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Background: Prurigo nodularis (PN) is a rare chronic inflammatory skin disease with a high disease burden, but data on clinical and economic burden are still scarce. Objective: To describe the real-world epidemiologic, clinical and therapeutic characteristics and related economic burden of patients with PN compared to a benchmark population in Germany. Methods: This retrospective study was based on an excerpt of German Statutory Health Insurance data of patients with an initial PN diagnosis between 2012 and 2016. PN cohort contained no record of PN in eight quarters before the index quarter and was followed up for eight quarters (unless deceased). Benchmark cohort without PN was calculated using direct standardization and 1:1 matching to PN cohort. Results: Out of 4,536,002 insured patients, 2309 incident patients with PN were identified and matched to the benchmark cohort out of 3,018,382 patients without PN. Patients were mostly between 45 and 80 years when diagnosed with PN. Higher comorbidity rates were reported for PN than benchmark, with a rising disease burden at follow-up. Most patients with PN (91.3%) were diagnosed outpatient and had >50% more outpatient visits than the benchmark cohort. Hospitalization rates were higher in PN (53.9%) versus benchmark (35.1%), yielding twice longer mean hospital stays for PN (12 days) compared to benchmark (6 days) (p < 0.001). The most common initial therapy for patients with PN was topical corticosteroids (47.6%); ≥10% of patients were treated with antidepressants, antihistamines or systemic corticosteroids. Therapy rates were higher for PN compared to benchmark (p < 0.001). Mean initial costs were twofold higher in PN versus benchmark for outpatient, inpatient and drugs. During follow-up, an increase of >70% in mean PN costs compared to benchmark was identified for outpatient, inpatient and concomitant treatments (p < 0.001). Conclusion: This study highlights the significantly higher clinical and economic burden incurred by PN compared to benchmark patients in Germany, reflecting the unmet medical need for PN. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic, relapsing immunoinflammatory skin condition characterized by sensations such as pruritis, pain, and neuronal hypersensitivity. The mechanisms underlying these sensations are multifactorial and involve complex crosstalk among several cutaneous components. This review explores the role these components play in the pathophysiology of atopic dermatitis. In the skin intercellular spaces, sensory nerves interact with keratinocytes and immune cells via myriad mediators and receptors. These interactions generate action potentials that transmit pruritis and pain signals from the peripheral nervous system to the brain. Keratinocytes, the most abundant cell type in the epidermis, are key effector cells, triggering crosstalk with immune cells and sensory neurons to elicit pruritis, pain, and inflammation. Filaggrin expression by keratinocytes is reduced in atopic dermatitis, causing a weakened skin barrier and elevated skin pH. Fibroblasts are the main cell type in the dermis and, in atopic dermatitis, appear to reduce keratinocyte differentiation, further weakening the skin barrier. Fibroblasts and mast cells promote inflammation while dermal dendritic cells appear to attenuate inflammation. Inflammatory cytokines and chemokines play a major role in AD pathogenesis. Type 2 immune responses typically generate pruritis, and the type 1 and type 3 responses generate pain. Type 2 responses and increased skin pH contribute to barrier dysfunction and promote dysbiosis of the skin microbiome, causing the proliferation of Staphyloccocus aureus. In conclusion, understanding the dynamic interactions between cutaneous components in AD could drive the development of therapies to improve the quality of life for patients with AD. [ABSTRACT FROM AUTHOR]

Introduction: Sleep is often disturbed in patients with prurigo nodularis (PN). To address the lack of validated patient-reported outcome (PRO) measures for quantifying sleep disturbance in PN, we evaluated the Sleep Disturbance Numerical Rating Scale (SD NRS) as a single-item PRO measure for quantifying sleep disturbance in PN. Methods: Adults with PN participated in qualitative interviews, which included concept elicitation and cognitive debriefing of the SD NRS. The SD NRS was evaluated psychometrically using data from a phase 2 randomized trial in adults with PN (NCT03181503). Other PRO assessments included the Average Pruritus (AP) NRS, AP Verbal Rating Scale (VRS), peak pruritus (PP) NRS, PP VRS, and Dermatology Life Quality Index (DLQI). Reliability, validity, and responsiveness of the SD NRS were evaluated, and meaningful within-patient change was estimated from qualitative interview responses and quantitative trial data. Results: All interview participants (N = 21) experienced sleep disturbance and most (95%) understood the SD NRS as intended. The SD NRS demonstrated test–retest reliability based on intra-class correlation coefficients for itch-stable participants of 0.87 for the AP VRS and 0.76 for the PP VRS. At baseline, Spearman's rank-order correlation coefficients were moderate to strong (0.3–0.8) between the SD NRS and the AP NRS, AP VRS, PP NRS, PP VRS, and DLQI. Known-groups validity was demonstrated by higher (worse) SD NRS scores in participants with worse scores on the AP NRS, AP VRS, PP VRS, and DLQI. Improvements in SD NRS scores were greater in participants classified as "improved" versus "worsened/unchanged" on the anchor PROs. A 2- to 4-point decrease on the 11-point SD NRS scale was identified as a meaningful within-patient change. Conclusion: The SD NRS is a well-defined, reliable, and valid PRO measure that can be used in daily practice and clinical trials to capture sleep disturbance in adults with PN. Plain Language Summary: Patients with the skin disease prurigo nodularis often sleep badly because their skin is very itchy in the evening and at night. In assessing the effectiveness of new treatments for prurigo nodularis, it is useful to know whether patients sleep better when taking them. Here, we tested whether the "Sleep Disturbance Numerical Rating Scale" (SD NRS), a tool for measuring sleep, can be used by patients with prurigo nodularis. The SD NRS asks patients to score their sleep loss during the previous night on a scale of 0 ("no sleep loss") to 10 ("I did not sleep at all"). When we interviewed 21 patients with prurigo nodularis, 19 of them had problems falling asleep and 18 of them woke up every night. Most of the patients found the SD NRS easy to use. To further explore whether the SD NRS is suitable for patients with prurigo nodularis, we also analyzed data from a European clinical study in which patients with prurigo nodularis received nemolizumab, a new treatment being developed for the disease. Patients completed the SD NRS each morning during the clinical study. We found that the SD NRS has the necessary properties to be useful for assessing sleep on a daily basis. We also determined that a 2- to 4-point decrease on the SD NRS scale would represent a meaningful improvement in sleep for patients with prurigo nodularis. We conclude that the SD NRS is a useful tool for assessing sleep in prurigo nodularis patients participating in clinical studies. [ABSTRACT FROM AUTHOR]

