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Background: Chronic pruritus of unknown origin (CPUO) is a highly debilitating disease that lacks effective treatment. There have been case reports of effective use of Janus Kinase (JAK) inhibitors in CPUO, including a case treated with baricitinib, a selective JAK 1/2 inhibitor. Objectives: To evaluate if itch in a cohort of CPUO patients was effectively reduced after treatment with baricitinib. Patients and Methods: This is a retrospective case series examining all patients with CPUO who were treated with baricitinib from February 2022 to August 2023 at the National Skin Center, Singapore. Itch scores on a 0–10 numerical rating scale (NRS) at 0.5‐point intervals were recorded and analyzed over time. Results: Sixteen patients (56% women, mean age of 62.2 ± 19.7 years old) with CPUO were included in the analysis. Their mean [range] duration of chronic itch was 15.4 [1–50] years, and the mean follow‐up period of baricitinib treatment was 10.2 ± 6.7 months. The median [IQR] NRS itch score before and after baricitinib treatment were 8.5 [6.5–10.0] and 3.5 [1.25–5.0], respectively, with a mean reduction in the itch score of 4.9 ± 2.7 (p < 0.0001). All except one patient reported significant improvement in itch severity. There were no reports of symptomatic side effects, except for a drop in hemoglobin in a patient with thalassemia and a dry throat in another patient. There were five cases of mild elevation in creatine kinase levels, three of which normalized over time, and two cases of mild elevation in creatinine levels. Conclusion: This study suggests that baricitinib can effectively reduce pruritus in patients with CPUO and supports the conduct of randomized placebo‐controlled trials to better elucidate the efficacy of JAK inhibitors in management of CPUO. [ABSTRACT FROM AUTHOR]

B-type natriuretic peptide (BNP) is an itch-selective neuropeptide that was shown to play a role in both histaminergic and nonhistaminergic itch in mice. It was also shown that elevated serum BNP is linked to increased pruritus in nondiabetic hemodialysis patients. This study examined plasma BNP levels of 77 patients and N-terminal pro-BNP levels of 33 patients with differing types of chronic itch to see whether BNP and N-terminal pro-BNP levels can correlate with itch severity. Plasma BNP and N-terminal pro-BNP levels of all patients with itch correlated with itch numerical rating scale and in particular for patients with chronic pruritus of unknown origin. On the basis of this clinical observation, this study further showed that increasing pathophysiological levels of BNP in mice by intravenous or osmotic pump induced significant scratching. In addition, pharmacological and ablation strategies determined that BNP acts centrally by activating the natriuretic peptide receptor A in the dorsal horn of the spinal cord. These data support that BNP and N-terminal pro-BNP levels are associated with chronic itch and may be used in clinical setting., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Summary: Chronic pruritus is defined as prolonged itching symptoms associated with a variety of skin conditions. These pruritic conditions clinically manifest in a dermatitis phenotype and commonly are of allergic origin with hypersensitivities towards environmental allergens. Interleukin‐31 (IL‐31) is a common player in allergic pruritus across species. The objective of the study was evaluation of the clinical efficacy of a therapeutic vaccine targeting IL‐31 in horses with chronic pruritus of unknown origin (CPUO) and that could not be explained by insect bite hypersensitivity (IBH). This consecutive case series pilot study included client‐owned horses with a long history of CPUO. Four horses affected by year‐round CPUO were vaccinated with a vaccine consisting of equine IL‐31 (eIL‐31) covalently coupled to a virus‐like particle (VLP) derived from cucumber mosaic virus containing a tetanus toxoid universal T cell epitope (CuMVTT). Clinical signs and pruritic behaviour were documented by photography and owner questionnaire pre and post vaccination. In addition, in three CPUO horses, levels of IL‐31, thymic stromal lymphopoietin (TSLP) and monocyte chemoattractant protein 1 (MCP‐1) were quantified from skin punch biopsies. IL‐31, TSLP and MCP‐1 levels were upregulated in pruritic, alopecic skin lesions compared to healthy skin of the same horse. Clinical signs and pruritic behaviour improved in all four horses upon vaccination with eIL‐31‐CuMVTT vaccine. The vaccine was well tolerated without safety concerns throughout the study. The main limitations of this study are the absence control treated horses and allergy diagnostics. It was concluded that Anti‐IL‐31 therapy might be applied as an allergen‐independent treatment option for horses with CPUO overcoming the challenges of identifying the allergic trigger. [ABSTRACT FROM AUTHOR]

Chronic pruritus of unknown origin is established when no underlying origin for pruritus can be determined. This retrospective cohort study aimed to determine the clinical profile and disease-related burden of chronic pruritus of unknown origin. A total of 263 patients (female/male: 154/109, median age 55 years) were included. Moderate to severe itch intensities were recorded (median average itch: 5.5/10, n = 200; median worst itch: 7.5/10, n = 199). In most cases pruritus lasted longer than 1 year (77.6%), occurred daily (68.2%), occurred in attacks (72.8%), and was often accompanied by dysaesthesias, such as burning, tingling and stinging. Quality of life was moderately impaired, while 22.2% and 12.4% of patients showed pathological anxiety and depression scores. Scratch lesions were associated with higher intensities of itch and greater impairment of quality of life, while women were more burdened by the disease than men. Chronic pruritus of unknown origin may occur at any age and the majority of patients endure severe itch with substantial disease-related burden.

