Plasma metabolomic profiling reveals a novel circulating biomarker signature in chronic pruritus of unknown origin.

Chronic pruritus of unknown origin (CPUO) is characterized by chronic itch for 6 weeks or greater without an identifiable primary cause. Studies are needed to investigate circulating blood biomarkers to elucidate disease pathogenesis. The objective of this study was to investigate changes in circulating blood metabolites in CPUO patients and to identify potential therapeutic targets. Our cross-sectional study collected plasma from 11 CPUO patients and 11 matched control patients for mass-spectrometry based metabolite data analysis. 15 metabolites differed significantly in the blood of CPUO patients compared to controls, including nine amino acids (isoleucine, L-tyrosine, threonine, DL-tryptophan, L-valine, methionine, glycine, lysine, and L-phenylalanine), four amino acid derivatives (creatinine, DL-carnitine, acetyl-L-carnitine, and indole-3-acrylic acid), and two aromatic and fatty acid derivatives (2-hydroxycinnamic acid and oleamide). These metabolites were also correlated with itch severity. Metabolic set enrichment analysis (MSEA) identified downregulation of several pathways in CPUO: phenylalanine, tyrosine, tryptophan biosynthesis; catecholamine biosynthesis; and glycine, serine, and threonine metabolism. Our study identified decreases in several circulating plasma metabolites in CPUO patients and downregulation of pathways related to catecholamine biosynthesis and tryptophan biosynthesis, providing insight into the pathogenesis of CPUO.

The effect of photobiomodulation on histamine and Mucuna pruriens-induced pruritus, hyperknesis and alloknesis in healthy volunteers: A double-blind, randomized, sham-controlled study.

BACKGROUND: Photobiomodulation, also referred to as Low-Level Light Therapy (LLLT), has emerged as a promising intervention for pruritus, a prevalent and often distressing symptom. OBJECTIVES: This study investigated the efficacy of low-level light therapy (LLLT) in alleviating pruritus, hyperknesis, and alloknesis induced by histamine and Mucuna pruriens. METHODS: In a double-blind, randomized, sham-controlled trial with a split-body design, healthy volunteers underwent 6 minutes of LLLT and sham treatments in separate upper back quadrants. The histamine model was applied to the upper quadrants, and Mucuna pruriens to the lower quadrants. Pruritus intensity, alloknesis, hyperknesis, flare area, and skin temperature were measured pre and post treatment. RESULTS: Seventeen individuals (eight females, nine males) participated in the study. In the histamine model, LLLT notably reduced itch intensity (difference = 13.9 (95% CI: 10.5 - 17.4), p = 0.001), alloknesis (difference = 0.80 (95% CI: 0.58-1.02), p = 0.001), and hyperknesis (difference = 0.48 (95% CI: 0.09-0.86), p = 0.01). Skin temperature changes were not significantly different between the two groups (difference = -2.0 (95% CI: -6.7-2.6), p = 0.37). For the Mucuna pruriens model, no significant differences were observed in any measures, including itch intensity (difference = 0.8 (95% CI: -2.3 - 3.8), p = 0.61) hyperknesis (difference = 0.08 (95% CI: -0.06-0.33), p = 0.16) and alloknesis (difference = 0. 0.09 (95% CI: -0.08-0.256), p = 0.27). CONCLUSIONS: LLLT effectively reduced histamine-induced pruritus, alloknesis, and hyperknesis; however, LLLT was ineffective against Mucuna pruriens-induced pruritus. Further investigations are required to determine LLLT's effectiveness of LLLT in various pruritus models.

A case report on acquired reactive perforating collagenosis.

INTRODUCTION: Acquired reactive perforating collagenosis (ARPC) is a rare perforating skin disease with unclear pathogenesis, often leading to misdiagnosis. Utilizing noninvasive skin microscopy improves diagnostic accuracy while reducing misdiagnosis rates. PATIENT CONCERNS: Given its association with systemic diseases, comprehensive examinations are crucial for early detection of related diseases such as tumors. Clinically, it still lacks standardized guidelines for the treatment. Clinical treatment is mostly based on symptomatic treatment. Oral administration of pregabalin capsules can significantly relieve itching symptoms, and narrow-wave ultraviolet irradiation can accelerate the recovery of skin lesions. DIAGNOSIS: Dermoscopy and skin biopsy was used to confirm this case was ARPC. INTERVENTIONS: Treatment was based on oral administration of 20 mg prednisone, 1 tablet of loratadine, 1 tablet of pregabalin in the morning and evening, and external application of halomethasone ointment. OUTCOMES: Itching symptoms were significantly relieved. CONCLUSION: This case report demonstrates that clinical dermoscopy can improve the diagnosis rate of ARPC, and pregabalin capsules can significantly relieve itching symptoms.