Background: Lebrikizumab improved itch, interference of itch on sleep, and quality of life (QoL) in patients with moderate-to-severe atopic dermatitis (AD), in two Phase 3 trials at 16weeks compared to placebo. Objectives: We assess improvements in itch and sleep interference due to itch and their impact on QoL measurements after treatment. Methods: Data were analyzed from ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967) in patients with moderate-to-severe AD. QoL was evaluated using Dermatology Life Quality Index (DLQI) at Week 16 in patients (>16years of age) who were itch responders/non-responders (defined as ≥4-point improvement in Pruritus Numeric Rating Scale) or Sleep-Loss Scale responders/non-responders (defined as ≥2-point improvement in itch interference on sleep). Results: In ADvocate1 and ADvocate2, significantly greater proportions of itch responders had a clinically meaningful improvement in measures related to QoL (DLQI scores (0/1), ≤5 DLQI total score and ≥4-point DLQI improvement) compared to itch non-responders. In both studies, a significantly greater proportion of Sleep-Loss Scale responders, reported a DLQI score of (0/1), DLQI total score of ≤5 and DLQI improvement of ≥4 points compared to Sleep-Loss Scale non-responders. Conclusions: Improvement in itch and sleep interference due to itch is associated with improvement in the QoL of patients after treatment with lebrikizumab for moderate-to-severe AD. ClinicalTrials.gov registration NCT04146363 (ADvocate1) and NCT04178967 (ADvocate2). [ABSTRACT FROM AUTHOR]

Chronic pruritus is a prevalent interdisciplinary symptom with a strong influence on health-related quality of life. Patients need extensive diagnostics and long-term treatment. This retrospective and prospective cohort study compared routine and universitybased specialized care in terms of cost-effectiveness and patient benefit. Direct medical and non-medical costs and patient-reported outcomes (PRO; pruritus intensity, quality of life, treatment needs and benefits) were assessed. Data analyses were conducted using descriptive methods and non-parametric statistical tests. A total of 300 adult patients (54.3% female) participated in the study. Six months after the treatment start in a specialized German pruritus care unit, the total costs were significantly reduced (mean total costs 686 € vs 433 € per patient per half year (total cohort); p< 0.001; mean out-ofpocket costs 198 € vs 124 € per half year (total cohort), p<  0.001). Pruritus intensity (numerical rating scale 5.3 vs 3.7, p<0.001), quality of life (Dermatology Life Quality Index 8.9 vs 5.7, p<0.001) and patient benefit (Patient Benefit Index Pruritus 1.2 vs 2.1, p<0.001) improved significantly (total cohort). The results of this study show, that treatment of chronic pruritus patients in a specialized itch centre leads to an improvement in patient benefit and reduces the economic burden at the same time. [ABSTRACT FROM AUTHOR]

