Chronic Itch Affects Patients' Ability to Experience Pleasure: Anhedonia in Itchy Disorders.

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.

Interleukin Profiling in Atopic Dermatitis and Chronic Nodular Prurigo.

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.

Chronic Prurigo.

Chronic prurigo (CPG) is a neuroinflammatory dermatosis characterized by prolonged pruritus lasting more than 6 weeks, pruriginous skin lesions, and repeated scratching. Patients with CPG suffer significantly from psychological distress and a marked impairment in their quality of life. The most common subtype of CPG is chronic nodular prurigo (CNPG, also called prurigo nodularis). In addition to the clinical features of CPG and the burden of disease, this CME article provides an overview of the significant advances in understanding the pathophysiology, including the associated therapeutic options for CPG. Dupilumab is the first approved therapy for moderate and severe CNPG to date from the European Medicines Agency (EMA) and the US Food & Drug Administration (FDA). It also highlights other agents currently being studied in Phase II and Phase III clinical, randomized, placebo-controlled trials. These include biologics such as nemolizumab (anti-IL-31-RA-mAb), vixarelimab/KPL-716 (anti-Oncostatin-M receptor ß-mAb), and barzolvolimab/CDX-0159 (anti-KIT-mAb), as well as Janus kinase inhibitors such as povorcitinib/INCB054707 and abrocitinib, and opioid modulators such as nalbuphine.

Validation of a scoring algorithm for the clinician-reported outcome tool 'prurigo activity and severity (PAS)' based on clinical studies of dupilumab in adults with prurigo Nodularis.

BACKGROUND: Prurigo nodularis (PN) also known as chronic prurigo, is a chronic inflammatory skin disease characterized by intensely itchy nodules/lesions which occur due to intensive scratching. PN management is, in part, based on clinician evaluations of PN lesions, which can be supported by clinician-reported outcomes (ClinRO) such as the Prurigo Activity and Severity (PAS) instrument. A 5-item version of PAS was included in recent phase-3 dupilumab PN trials (PRIME [NCT04183335]/PRIME2 [NCT04202679]). The PAS score was derived using the unweighted sum of 3-items of the 5-item PAS (range, 0-11; higher score indicates worse activity and severity): Item 2 (number of lesions), Item 5a (percentage of lesions with excoriations/crusts) and Item 5b (percentage of healed lesions) for use in clinical practice and for communication of treatment benefit to physicians. OBJECTIVES: To evaluate the measurement properties of PAS score and derive within-patient (responder definition) and between-group improvement thresholds for interpreting changes in PAS score in patients with PN. METHODS: The data source was the pooled treatment group, intention-to-treat (ITT) data from the phase-3 PRIME (NCT04183335) and PRIME2 (NCT04202679) studies evaluating the efficacy of dupilumab in adult patients with PN with ≥20 nodules and severe itch uncontrolled with topical therapies. PAS score reliability, validity and sensitivity to change were evaluated, and anchor- and distribution-based methods were applied to derive meaningful change thresholds. RESULTS: The pooled ITT population included 311 patients (mean age 49.5 years, 65.3% female). Adequate to good psychometric properties were demonstrated for PAS score. The within-patient meaningful improvement threshold was estimated as 3.0 points (absolute change) and 37% (per cent change). A 1.7-point (absolute change) and 20% (per cent change) improvement were estimated to reflect a between-group meaningful change in PAS score. CONCLUSIONS: PAS score is a simple, clinically relevant indicator of PN lesion activity and severity supported by suitable psychometric performance.

Development and Validation of a Patient-Reported Outcome Measure to Assess Disease Control in Chronic Prurigo.

