin, tingling, and burning or hot sensation. Of patients currently experiencing symptoms, numbness and itch/pruritus were ranked as the most intense, followed by tingling, burning or hot sensation, and then painful or raw skin. Most patients consult multiple healthcare providers (HCPs) before receiving a diagnosis for their condition.Conclusion: Itch is overwhelmingly the most prevalent symptom of the condition, although half of patients also report experiencing sensitive skin, painful or raw skin, numbness, or tingling.
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Prurito , Humanos , Prurito/diagnóstico , Prurito/etiología , Femenino , Masculino , Persona de Mediana Edad , Adulto , Parestesia/diagnóstico , Parestesia/etiología , Anciano , Encuestas y Cuestionarios , Adulto Joven , Hipoestesia/diagnóstico , Hipoestesia/etiología , Autoinforme , PrevalenciaRESUMEN
The majority of somatosensory DRG neurons express GABAA receptors (GABAAR) and depolarise in response to its activation based on the high intracellular chloride concentration maintained by the Na-K-Cl cotransporter type 1 (NKCC1). The translation of this response to peripheral nerve terminals in people is so far unclear. We show here that GABA (EC50 = 16.67µM) acting via GABAAR produces an influx of extracellular calcium in approximately 20% (336/1720) of isolated mouse DRG neurons. In contrast, upon injection into forearm skin of healthy volunteers GABA (1mM, 100µl) did not induce any overt sensations nor a specific flare response and did not sensitize C-nociceptors to slow depolarizing electrical sinusoidal stimuli. Block of the inward chloride transporter NKCC1 by furosemide (1mg/100µl) did not reduce electrically evoked pain ratings nor did repetitive GABA stimulation in combination with an inhibited NKCC1 driven chloride replenishment by furosemide. Finally, we generated a sustained period of C-fiber firing by iontophoretically delivering codeine or histamine to induce tonic itch. Neither the intensity nor the duration of histamine or codeine itch was affected by prior injection of furosemide. We conclude that although GABA can evoke calcium transients in a proportion of isolated mouse DRG neurons, it does not induce or modify pain or itch ratings in healthy human skin even when chloride gradients are altered by inhibition of the sodium coupled NKCC1 transporter.
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Furosemida , Ganglios Espinales , Voluntarios Sanos , Hiperalgesia , Miembro 2 de la Familia de Transportadores de Soluto 12 , Ácido gamma-Aminobutírico , Humanos , Animales , Ratones , Ácido gamma-Aminobutírico/metabolismo , Masculino , Adulto , Furosemida/farmacología , Miembro 2 de la Familia de Transportadores de Soluto 12/metabolismo , Ganglios Espinales/metabolismo , Ganglios Espinales/efectos de los fármacos , Hiperalgesia/metabolismo , Hiperalgesia/inducido químicamente , Hiperalgesia/fisiopatología , Femenino , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Dolor Agudo/metabolismo , Dolor Agudo/fisiopatología , Calcio/metabolismo , Receptores de GABA-A/metabolismo , Prurito/inducido químicamente , Prurito/metabolismo , Prurito/fisiopatología , Adulto JovenRESUMEN
Chronic itch often clinically coexists with anxiety symptoms, creating a vicious cycle of itch-anxiety comorbidities that are difficult to treat. However, the neuronal circuit mechanisms underlying the comorbidity of anxiety in chronic itch remain elusive. Here, we report anxiety-like behaviors in mouse models of chronic itch and identify γ-aminobutyric acid-releasing (GABAergic) neurons in the lateral septum (LS) as the key player in chronic itch-induced anxiety. In addition, chronic itch is accompanied with enhanced activity and synaptic plasticity of excitatory projections from the thalamic nucleus reuniens (Re) onto LS GABAergic neurons. Selective chemogenetic inhibition of the Re â LS circuit notably alleviated chronic itch-induced anxiety, with no impact on anxiety induced by restraint stress. Last, GABAergic neurons in lateral hypothalamus (LH) receive monosynaptic inhibition from LS GABAergic neurons to mediate chronic itch-induced anxiety. These findings underscore the potential significance of the Re â LS â LH pathway in regulating anxiety-like comorbid symptoms associated with chronic itch.
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Ansiedad , Neuronas GABAérgicas , Área Hipotalámica Lateral , Prurito , Animales , Ratones , Neuronas GABAérgicas/metabolismo , Enfermedad Crónica , Modelos Animales de Enfermedad , Núcleos Talámicos de la Línea Media/metabolismo , Masculino , Conducta Animal , Vías Nerviosas , Plasticidad Neuronal , Núcleos SeptalesRESUMEN
Anhedonia, the reduced ability to experience pleasure, is a prevalent symptom in various psychiatric disorders, but has not been investigated in dermatological conditions, particularly those characterized by chronic itch. This study aimed to examine the prevalence and clinical correlates of anhedonia in patients with chronic itch. A cross-sectional study was conducted in 137 patients with chronic itch, classified according to the International Forum for the Study of Itch (IFSI) classification. Anhedonia was assessed using the Snaith-Hamilton Pleasure Scale (SHAPS) and Anticipatory and Consummatory Interpersonal Pleasure Scale (ACIPS). Itch severity, quality of life, and psychological distress were assessed using the Visual Analogue Scale (VAS), Verbal Rating Scale (VRS), ItchyQoL, and Hospital Anxiety and Depression Scale (HADS), respectively. The mean SHAPS score was 1.0 ± 1.7 points, and the mean ACIPS total score was 76.9 ± 16.2 points. In the study sample, 13.1% of patients were identified as anhedonic, with a higher prevalence observed in those with severe and very severe itch. Anhedonia was significantly correlated with itch severity (R = 0.2, p=0.02 for 24 h VASmean and SHAPS; R = 0.2, p = 0.01 for 24 h VASmax and SHAPS), anxiety symptoms (R = 0.3, p < 0.001 for SHAPS and HADS-anxiety), depression symptoms (R = 0.4, p < 0.001 for SHAPS and HADS-depression), and impairment in quality of life (R = 0.2, p = 0.014 for SHAPS and ItchyQoL). Anhedonia is a significant and prevalent aspect of psychological distress in patients with chronic itch. Addressing this symptom may not only improve patients' overall mental health but also enhance the effectiveness of treatments for chronic itch. Future research is needed to elucidate further the mechanisms underlying the relationship between anhedonia and chronic itch and to develop targeted interventions for this population.