Background: Abrocitinib, an oral Janus kinase 1 inhibitor, provided significant itch relief by week 2 in patients with moderate-to-severe atopic dermatitis (AD) in the phase III JADE COMPARE trial. Objectives: This post-hoc analysis of JADE COMPARE aimed to further characterize itch response and determined whether early itch relief could predict subsequent improvements in AD severity. Methods: JADE COMPARE was a randomized, double-blind, double-dummy, placebo-controlled trial. Adult patients (aged ≥ 18 years) with moderate-to-severe AD were randomly assigned to receive oral abrocitinib 200 mg or 100 mg once daily, subcutaneous dupilumab 300 mg every other week (after a 600-mg loading dose), or placebo, plus medicated topical therapy for 16 weeks. Assessments were ≥ 4-point improvement in Peak Pruritus Numerical Rating Scale (PP-NRS4) from days 2 to 15, Eczema Area and Severity Index (EASI), Investigator's Global Assessment (IGA) response, and Dermatology Life Quality Index (DLQI) scores at week 12. Association between week 2 PP-NRS4 and efficacy at week 12 was evaluated by chi-squared tests. The predictive value of early response for later efficacy was assessed by area under the receiver operating characteristic curve. Results: As early as day 4 after treatment, a significantly greater proportion of patients achieved PP-NRS4 response with abrocitinib 200 mg (18.6%) versus dupilumab (5.6%; p < 0.001) and placebo (6.0%; p < 0.003). A similar trend was observed with abrocitinib at the 100-mg dose, with significantly greater PP-NRS4 response rates versus placebo as early as day 9. With both doses of abrocitinib, week 12 IGA 0/1, EASI-75, EASI-90, and DLQI 0/1 response rates were greater in week 2 PP-NRS4 responders than nonresponders; no differences were observed between week 2 PP-NRS4 responders and nonresponders in the dupilumab and placebo groups. Early improvement in PP-NRS at week 2 was associated with skin clearance at week 12 in abrocitinib-treated patients. Conclusions: Abrocitinib resulted in rapid relief from itch in patients with moderate-to-severe AD, with significant improvement in itch as early as day 4 after treatment with abrocitinib 200 mg compared with dupilumab and placebo. Abrocitinib-induced itch relief by week 2 was associated with subsequent improvements at week 12. [Video abstract available.] Trial registration: ClinicalTrials.gov identifier: NCT03720470. 2fQ_82bhGurT9XTD9WAh-8 Early itch response with abrocitinib is associated with later efficacy outcomes in patients withmoderate-to-severe atopic dermatitis: subgroup analysis of the randomized phase III JADE COMPARE trial (MP4 335,375kb) Plain Language Summary: An investigation into whether quick relief from itch with abrocitinib, a new medicine for atopic dermatitis, leads to later improvements in skin rash Atopic dermatitis (AD), also called atopic eczema, is a skin disease that affects people throughout their lives. About 10% of adults worldwide have AD. Itch is the most bothersome symptom reported by people with AD and scratching this itch can damage the skin, resulting in painful sores. It is unknown if relief from itch can influence other symptoms of AD. We analyzed data from the JADE COMPARE study, which included 837 people who received treatment with abrocitinib, dupilumab or placebo. We studied how fast itch relief occurred after people received these treatments. We also wanted to study if rapid itch relief was associated with improvement in other signs of AD later on with continued treatment. We found that as early as 4 days after treatment, abrocitinib 200 mg provided significant relief from itch compared with dupilumab or placebo. People who had rapid itch relief within 2 weeks of treatment with abrocitinib were more likely to have clear or almost clear skin and improved quality of life after 12 weeks of continued treatment with abrocitinib. Rapid itch relief did not appear to increase the likelihood of clear skin at week 12 in people who received dupilumab. Larger studies are needed to confirm this result. This study provides important evidence for physicians as they analyze itch relief and determine treatment options for people with AD. [ABSTRACT FROM AUTHOR]

Background Skin pain is a common and burdensome symptom of atopic dermatitis (AD), and its severity increases with disease progression. The Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) is a validated 11-item patient-reported instrument developed in accordance with regulatory agency guidance for assessment of the daily symptoms of patients with AD, including skin pain. Objective To establish content validity and evaluate the psychometric properties of the skin pain numerical rating scale (NRS) item of the PSAAD. Methods: The skin pain NRS is a single-item measure from the PSAAD and is used to assess skin pain severity over the past 24 hours with the question "How painful was your skin over the past 24 hours?" on a 10-point scale from 0 (not painful) to 10 (extremely painful). A qualitative validation analysis consisting of concept elicitation (CE) interviews; electronic completion of the PSAAD measure, including the skin pain NRS; and cognitive debriefing (CD) interviews was conducted for adults and adolescents with mild-to-severe AD. Evaluation of psychometric properties of the skin pain NRS--including test-retest reliability, estimation of meaningful within-patient change (MWPC), known-group validity, ability to detect change, construct validity, quality of completion, and ceiling and floor effects--was conducted based on a post hoc qualitative and quantitative analysis of pooled data, with skin pain NRS as part of the PSAAD in the abrocitinib monotherapy phase 3 trials JADE MONO-1 (NCT03349060) and JADE MONO-2 (NCT03575871). Data from patients (≥12 years of age) with moderate-to-severe AD were pooled across all treatment arms. Results: Among 30 CE interviews (adolescents [12-17 years], n=15; adults [≥18 years], n=15) conducted over 2 rounds of testing, 20 of 30 (67%) patients reported skin pain. During CD interviews (n=30), 100% of patients interpreted the skin pain NRS item as intended, and 73% reported it as relevant. The psychometric validation analysis included 736 patients (JADE MONO-1, N=347; JADE MONO-2, N=389). The test-retest reliability of the skin pain NRS was evidenced by large intraclass correlation coefficients (ICC; 0.76 and 0.72 in JADE MONO-1 and MONO-2, respectively) for a single daily skin pain score, which increased to 0.93 and 0.91 for a measurement averaging at least 4 scores per week. Convergent validity was demonstrated by correlations between skin pain and other clinician- and patient-reported AD measures (median correlation >0.4 starting at week 4). The skin pain NRS distinguished between "clear" and "severe" disease severity groups, assessed using the Patient Global Assessment (PtGA) and Investigator's Global Assessment (IGA) as continuous and categorical anchors (P<0.0001); differences were also significant among other disease severity groups using the PtGA and IGA as continuous anchors (P<0.0001). Based on the PtGA and IGA anchor analysis, the estimated MWPC was 1.9 and ranged from 2.7 to 3.9 points using the empirical cumulative distribution function analysis. Ability to detect change was demonstrated by linear relationships between disease severity measures and skin pain scores (correlation of ≥0.5 between the skin pain NRS and the PtGA). More than 90% of patients provided at least 4 daily skin pain scores each week. No floor or ceiling effects were observed. Conclusions: The qualitative and quantitative data from initial PSAAD development and psychometric evaluation of the skin pain NRS from the PSAAD support its content validity, reliability, construct validity, and ability to detect change. These findings corroborate the 4-point improvement in skin pain as the adequate and meaningful cut-off to define a skin pain responder in JADE MONO-1 and MONO-2. [ABSTRACT FROM AUTHOR]