Importance: Chronic prurigo (CPG), including prurigo nodularis, is a difficult disease to treat and considerably affects patients' quality of life. Helping patients obtain control of CPG is a major treatment goal. Objective: To develop and validate the Prurigo Control Test (PCT), a tool for assessing disease control in CPG, and to identify a cutoff value for controlled disease to aid treatment decisions. Design, Setting, and Participants: This qualitative study followed the current recommendations for patient-reported outcome measure development in the generation and validation of the PCT. The final PCT was obtained after item generation, followed by reduction and selection, and was then tested for internal consistency and test-retest reliability, convergent validity, known-group validity, screening accuracy, and banding. The item-generation phase resulted in an unselected list of 69 potential PCT items. Impact analysis, interitem correlation, and review for content (face) validity resulted in final set of 5 PCT items. The validation study was performed among patients across 2 expert centers in Germany. Data were analyzed from February 2017 to November 2019. Main Outcomes and Measures: A 5-item PCT with a recall period of 2 weeks was developed. A cutoff value of 10 points or higher was determined as suitable for identifying patients with well-controlled vs poorly controlled CPG. Results: Of the 95 patients included in the validation study, the median (range) age was 63 (19-87) years, 50 patients (53%) were women, and the median (range) disease duration was 72 (9-774) months. The validation study yielded good internal consistency reliability (Cronbach α, 0.86) and a high degree of convergent validity. The PCT demonstrated good known-group validity and could discriminate between patients who differed in prurigo control. Test-retest reliability was high, and the intraclass correlation coefficient was 0.94, indicating excellent reproducibility. Conclusions and Relevance: This qualitative study showed that the PCT is able to assess disease control in patients with CPG. Its retrospective approach, brevity, and simple scoring likely make the PCT suitable for clinical practice and trials.

Chronic Prurigo Including Prurigo Nodularis: New Insights and Treatments.

Chronic prurigo (CPG) is a neuroinflammatory, fibrotic dermatosis that is defined by the presence of chronic pruritus (itch lasting longer than 6 weeks), scratch-associated pruriginous skin lesions and history of repeated scratching. Patients with CPG experience a significant psychological burden and a notable impairment in their quality of life. Chronic prurigo of nodular type (CNPG; synonym: prurigo nodularis) represents the most common subtype of CPG. As CNPG is representative for all CPG subtypes, we refer in this review to both CNPG and CPG. We provide an overview of the clinical characteristics and assessment of CPG, the burden of disease and the underlying pathophysiology including associated therapeutic targets. The information provided results from a PubMed search for the latest publications and a database search for current clinical trials (ClinicalTrials.gov, EU Clinical Trials Register [European Medicines Agency]; using the following terms or combinations of terms: 'chronic prurigo', 'prurigo', 'prurigo nodularis', 'pathophysiology', 'therapy', 'biologics', 'treatment'). Dupilumab is the first authorized systemic therapy by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) for CNPG to date. Topical and systemic agents that are currently under investigation in clinical randomized, placebo-controlled phase II and III trials such as biologics (e.g., nemolizumab, vixarelimab/KPL-716, barzolvolimab/CDX-0159), small molecules (ruxolitinib cream, povorcitinib/INCB054707, abrocitinib) and the opioid modulator nalbuphine are highlighted. In the last past 15 years, several milestones have been reached regarding the disease understanding of CPG such as first transcriptomic analysis, first terminology, first guideline, and first therapy approval in 2022, which contributed to improved medical care of affected patients. The broad range of identified targets, current case observations and initiated trials offers the possibility of more drug approvals in the near future.

Scratching increases epidermal neuronal branching and alters psychophysical testing responses in atopic dermatitis and brachioradial pruritus.