Sleep-loss related to itch in atopic dermatitis: assessing content validity and psychometric properties of a patient-reported sleep-loss rating scale.

BACKGROUND: Sleep loss is a key factor contributing to disease burden in people with atopic dermatitis (AD). Mitigating itch to improve sleep is an important outcome of AD treatment. This study explored the content validity and measurement properties of the Sleep-Loss Scale, a single-item rating scale for assessing itch interference with sleep in clinical trials of AD treatments. METHODS: Concept elicitation and cognitive debriefing interviews were conducted with 21 adults and adolescents (12-17 years of age) with moderate-to-severe AD to develop a conceptual model of patient experience in AD and explore the content validity of the scale. Data collected from adults with moderate-to-severe AD enrolled in a phase 2b study (NCT03443024) were used to assess Sleep-Loss Scale's psychometric performance, including reliability, construct validity, and ability to detect change. Meaningful within-patient change (MWPC) thresholds were also determined using anchor-based methods. RESULTS: Qualitative findings from concept elicitation highlighted the importance of sleep-loss related to itch in AD. Debriefing analysis of the Sleep-Loss Scale indicated that the scale was relevant, appropriate, and interpreted as intended. Trial data supported good reliability, construct validity and ability to detect improvement. MWPC was defined as a 1-point improvement using trial data, a finding supported by qualitative data. CONCLUSIONS: The Sleep-Loss Scale provides a valid and reliable patient-reported measure of the impact of itch on sleep in patients with AD, and can detect change, indicating it is fit-for-purpose to evaluate the efficacy of AD treatments in moderate-to-severe patients.

The involvement of keratinocytes in pruritus of chronic inflammatory dermatosis.

Frequent itching and incessant scratching are commonly observed in various chronic inflammatory skin conditions, including atopic dermatitis and psoriasis. The persistent and prolonged nature of pruritus can worsen one's quality of life. Keratinocytes (KCs), the predominant cells of the epidermis, have been confirmed to interact with sensory neurons and immune cells and be involved in chronic skin inflammatory diseases associated with pruritus. Initially, KCs and sensory neurons form a unique synapse-like connection within the epidermis, serving as the structural foundation for their interaction. Additionally, several receptors, including toll-like receptors and protease-activated receptor 2, expressed on KCs, become activated in an inflammatory milieu. On the one hand, activated KCs are sources of pro-inflammatory cytokines and neurotrophic factors, such as adenosine triphosphate, thymic stromal lymphopoietin, and nerve growth factor, which directly or indirectly participate in stimulating sensory neurons, thereby contributing to the itch sensations. On the other hand, KCs also function as primary transducers alongside intraepidermal nerve endings, directly initiating pruritic responses. This review summarizes the current literature and highlights the critical role of KCs in the development and persistence of chronic itch in inflammatory skin disorders.

Treatment of patients with evidence of mast cell-mediated itch in the absence of hives with omalizumab.

PURPOSE: The presence of wheals or hives has been viewed as a hallmark symptom of urticaria, a highly debilitating disease. This study explores our experience with omalizumab in patients with apparent mast-cell mediated pruritus in the absence of hives. MATERIALS AND METHODS: This is a retrospective case series examining all patients with mast cell-mediated pruritus in the absence of hives from April 2022 to May 2024 at a tertiary referral clinic at Icahn School of Medicine at Mount Sinai in New York. Peak pruritus-numerical rating scale (PP-NRS) itch score changes over time were recorded and analyzed. RESULTS: Six patients (67% women; mean [SD] age, 47.67 [13.52] years) were included in the analysis. The median [IQR] pruritus PP-NRS itch score before omalizumab injection was 9 [6 - 10] and the final median [IQR] PP-NRS itch score was 2.5 [0 - 5]. The mean [SD] reduction in the PP-NRS itch score was 6 [3.16]. CONCLUSIONS: This study suggests that patients with evidence of mast cell-mediated pruritus can be identified based on clinical features and may benefit from omalizumab therapy.

The Severity, Quality of Life, and Correlated Factors of Chronic Kidney Disease-associated Pruritus between Hemodialysis and Kidney Transplant Patients: A Cross-sectional Study.