Introduction Chronic pruritus is a characteristic of atopic dermatitis (AD), contributing to poor quality of life in patients. Alterations in neuroanatomy and neuroarchitecture associated with pruritus secondary to AD are not fully understood. Objectives: To explore the role of dupilumab treatment effect on epidermal neuroanatomy by quantifying intraepidermal nerve fiber density (IENFD). Method DIFFERENSTAD (NCT04823130) was an open-label, exploratory study that enrolled patients = 18 years old with moderate-to-severe AD, pruritus lasting > 6 weeks, and Worst Itch Numerical Rating Scale (WI-NRS) = 4, and matched healthy controls. Patients with AD received dupilumab 300 mg every 2 weeks for 16 weeks. Skin biopsies were obtained from patients' lesional skin at baseline and localization-matched skin at Week 17 (end of treatment, EoT) and from healthy controls. The primary endpoint, IENFD, was defined as number of nerve fibers crossing the basement membrane per millimeter. Results: 31 patients with moderate-to-severe AD and 10 matched controls were enrolled. IENFD in patients with AD significantly increased from baseline to EoT (mean [SE]: 7.7 [1.3] at baseline vs 12.1 [2.0] at EoT for patients with AD; P = 0.0017), to levels comparable with the control group (mean [SE]: 12.4 [2.3]; P for control group vs EoT in patients with AD = 0.9374). Mean (SE) Eczema Area and Severity Index (EASI) total score and WI-NRS in dupilumab-treated patients were 22.5 (1.5) and 8.5 (0.3) at baseline, and 5.1 (1.1) and 3.1 (0.5) at EoT (both change from baseline P < 0.0001), respectively. The safety profile was consistent with the known safety profile for dupilumab. Conclusions: Dupilumab treatment significantly increased IENFD to levels similar to those of healthy subjects, suggesting restored neuroanatomy in patients with moderate-to-severe AD. Dupilumab also significantly improved clinical signs and pruritus symptoms of AD. [ABSTRACT FROM AUTHOR]

Introduction: Pruritus has been shown to be a common and burdensome complaint in the general population. In some diseases, there is an even higher rate and intensity of pruritus such as in chronic kidney diseases. In particular, patients requiring dialysis commonly suffer from pruritus with proportions between 22.0 and 90.0%. Few data on the characteristics and burden of such pruritus have been published. Therefore, the aim of this study was to investigate the extent and profiles of pruritus in such patients related to skin lesions and care. Methods: A non-interventional cross-sectional study in 14 centres for haemodialysis across Germany was conducted. The survey explored the prevalence, severity, and resulting burden of pruritus and skin lesions. Results: In total, 302 patients with uraemia (56.5% male, mean age 66.0 ± 14.4 years, mean duration of dialysis 3.9 ± 4.8 years) were included. Skin lesions appeared since start of dialysis in 50.0% of patients, with xerosis (94.7%) and desquamation (25.8%) being the most frequent and disturbing findings. Pruritus was reported by 60.9% of patients undergoing dialysis with a current mean numerical rating scale of 5.1 ± 2.4 occurring most frequently in the back, legs, and arms. About 89.0% of patients with xerosis and 69.0% with desquamation reported self-medication. However, only 40.0% and 28.0% sought medical help, respectively, indicating a remarkable lack of healthcare. Discussion: The current data suggest a more intensive focus on the skin symptoms and signs related to uraemia in the patients with dialysis and thus underline claims from a previous German large-scale study. Recommendations for early treatment and prevention of skin lesions in dialysis patients should be developed. Further research should be conducted focusing on recognizing subgroups of patients of particular vulnerability to pruritus and skin lesions, which may facilitate identifying patients at risk in an early moment. Moreover, a more specific tool for screening of skin lesions as well as pruritus may be useful since the existing instruments lack such specificity. [ABSTRACT FROM AUTHOR]