Background: Chronic scratching imposes a major stress on the skin and can lead to itch intensity worsening, and consequently, patients may enter an itch-scratch cycle. This repetitive mechanical stress can result in lichenification, worsening of epidermal barrier function, and enhanced cutaneous inflammation. Furthermore, a reduction of intraepidermal nerve fibers was previously described in lichenification. Aim: The aim of this study was to investigate the influence of chronic scratching on the epidermal neuroanatomy and on sensory changes, in particular the prevalence of hyperknesis and alloknesis in patients after mechanical, chemical, and electrical stimuli. Methods: Analyses were performed on pruritic lichenified (chronically scratched), pruritic non-lichenified (not chronically scratched), and non-pruritic non-lesional (unaffected) skin areas of patients with inflammatory pruritus, i.e., atopic dermatitis (n = 35), and neuropathic pruritus, i.e., brachioradial pruritus (n = 34) vs. healthy matched controls (n = 64). Our fine-grained spatial skin characterization enabled specifically studying the differential effects of chronic scratching in inflammatory and neuropathic itch. Results: Analysis of intraepidermal nerve fiber density showed rarefaction of fibers in all three skin areas of patients compared with healthy controls in both diagnoses. Even more, the two pruritic areas had significantly less nerve fibers than the unaffected skin, whereas electrically induced itch was massively increased. Epidermal branching of the remaining nerve fibers in lichenified/chronically scratched skin was increased, particularly in patients with brachioradial pruritus, which may contribute to the pronounced local neuronal sensitivity. Hyperknesis and alloknesis were found to increase independently of lichenification. Conclusion: Our results indicate that chronic scratching may not affect intraepidermal nerve fiber density but leads to a stronger branching pattern of intraepidermal nerve fibers, which may contribute to local hypersensitivity. The increased sensitivity in the pruritic areas suggests mechanisms of peripheral sensitization, whereas the increased sensation of electrically and chemically induced itch in unaffected skin indicates central sensitization for itch.

Perceived Stigmatization among Dermatological Outpatients Compared with Controls: An Observational Multicentre Study in 17 European Countries.

Perceived stigmatization places a large psychosocial burden on patients with some skin conditions. Little is known about the experience of stigmatization across a wide range of skin diseases. This observational cross-sectional study aimed to quantify perceived stigmatization and identify its predictors among patients with a broad spectrum of skin diseases across 17 European countries. Self-report questionnaires assessing perceived stigmatization and its potential predictors were completed by 5,487 dermatology outpatients and 2,808 skin-healthy controls. Dermatological diagnosis, severity, and comorbidity were clinician-assessed. Patients experienced higher levels of perceived stigmatization than controls (p < 0.001, d = 0.26); patients with psoriasis, atopic dermatitis, alopecia, and bullous disorders were particularly affected. Multivariate regression analyses showed that perceived stigmatization was related to sociodemographic (lower age, male sex, being single), general health-related (higher body mass index, lower overall health), disease-related (higher clinician-assessed disease severity, presence of itch, longer disease duration), and psychological (greater distress, presence of suicidal ideation, greater body dysmorphic concerns, lower appearance satisfaction) variables. To conclude, perceived stigmatization is common in patients with skin diseases. Factors have been identified that will help clinicians and policymakers to target vulnerable patient groups, offer adequate patient management, and to ultimately develop evidence-based interventions.

Clinical aspects and management of chronic itch.

Chronic pruritus (CP) (ie, itch that persists for more than 6 weeks) poses significant challenges to patients' health and quality of life. It is a common reason for visits to dermatologists and general practitioners and can be caused by a range of conditions, including systemic diseases such as chronic kidney disease or liver diseases, malignancies, neuropathic conditions, and dermatoses such as atopic dermatitis. CP often does not develop in parallel with the course of the disease and can become an entity of its own, which must be treated with antipruritic drugs, even if the underlying cause is already under therapy. Depending on the etiology of CP, different pathways in the pathogenesis have been analyzed recently, following which new treatments have been developed and tested in randomized controlled trials. This article discusses the recent results of these studies and highlights how best to manage health care for patients with CP.

[Naloxone as rescue therapy for acute, severe pruritus]. / Naloxon als Rescue-Therapie bei akutem, schwerstem Pruritus.

This article presents the case of a patient with massive pruritus sine materia. Naloxone was proven as quick and effective therapy which led to a complete reduction of itching.

Transcriptomic, Epigenomic, and Neuroanatomic Signatures Differ in Chronic Prurigo, Atopic Dermatitis, and Brachioradial Pruritus.