Chronic pruritus of unknown origin is established when no underlying origin for pruritus can be determined. This retrospective cohort study aimed to determine the clinical profile and disease-related burden of chronic pruritus of unknown origin. A total of 263 patients (female/male: 154/109, median age 55 years) were included. Moderate to severe itch intensities were recorded (median average itch: 5.5/10, n = 200; median worst itch: 7.5/10, n = 199). In most cases pruritus lasted longer than 1 year (77.6%), occurred daily (68.2%), occurred in attacks (72.8%), and was often accompanied by dysaesthesias, such as burning, tingling and stinging. Quality of life was moderately impaired, while 22.2% and 12.4% of patients showed pathological anxiety and depression scores. Scratch lesions were associated with higher intensities of itch and greater impairment of quality of life, while women were more burdened by the disease than men. Chronic pruritus of unknown origin may occur at any age and the majority of patients endure severe itch with substantial disease-related burden. [ABSTRACT FROM AUTHOR]

Background: Chronic pruritus is defined as itch lasting for greater than six weeks. Pruritus is a burdensome manifestation of several internal and external disease states with a significant impact on quality of life. Dupilumab has shown promise in treating a number of conditions including atopic dermatitis (AD) and asthma. Its success in reducing pruritus in AD has generated interest regarding its potential application in other pruritic conditions, such as chronic pruritus of unknown origin, uremic pruritus, and pruigo nodularis. Methods: In this retrospective analysis, we present a series of 20 recalcitrant pruritus patients seen at a tertiary center treated with off-label dupilumab at standard AD dosing. Results: Dupilumab was successful at reducing itch in all treated patients, leading to complete resolution in 12/20 patients and an overall mean NRSi reduction of 7.55. Dupilumab was well tolerated with no significant adverse effects. Conclusions: Our case series suggests dupilumab may be a safe and efficacious therapeutic option in several pruritic conditions and demonstrates the need for further studies to better ascertain its place in the pruritus treatment armamentarium.

Chronic pruritus, or itch, is common and debilitating, but the neuroimmune mechanisms that drive chronic itch are only starting to be elucidated. Recent studies demonstrate that the IL-33 receptor (IL-33R) is expressed by sensory neurons. However, whether sensory neuron–restricted activity of IL-33 is necessary for chronic itch remains poorly understood. We sought to determine if IL-33 signaling in sensory neurons is critical for the development of chronic itch in 2 divergent pruritic disease models. Plasma levels of IL-33 were assessed in patients with atopic dermatitis (AD) and chronic pruritus of unknown origin (CPUO). Mice were generated to conditionally delete IL-33R from sensory neurons. The contribution of neuronal IL-33R signaling to chronic itch development was tested in mouse models that recapitulate key pathologic features of AD and CPUO, respectively. IL-33 was elevated in both AD and CPUO as well as their respective mouse models. While neuron-restricted IL-33R signaling was dispensable for itch in AD-like disease, it was required for the development of dry skin itch in a mouse model that mirrors key aspects of CPUO pathology. These data highlight how IL-33 may be a predominant mediator of itch in certain contexts, depending on the tissue microenvironment. Further, this study provides insight into future therapeutic strategies targeting the IL-33 pathway for chronic itch. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Chronic pruritus is defined as itch lasting for greater than six weeks. Pruritus is a burdensome manifestation of several internal and external disease states with a significant impact on quality of life. Dupilumab has shown promise in treating a number of conditions including atopic dermatitis (AD) and asthma. Its success in reducing pruritus in AD has generated interest regarding its potential application in other pruritic conditions, such as chronic pruritus of unknown origin, uremic pruritus, and pruigo nodularis., Methods: In this retrospective analysis, we present a series of 20 recalcitrant pruritus patients seen at a tertiary center treated with off-label dupilumab at standard AD dosing., Results: Dupilumab was successful at reducing itch in all treated patients, leading to complete resolution in 12/20 patients and an overall mean NRSi reduction of 7.55. Dupilumab was well tolerated with no significant adverse effects., Conclusions: Our case series suggests dupilumab may be a safe and efficacious therapeutic option in several pruritic conditions and demonstrates the need for further studies to better ascertain its place in the pruritus treatment armamentarium., Competing Interests: Lisa L. Zhai, Kevin T. Savage, Connie C. Qiu, Annie Jin and Rodrigo Valdes-Rodriguez have no conflicts. Nicholas K. Mollanazar reports serving as an investigator in trials sponsored by Sanofi and Regeneron Pharmaceuticals. No other disclosures are reported.