Background Objectives Methods Results Conclusions Prurigo nodularis (PN) is an intensely pruritic disease characterized by itchy nodules on the trunk/extremities; it is often accompanied by skin pain and sleep disruption with negative impacts on the quality of life (QoL). The patient‐reported outcome (PRO) instruments, Worst Itch‐Numeric Rating Scale (WI‐NRS), Skin Pain‐NRS, Sleep‐NRS and Dermatology Life Quality Index (DLQI) have been psychometrically validated and the clinically meaningful within‐patient improvement thresholds (responder definition) have been established through data pooled from the two Phase‐3 trials (PRIME, NCT04183335 and PRIME2, NCT04202679) of dupilumab in adults with PN uncontrolled on topical therapies.To estimate the proportion of dupilumab‐treated patients (vs. placebo) achieving clinically meaningful improvement in itch, skin pain, sleep and QoL, either alone or in combination, from the data pooled from PRIME and PRIME2 trials.The patient‐level data pooled from the two Phase‐3 trials (N = 311) were used for this post hoc analysis. Thresholds of clinically meaningful within‐patient improvement in PRO instrument scores from baseline at Week 24 used for defining responders were 4 (WI‐NRS and Skin Pain‐NRS), 2 (Sleep‐NRS) and 9 points (DLQI). The proportion of dupilumab‐treated patients, versus placebo, achieving the thresholds, and the time taken to achieve the thresholds were evaluated for the individual and combination of PROs.Responder rates were significantly higher with dupilumab, versus placebo at Week 24 for WI‐NRS (58.8% vs. 19.0%, p < 0.0001), Skin Pain‐NRS (49.7% vs. 20.9%, p < 0.0001), Sleep‐NRS (42.5% vs. 23.4%, p < 0.0001) and DLQI (64.7% vs. 22.8%, p < 0.0001). Proportion of patients achieving simultaneous improvement in symptoms and QoL (24.8% vs. 6.3%, p < 0.0001) were significantly higher in dupilumab‐treated patients versus placebo. The time needed for achieving clinically meaningful improvement in symptoms were significantly lower in dupilumab‐treated patients, versus placebo.Significantly greater proportion of dupilumab‐treated patients with PN, versus placebo, demonstrated clinically meaningful improvements in PRO measures of symptoms and QoL. [ABSTRACT FROM AUTHOR]

The article focuses on oral Janus kinase 1 GAK1) inhibitor abrocitinib, which reduces interleukin-4 and interleukin-13 signaling, is being investigated for the treatment of atopic dermatitis and the data from trials comparing JAK1 inhibitors with monoclonal antibodies, such as dupilumab, that block interleukin-4 receptors are limited. Topics include the abrocitinib dose differed significantly from dupilumab with respect to most other key secondary end-point comparisons at week 16.

Prurigo nodularis is an itchy skin disease with unknown epidemiology. This study aimed to describe the epidemiology of prurigo nodularis compared with that of psoriasis. The German sickness fund claims database, with 2,783,175 continuously insured patients, included 1,720 patients diagnosed with prurigo nodularis and 51,390 with psoriasis. Patients with prurigo nodularis were averagely 8 years older than psoriasis patients and more often were women (p < 0.001). Annual incidence was a constant 0.02% in prurigo nodularis, and decreased steadily from 0.53 to 0.42% in psoriasis; cumulative incidence was 0.1% for prurigo nodularis and 1.9% for psoriasis. Prevalence was 0.1% for prurigo nodularis and 4.7% for psoriasis, with a one-year mortality of 5.4% for prurigo nodularis and 1.2% for psoriasis (p < 0.001). The most frequent preexisting comorbidities in patients with prurigo nodularis were inflammatory dermatoses and depression. This epidemiological study found a low prevalence of prurigo nodularis, manifesting different demographics and comorbidities compared with psoriasis. [ABSTRACT FROM AUTHOR]