BACKGROUND: Chronic kidney disease-associated pruritus (CKD-aP) mainly occurs in hemodialysis (HD) patients and could persist in kidney transplant (KT) recipients. This study aims to compare the severity, correlation of various biochemical factors, and quality of life (QoL) concerning pruritus in CKD. METHODS: A cross-sectional study was conducted on HD and KT recipients with chronic pruritus, where the 5-Dimensional (5-D) Itch Scale and Dermatology Life Quality Index (DLQI) were used to evaluate pruritus severity and QoL. Results: Among the 60 subjects, 76.7% of HD patients had moderate-to-severe pruritus, whereas in the KT group, 83.3% experienced mild pruritus (p < 0.001). The median DLQI score was 5 (3-6) and 3 (2-4), respectively (p < 0.001). There was a correlation between hs-CRP and the 5-D itch score in the HD group (r = 0.443; p < 0.05), whereas e-GFR was correlated with the 5-D itch score in the KT group (r = -0.424; p < 0.05). CONCLUSION: Moderate-to-severe pruritus was more common in HD patients. While pruritus in KT recipients had a mild effect on QoL, pruritus in the HD group had a mild-moderate impact on QoL. There was a correlation between hs-CRP and e-GFR and the severity of pruritus in HD and KT recipients, respectively.

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.

Mucocutaneous Manifestations in Patients with Dengue Fever: From the EPIDENGUE Cohort on Reunion Island.

Nearly 4 billion people live in a dengue risk area worldwide. The prevalence of dengue-related mucocutaneous manifestations and their association with severe dengue differ across studies. The aim of the study was to describe the characteristics of patients with dengue-related mucocutaneous manifestations and to investigate those were associated with severe dengue. A retrospective study was conducted in 2019 among patients with a positive RT-PCR for dengue at the University Hospital of Reunion, which has been experiencing a re-emergence of dengue since 2018. Of 847 patients with confirmed dengue, 283 (33.4%) developed mucocutaneous manifestations. Only manifestations of dehydration such as glossitis, dysgeusia, or conjunctivitis were associated with severe dengue, unlike pruritus and rash, in bivariate analysis but not in multivariate analysis. The rash and pruritus of dengue appear to be accompanied by a pronounced flu-like syndrome in younger people without comorbidity or severity, although careful examination of mucous membranes would better identify signs of dehydration and thus cases likely to worsen.

Systematic review on antipruritic therapies for patients with Epidermolysis bullosa.

INTRODUCTION: Itch is one of the most burdensome symptoms in epidermolysis bullosa (EB), indicating a hitherto unmet therapeutic need. This review leverages existing data on efficacy of itch treatment in EB to support sound decision making. METHODS: A systematic literature search was performed on 29 March 2022. Studies written later than 1991 and reporting outcomes in patients with EB treated for itch were considered. RESULTS: Of the 3,099 articles screened, 21 studies met eligibility criteria, comprising 353 patients (65.9%) diagnosed for recessive dystrophic EB. Only two studies (9.5%) evaluated itch as primary endpoint, of which solely one revealed a significant relief of self-reported itch upon topical skin care. In those studies assessing itch as secondary endpoint (19/21, 90.5%), only 36.8% studies (n = 7/19) revealed a statistically significant itch reduction of up to 42%. Methodological limitations (heterogeneity of outcomes, inconsistent data assessment) in addition to limited superiority over control were implicated to account for low treatment efficacy observed in most studies. CONCLUSION: Current data quality impairs comparative efficacy analyses of itch treatments in EB. Large scale randomized clinical trials and more personalized approaches applying validated measurement instruments for core outcomes are needed to substantiate evidence-based treatment approaches for EB-associated itch.

Treatment of Brachioradial Pruritus: A Tertiary Center Retrospective Analysis.

This retrospective study investigates the efficacy of 2 treatment regimens, pregabalin alone versus pregabalin combined with ketamine, amitriptyline, and lidocaine cream, in reducing itch in patients with brachioradial pruritus at a tertiary care center. Electronic medical records of 64 brachioradial pruritus patients seen at the University of Miami Itch Center were analyzed. A significant reduction in itch scores was seen with both treatments, with no significant difference between the groups. A small number of patients experienced adverse effects, including drowsiness and weight gain with pregabalin and skin irritation with ketamine, amitriptyline, and lidocaine cream. Ultimately, our findings underscore the potential of utilizing combined therapy for difficult-to-treat brachioradial pruritus cases and implementing individualized approaches for managing neuropathic pruritus. Further controlled clinical trials are needed to establish optimal treatment protocols.

Exploring symptom clusters in Chinese patients with peritoneal dialysis: a network analysis.

BACKGROUND: In recent years, the research on symptom management in peritoneal dialysis (PD) patients has shifted from a single symptom to symptom clusters and network analysis. This study collected and evaluated unpleasant symptoms in PD patients and explored groups of symptoms that may affect PD patients with a view to higher symptom management. METHODS: The symptoms of PD patients were measured using the modified Dialysis Symptom Index. The symptom network and node characteristics were assessed by network analysis, and symptom clusters were explored by factor analysis. RESULTS: In this study of 602 PD patients (mean age 47.8 ± 16.8 years, 47.34% male), most had less than 2 years of dialysis experience. Five symptom clusters were obtained from factor analysis, which were body symptom cluster, gastrointestinal symptom cluster, mood symptom cluster, sexual disorder symptom cluster, and skin-sleep symptom cluster. Itching and decreased interest in sex may be sentinel symptoms, and being tired or lack of energy and feeling anxious are core symptoms in PD patients. CONCLUSIONS: This study emphasizes the importance of recognizing symptom clusters in PD patients for better symptom management. Five clusters were identified, with key symptoms including itching, decreased interest in sex, fatigue, and anxiety. Early intervention focused on these symptom clusters in PD patients holds promise for alleviating the burden of symptoms.