Scratching and scratch-induced injuries, including neuroanatomical alterations, are key characteristics of chronic pruritus entities of different origins. The aim of this study was to link gene expression (array hybridization, qPCR) with DNA methylation (array hybridization) and neuroanatomy (PGP9.5 staining) in chronic nodular prurigo (CNPG), atopic dermatitis (AD), brachioradial pruritus (BRP), and matched healthy controls. Specific signatures of gene expression and DNA methylation clearly discriminated pruritic lesional skin from nonpruritic skin in CNPG and from healthy skin of volunteers, respectively. Although intraepidermal nerve fiber density was indiscriminately reduced, the level of epidermal branching, assessed by a semiquantitative pattern analysis, differentiated the entities (CNPG > BRP > AD). Correspondingly, repellent SEMA3A showed the highest expression in AD, whereas axonal growth-promoting nerve GF was most prominent in CNPG and BRP. Overexpression of genes for nerve fiber regeneration (NELL2/NFKB/ARTN) was found in AD and CNPG but not in BRP. Our findings suggest that differential branching patterns rather than mere innervation density separate chronic itch conditions and reflect disease-specific local expression profiles. In pruritic dermatoses (AD and CNPG), nerve injury and subsequent sprouting may primarily result from chronic scratching, whereas genuine neuropathy is expected to underlie BRP.

Introduction of a Specific Dermatological Rehabilitation Programme for Patients with Chronic Pruritus: A Pilot Study.

Chronic pruritus is a common symptom, associated with several severe medical conditions, great psychological burden, and reduced quality of life. It also poses socio-economic challenges concerning patients' work loss and healthcare costs. In Germany, medical rehabilitation programmes represent an integral part of the medical care of patients with chronic inflammatory skin diseases. However, such programmes play only a rudimentary role in the treatment of other dermatological diseases, such as dermatological oncology, genetic skin diseases, and chronic pruritus. Therefore, a specific antipruritic dermatological rehabilitation programme was developed in cooperation between the Department of Dermatology of the Medical Rehabilitation Center Bad Bentheim and the Center for Chronic Pruritus of the University Hospital of Muenster, Germany. This prospective study compared short-term patient-reported outcomes (n = 121) at the beginning and end of the rehabilitation programme. The majority of subjects had chronic pruritus on primary diseased, inflamed skin. Significant improvements in pruritus intensity (p ≤ 0.001), quality of life (p ≤ 0.001), anxiety symptoms (p ≤ 0.001) and depression (p ≤ 0.001), as well as an overall patient-relevant benefit (Patient Benefit Index 2.6 ± 1.06) and treatment-related patients' satisfaction, were shown. This suggests that implementation of this standardized rehabilitation programme for treatment of patients with chronic pruritus was successful.

S2k guideline: Diagnosis and treatment of chronic pruritus.

Pruritus is a cross-disciplinary leading symptom of numerous diseases and represents an interdisciplinary diagnostic and therapeutic challenge. In contrast to acute pruritus, chronic pruritus (CP) is a symptom of various diseases that is usually difficult to treat. Scratching and the development of scratch-associated skin lesions can alter the original skin status. In the presence of an itch-scratch-cycle, even secondary diseases such as chronic prurigo can develop. Chronic pruritus leads to considerable subjective suffering of those affected, which can result in restrictions on the health-related quality of life such as sleep disturbances, anxiety, depressiveness, experience of stigmatization and/or social withdrawal up to clinically relevant psychic comorbidities. Medical care of patients should therefore include (a) interdisciplinary diagnosis and therapy of the triggering underlying disease, (b) therapy of the secondary symptoms of pruritus (dermatological therapy, sleep promotion, in the case of an accompanying or underlying psychological or psychosomatic disease an appropriate psychological-psychotherapeutic treatment) and (c) symptomatic antipruritic therapy. The aim of this interdisciplinary guideline is to define and standardize the therapeutic procedure as well as the interdisciplinary diagnosis of CP. This is the short version of the updated S2k-guideline for chronic pruritus. The long version can be found at www.awmf.org.