Prurigo nodularis (PN) or chronic nodular prurigo is a debilitating, and severely pruritic neuroimmune skin disease, predominantly characterized by the presence of multiple pruriginous nodules symmetrically distributed in large areas of the trunk and extremities. Other pruriginous lesions such as papules, plaques and umbilicated lesions can also be present. Prurigo nodularis dramatically reduces quality of life among patients, including disruption of physical, emotional and psychosocial domains. Therapeutic goals are primarily to reduce pruritus and improve lesion healing. Interleukin-31 (IL-31) is a neuroimmune cytokine highly expressed in PN lesional skin that bridges the immune and nervous systems, functioning as a central mediator of main pathophysiological processes in PN. Prurigo nodularis has a unique immunophenotype, with recent studies revealing activation of Type-2-inflammation, and also induction of Th17 and Th22 pathways. Nemolizumab, an IL-31 receptor alpha antagonist, was shown to downregulate these pathways and was associated with significant improvements in pruritus and lesion healing in patients with PN in a phase-2-trial. Here, the authors report additional outcomes on excoriations and healing of pruriginous lesions from the OLYMPIA 2 phase-3-study after 16 weeks of treatment with nemolizumab. This study aims to assess the safety and efficacy of nemolizumab compared with placebo in ≥18-year-old patients with moderate-to-severe PN after a 16-week treatment period. OLYMPIA 2 (NCT04501679) was a phase 3, global, multicenter, double-blind study in adults with PN presenting ≥20 nodules, Investigator's Global Assessment (IGA) score ≥3 (range 0–4) and Peak Pruritus Numerical Rating Scale (PP-NRS) score ≥7.0 (range: 0–10). Patients were randomized (2 : 1) to receive nemolizumab (n = 183) or matching placebo (n = 91). Following an initial 60 mg loading dose, patients weighing <90 kg received 30 mg every 4 weeks (q4w) and those weighing ≥90 kg received 60 mg q4w, for a period of 16 weeks, during which, treatment with topical corticosteroids (TCS) or topical calcineurin inhibitors (TCI)was not allowed. The primary endpoints were proportion of patients with a ≥4-point improvement in weekly average PP-NRS and proportion of patients with IGA Success for nodule healing [score of 0 (clear) or 1 (almost clear) and a ≥2-grade improvement] at Week (W) 16. Key secondary endpoints included proportion of patients with ≥4-point improvement in PP-NRS at W4 and Sleep Disturbance NRS (SD-NRS) at W4 and W16. Other secondary endpoints included percentage of patients with pruriginous lesions with excoriations/crusts [Prurigo activity score (PAS) item 5a], healed pruriginous lesions (PAS item 5b) and <20 pruriginous lesions (PAS item 2) at each visit through W16. The baseline demographic and clinical characteristics were balanced between the groups. At W16, both primary endpoints, were met (P < 0.0001). A significantly higher proportion of patients in the nemolizumab-treated group vs. placebo-treated group achieved a ≥4-point improvement in weekly average PP-NRS score (56.3% vs. 20.9%) and IGA success (37.7% vs. 11.0%) at W16. The study also met all key secondary endpoints on pruritus and sleep disturbance (P < 0.0001). Among other secondary endpoints, a significantly higher proportion of patients in the nemolizumab-treated group vs. placebo-treated group achieved mild disease activity with ≤25% excoriations/crusts (PAS item 5a) (56.8% vs. 23.1%; P < 0.0001 at W16), >75% healed lesions (PAS item 5b) (55.2% vs. 16.5%; P < 0.0001 at W16) and <20 pruriginous lesions (PAS item 2) (54.6% vs. 22.0%; P < 0.0001 at W16) at each visit, from baseline through W16. Treatment-emergent adverse events (AEs) were reported in 61.2% of nemolizumab-treated patients and 52.7% of placebo-treated patients, while serious AEs were reported in 2.2% of nemolizumab-treated patients and 5.5% of placebo-treated patients. Nemolizumab monotherapy (without TCS or TCI) demonstrated a significant reduction of pruritus as well as excoriations and number of pruriginous lesions after 16 weeks of treatment in patients with moderate-to-severe PN. The safety profile was consistent with that previously observed. [ABSTRACT FROM AUTHOR]

Background: Prurigo nodularis is a chronic pruritic skin disease with multiple nodular skin lesions. Nemolizumab is a monoclonal antibody targeting the interleukin-31 receptor, which is involved in the pathogenesis of prurigo nodularis.Methods: We conducted a 12-week, randomized, double-blind, phase 2 trial of nemolizumab (at a dose of 0.5 mg per kilogram of body weight) administered subcutaneously at baseline, week 4, and week 8, as compared with placebo, in patients with moderate-to-severe prurigo nodularis and severe pruritus. Moderate-to-severe prurigo nodularis was defined as 20 or more nodules, and severe pruritus was defined as a mean score of at least 7 for the worst daily intensity of pruritus on the numerical rating scale (scores range from 0 [no itch] to 10 [worst itch imaginable]). The primary outcome was the percent change from baseline in the mean peak score for pruritus on the numerical rating scale at week 4. Secondary outcomes included additional measures of itching and disease severity. Safety assessments were performed through week 18.Results: A total of 70 patients were randomly assigned in a 1:1 ratio to receive nemolizumab (34 patients) or placebo (36). The initial pruritus score on the numerical rating scale was 8.4 in each group. At week 4, the peak pruritus score on the numerical rating scale was reduced from baseline by 4.5 points (change, -53.0%) in the nemolizumab group, as compared with a reduction of 1.7 points (change, -20.2%) in the placebo group (difference, -32.8 percentage points; 95% confidence interval, -46.8 to -18.8; P<0.001). Results for secondary outcomes were in the same direction as for the primary outcome. Nemolizumab was associated with gastrointestinal symptoms (abdominal pain and diarrhea) and musculoskeletal symptoms.Conclusions: Nemolizumab resulted in a greater reduction in pruritus and severity of skin lesions than placebo in patients with prurigo nodularis but was associated with adverse events. Larger and longer trials are needed to determine the durability and safety of nemolizumab for the treatment of prurigo nodularis. (Funded by Galderma; ClinicalTrials.gov number, NCT03181503.). [ABSTRACT FROM AUTHOR]

Chronic prurigo impairs quality of life and is immensely challenging to treat. Until recently, no clear definition or classification system was available for this disease. A European task force specialized in pruritus defined chronic prurigo as a distinct disease characterized by chronic pruritus, a lengthy scratching behaviour and the presence of pruriginous lesions. Papular, nodular, plaque, umbilicated and linear prurigo were identified as clinical subtypes according to the most prominent lesion type observed in the physical examination. Various clinical and pathophysiological aspects, which are common across the range of clinical manifestations of chronic prurigo, argue for chronic prurigo as a disease in its own right. Chronic prurigo should be clearly demarcated from other conditions such as so‐called acute or subacute prurigo forms as well as from psychogenic self‐inflicted skin lesions, since different diagnostic criteria apply for these diseases. This viewpoint essay provides a detailed definition and classification of chronic prurigo including its obligatory and associated diagnostic criteria and discusses chronic prurigo as a distinct disease as well as the demarcation to other relevant conditions. [ABSTRACT FROM AUTHOR]