Unmet Needs in Darier's Disease from a Patient's Perspective: Lessons Learnt from the German Registry.

The MDHHgermany registry was initiated to characterize the "real-life" situation of affected individuals with Darier's disease (DD; Morbus Darier, MD) and Hailey-Hailey disease (HH), including their treatment and healthcare. To gain deeper insights into medical care of patients with DD, various aspects such as demographics, subjective symptoms, patient satisfaction with medical care, past and current therapies were explored. Patients with diagnosed DD were included. Subjective symptoms such as itch, pain and burning sensation were assessed. Individual therapy goals were recorded and patients assessed previous/current therapies along with satisfaction of medical care and treatment. A total of 55 patients were recruited; 47 patients were eligible for the analysis. Pruritus was rated the most bothersome symptom. Some 42.6% had not received systemic treatment so far or systemic therapies were rated ineffective (32.6%). Most commonly oral retinoids were prescribed, followed by corticosteroids. Patient satisfaction with medical care and treatment proved to be mediocre. This "real-life" data show an alarming unmet need regarding patients' satisfaction with medical care and treatment, evidenced by the reported lack of disease control. Further studies and interventions are needed to improve the spectrum of available therapies. MDHHgermany provides a foundational platform for future clinical trials, epidemiological studies, and pathophysiological analyses.

ItchyQoL reveals differences in itch symptom experience in routine dermatologic care.

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

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.

Relationship between pruritus and sleep in participants with primary biliary cholangitis in the Phase 2b GLIMMER trial.

BACKGROUND: Cholestatic pruritus and fatigue are debilitating conditions associated with primary biliary cholangitis (PBC) and can significantly impact patients' quality of life. Pruritus in PBC often worsens at night and patients frequently report sleep disturbance, which contributes to cognitive symptoms and fatigue. Linerixibat is an ileal bile acid transporter inhibitor in clinical development for the treatment of pruritus associated with PBC and was recently assessed versus placebo in the Phase 2b GLIMMER trial. This post-hoc analysis assesses the relationship between pruritus severity and sleep disturbance in participants of GLIMMER regardless of treatment group. METHODS: GLIMMER (NCT02966834), a multicenter, double-blind, randomized, placebo-controlled trial, recruited 147 patients with PBC and moderate-to-severe pruritus. Following 4 weeks single-blind placebo, patients (randomized 3:1) received linerixibat or placebo for 12 weeks (to Week 16). Participants graded their itch (twice daily) and its interference with sleep (once daily) in an electronic diary using a 0-10 numerical rating scale (NRS). Weekly and monthly itch scores were calculated as the mean of the worst daily itch score over the respective time period. At study visits, participants completed the 5-D itch scale and the PBC-40 quality of life questionnaire, both of which contain an item specific to itch-related sleep disturbance. The impact of pruritus on sleep was assessed post hoc through correlations between the changes in NRS, 5-D itch, and PBC-40. RESULTS: Strong correlations were found between change from baseline in weekly itch and sleep NRS scores (r = 0.88 [95% confidence interval (CI): 0.83; 0.91]) at the end of treatment (Week 16), as well as in monthly itch and sleep NRS scores (r = 0.84 [95% CI: 0.80; 0.87]). Patients with improved weekly pruritus score severity category demonstrated reduced perceived sleep interference on average. Itch responders (≥2-point improvement in weekly itch score from baseline) displayed larger improvements in weekly sleep NRS score, 5-D itch, and PBC-40 sleep items, than itch non-responders (<2-point improvement). CONCLUSIONS: A strong correlation exists between changes in pruritus severity and sleep interference in patients with PBC; pruritus reduction could generate concomitant improvement in sleep.

Pruritic Horse: Approach to Allergic Skin Diseases in Horses.

Allergy to insects is the most common skin allergy in horses. Pruritus in affected patients can be extreme. Face, ears, mane, and tail area are commonly affected areas. Diagnosis of insect bite hypersensitivity (IBH) is clinical and is based on history, clinical signs, and response to repellents. Allergy tests are not to be used for diagnostic purposes. Currently, there is no specific treatment for IBH other than insect avoidance, treatment of secondary infections, and symptomatic relief of pruritus. Many allergic horses become also sensitized to pollens. For these patients, allergen specific immunotherapy is beneficial.