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Anhedonia , Placer , Prurito , Calidad de Vida , Índice de Severidad de la Enfermedad , Humanos , Prurito/psicología , Prurito/diagnóstico , Prurito/epidemiología , Femenino , Masculino , Persona de Mediana Edad , Estudios Transversales , Enfermedad Crónica , Adulto , Anciano , Prevalencia , Distrés PsicológicoRESUMEN
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.
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Hidroxicloroquina , Ratones Noqueados , Prurito , Receptores del Ácido Lisofosfatídico , Animales , Receptores del Ácido Lisofosfatídico/metabolismo , Receptores del Ácido Lisofosfatídico/genética , Prurito/inducido químicamente , Prurito/metabolismo , Prurito/genética , Prurito/tratamiento farmacológico , Ratones , Hidroxicloroquina/farmacología , Ganglios Espinales/metabolismo , Ganglios Espinales/efectos de los fármacos , Masculino , Hidrolasas Diéster Fosfóricas/metabolismo , Hidrolasas Diéster Fosfóricas/genética , Lisofosfolípidos/metabolismo , Ratones Endogámicos C57BL , Transducción de Señal/efectos de los fármacosRESUMEN
The clinical manifestations of atopic dermatitis (AD) and chronic nodular prurigo (CNPG) include pruritus and eczema/lesions, posing significant challenges for patients. Th2 cells and ILC2, marked by cytokine production-particularly IL-4/13-are crucial therapeutic targets. Despite displaying a dose-dependent lack of pruritus induction post-injection, IL-13 acts through the IL-13Rα1 and IL-13Rα2 receptor system. Our study focused on investigating ex vivo skin biopsies in AD (n = 17), CNPG (n = 14) and healthy controls (HC; n = 10), examining the gene expression landscape of interleukins linked with pruritus (IL-13, IL-4, IL-31) and their corresponding receptors. Compared to HC, results revealed a significant upregulation of IL-4, IL-13, and IL-13RA1 in AD, whereas CNPG did not show increased IL13 expression. Notably, the decoy receptor IL-13RA2 displayed intriguing patterns, with AD showing a marked increase compared to both HC and CNPG. Positive correlations between receptor expression and itch intensity and hyperkinesis sensation underscore clinical relevance, potentially serving as biomarkers. The findings suggest a pivotal role of IL-4 and IL-13, along with IL-13RA1, in pruritus pathogenesis in both entities, while IL-13 upregulation in AD is countered by IL-13RA2. The comparable expression of IL-13RA2 to HC in CNPG suggests the absence of this regulatory mechanism, potentially worsening the disease and leading to prolonged scratching behavior. These insights illuminate the intricate interplay of interleukins and receptors in different pruritus phenotypes, laying the groundwork for understanding underlying mechanisms and offering avenues for therapeutic intervention.
Asunto(s)
Dermatitis Atópica , Interleucina-13 , Interleucinas , Prurigo , Prurito , Humanos , Dermatitis Atópica/metabolismo , Dermatitis Atópica/genética , Dermatitis Atópica/patología , Dermatitis Atópica/inmunología , Prurigo/metabolismo , Prurigo/patología , Prurigo/genética , Femenino , Adulto , Masculino , Interleucina-13/metabolismo , Interleucina-13/genética , Interleucinas/metabolismo , Interleucinas/genética , Prurito/metabolismo , Prurito/genética , Persona de Mediana Edad , Interleucina-4/metabolismo , Interleucina-4/genética , Enfermedad Crónica , Piel/metabolismo , Piel/patología , Adulto Joven , Subunidad alfa1 del Receptor de Interleucina-13/metabolismo , Subunidad alfa1 del Receptor de Interleucina-13/genética , Subunidad alfa2 del Receptor de Interleucina-13/metabolismo , Subunidad alfa2 del Receptor de Interleucina-13/genéticaRESUMEN
Itching is a prominent clinical manifestation of sensitive skin; it reduces cutaneous barrier function, mainly caused by dryness. Scratching to relieve itching destroys the skin barrier, thus forming the itch-scratch cycle that results in additional disruption of skin barrier and chronic itching. Treatment involves alleviation from itching for sensitive skin. Recently, substance P (11-amino acid neuropeptide of the tachykinin family) and neurokinin 1 receptor (NK1R) have been considered to provide a key pathway to treat chronic itching. A single-center, open-label study was conducted comprising subjects with dry, itchy, and sensitive skin to evaluate the efficacy of two types of itch-relief moisturizers, mist and lotion, containing maltotetraose (MTO). In all, 35 subjects used mist containing MTO, resulting in significant improvement in itch score from 1 minute to 2 hours following single application. On the other hand, 34 subjects applied lotion containing MTO for 1 week, resulting in significant improvement in itch score, skin hydration, and clinical scores of erythema/redness and dryness; however, in both cases, improve-ment was not observed in the measurement of transepidermal water loss (TEWL). It was concluded that two types of itch-relief moisturizers containing MTO were effective for dry, itchy, and sensitive skin.