Chronic pruritus (CP) is defined by itching lasting 6 weeks or more and is known to be both a highly prevalent and burdensome symptom of many pruritogenic diseases. Its status as a symptom has many implications mainly that the symptom should evolve and subside with the disease. However, according to the clinical experience, CP often does not parallel the disease course and requires an own management. It is speculated that neuronal sensitization processes take place, which lead to disconnection of the symptom from the underlying disease and establishment of an own course of pruritus. It is thus discussed that pruritus can be both a symptom of diseases and an entity by itself. Further studies are needed to learn more and improve our understanding of this condition. This article compares its role in pruritogenic diseases, encourages discussion on the topic and provides an overview of the proper questions to ask. [ABSTRACT FROM AUTHOR]

Chronic pruritus is a bothersome symptom in psoriasis vulgaris and can profoundly reduce quality of life (QoL). In this exploratory analysis of the PSORITUS study, the impact of pruritus on QoL in 130 subjects with moderate-to-severe psoriasis was assessed using the ItchyQoL questionnaire. The majority of patients (n = 127) had to scratch their itchy skin regularly, which led to painful skin and frustration (mean ± standard deviation; SD ItchyQoL scores; 4.50 ± 0.56; 3.80 ± 1.09 and 4.20 ± 0.87, respectively). Changes in either temperature or season led to worsening of itching in most of the patients (n = 126; mean ± SD ItchyQoL score; 3.80 ± 1.02). Many patients felt ashamed (n = 125) or embarrassed (n = 127) due to their itchy skin (mean ± SD ItchyQoL scores; 3.90 ± 1.26 and 3.40 ± 1.19, respectively). The results demonstrated the ItchyQoL questionnaire as a validated tool responsive to treatment for detailed insights into chronic pruritus in patients with psoriasis. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with itch, eczematous lesions and impaired quality of life (QoL). Although the frequency of skin pain in AD is often underestimated, it is associated with a substantial health burden, similar to itch and is known to contribute to sleep disruption and mood disturbance. Abrocitinib is an oral, once-daily, selective Janus kinase-1 inhibitor approved for the treatment of moderate-to-severe AD. In phase 3 clinical trials JADE MONO-1 (NCT03349060) and JADE MONO-2 (NCT03575871), abrocitinib demonstrated rapid relief from itch and skin pain, as well as meaningful improvements in QoL compared with placebo. The interrelationships between abrocitinib treatment and improvements in itch, skin pain and QoL have not yet been investigated. This mediation analysis aimed to characterize the effect of abrocitinib treatment via itch and skin pain on dermatology-specific QoL in patients with AD. Data from JADE MONO-1 and JADE MONO-2 were pooled in this analysis. Adult patients with moderate-to-severe AD received abrocitinib (200 or 100 mg) as monotherapy or placebo for 12 weeks. Three separate models were evaluated whereby QoL was assessed using the Dermatology Life Quality Index (DLQI) score, and itch and skin pain were assessed via the Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) items #1 (How itchy was your skin over the past 24 h?) and #2 (How painful was your skin over the past 24 h?), respectively. The cross-sectional mediation model (CSMM) was run separately at weeks 2, 4, 8 and 12 using all available data at each timepoint. The longitudinal mediation model (LMM), which does not assume independence among measurements of itch, skin pain and DLQI at each timepoint, estimated relationships using all available data from all weeks simultaneously. Based on the results of the CSMM and LMM, a pseudosteady-state model, in which the relationship among variables was assumed to be the same across timepoints, was applied. Effects with P<0.05 were considered statistically significant. In the CSMM, the indirect effect of abrocitinib on DLQI mediated via itch was considered approximately stable (24–30%) for the first 8 weeks before increasing at week 12 (42%), while the indirect effect mediated via skin pain was considered approximately stable from week 2 to week 12 (33–41%). In the LMM, the indirect effect of abrocitinib treatment on DLQI mediated via both itch and skin pain was considered approximately stable from week 2 to week 12 (17–26% and 42–48%, respectively). The cross-sectional and longitudinal models were generally consistent and indicated a pseudo-steady-state period between weeks 2 and 12. Using the pseudo-steady-state model, the direct effect of abrocitinib on DLQI was estimated to be 34.8% (P<0.0001), and the indirect effects mediated via itch and skin pain were estimated to be 19.5% and 45.8%, respectively (P≤0.0001 for both). Improvements in dermatology-specific QoL with abrocitinib are mostly mediated indirectly via a reduction in skin pain and less so by relief of itch. These findings warrant further research to examine to what extent patients consider itch and skin pain as separate concepts in terms of their impact on dermatology-specific QoL. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by intense itch, skin pain and impaired quality of life. Skin pain is a common and bothersome symptom of AD and increases in prevalence and intensity with worsening disease severity. Abrocitinib is an oral, once-daily, selective Janus kinase-1 inhibitor approved for the treatment of moderate-to-severe AD. Abrocitinib treatment resulted in improvements in skin clearance as well as rapid itch reduction in patients with moderate-to-severe AD across multiple phase 3 studies. Work productivity loss and activity impairment were assessed in the phase 3 JADE MONO-2 (NCT03575871) trial, with greater improvements being associated with abrocitinib treatment compared with placebo. The mechanism(s) through which abrocitinib reduces work productivity loss and activity impairment are unclear. To describe the interrelationships among abrocitinib treatment, itch, skin pain, and work productivity and activity impairment using a mediation modelling analysis in patients with AD. Data from adult patients treated with abrocitinib monotherapy (200 or 100 mg) or placebo in JADE MONO-2 were included in this analysis. As separate outcomes, work productivity loss and activity impairment (outcome variables) were measured by the Work Productivity and Activity Impairment Questionnaire: Atopic Dermatitis version 2.0 (WPAI-AD 2.0). Itch and skin pain (mediator variables) were evaluated using the Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) item #1 (How itchy was your skin over the past 24 h?) and item #2 (How painful was your skin over the past 24 h?), respectively. Mediation modelling was conducted independently for work productivity loss and activity impairment. All available data at week 12 were used in the modelling. Effects with P<0.05 were considered statistically significant. The direct effects of abrocitinib were estimated to be 7.3% (P=0.779) and 17.5% (P=0.258) on work productivity loss and activity impairment, respectively. The indirect effects of abrocitinib treatment on work productivity loss and, separately, on activity impairment mediated via itch were estimated to be 50.6% (P=0.017) and 20.9% (P=0.062), respectively, and via skin, pain were estimated to be 42.1% and 61.5%, respectively, (P<0.05 for both). The indirect effect of abrocitinib treatment on work productivity loss is mediated approximately equally through the reduction in itch severity and skin pain. The effect of abrocitinib treatment on activity impairment is mostly mediated indirectly through the reduction of skin pain, along with a smaller indirect contribution from the reduction in itch. These findings support further research into the extent that patients consider itch and skin pain as separate concepts in terms of their impact on work productivity. [ABSTRACT FROM AUTHOR]

Few studies have validated standard measurement instruments for evaluation of chronic pruritus. The Chronic Pruritus Tools Questionnaire PRURITOOLS assembles a set of instruments for the assessment of pruritus, such as the visual analogue scale (horizontal 100-mm line), numerical rating scale (0-10), verbal rating scale, and information on pruritus quality and improvement during therapy. This study, with 40 subjects, analysed PRURITOOLS regarding convergent validity and test-retest reliability (60 min), followed by a feasibility questionnaire. Test-retest reliability for PRURITOOLS items was excellent (intraclass correlation coefficient 0.84-1). Strong to very strong correlations between the pruritus intensity scales indicated convergent validity. The feasibility questionnaire showed an overall acceptance of PRURITOOLS, and the majority of subjects (82.5%) considered it an appropriate questionnaire to measure pruritus. In conclusion, PRURITOOLS offers validated tools for rapid pruritus assessment in routine care or endpoints of clinical trials. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Abrocitinib, an oral, once-daily Janus kinase 1-selective inhibitor, improved itch severity, sleep, and work productivity versus placebo in patients with moderate-to-severe atopic dermatitis. Objective: The aim of this study was to investigate relationships among itch, sleep, and work productivity in the phase III JADE MONO-2 clinical trial. Methods: A repeated-measures longitudinal model was used to examine relationships between itch (using the Peak Pruritus Numerical Rating Scale [PP-NRS] or Nighttime Itch Scale [NTIS]) and sleep disturbance/loss (using the Patient-Oriented Eczema Measure sleep item and SCORing AD Sleep Loss Visual Analog Scale) and, separately, between itch and work productivity (using the Work Productivity and Activity Impairment-Atopic Dermatitis Version 2.0 questionnaire). Mediation modelling was used to investigate the effect of treatment (abrocitinib vs placebo) on work impairment via improvements in itch and sleep. Results: The relationships between itch/sleep and itch/work productivity were approximately linear. PP-NRS scores of 0, 4–6, and 10 were associated with 0 days, 3–4 days, and 7 days per week of disturbed sleep, respectively. PP-NRS or NTIS scores of 0–1, 4–5, and 10 were associated with 0–10%, 20–30%, and >50% overall work impairment, respectively. Seventy-five percent of the effect of abrocitinib on reducing work impairment was indirectly mediated by improvement in itch, followed by sleep. Conclusion: These results quantitatively demonstrate that reducing itch severity is associated with improvements in sleep and work productivity. Empirical evidence for the mechanism of action of abrocitinib showed that itch severity is improved, which reduces sleep loss/sleep disruption and, in turn, improves work productivity. Clinical Trial Registration: NCT03575871 Plain Language Summary: Atopic dermatitis (AD), also called atopic eczema, is a common skin disease that is associated with itch and reduced quality of life. Abrocitinib, a recently approved medicine for AD, was shown in clinical trials to improve itch, which is considered the most bothersome symptom to people with AD. Abrocitinib also improved sleep outcomes and work productivity in people with moderate or severe AD. It is unknown if improvement in itch can lead to improvement in sleep and work productivity. We analyzed data from the JADE MONO-2 study, which included 391 people who received treatment with abrocitinib or placebo for 12 weeks. We used mathematical modelling to study relationships between itch and sleep or work productivity. We also wanted to study if the improvements in itch and sleep with abrocitinib treatment had an impact on work productivity. We found that a relationship existed between itch, sleep disturbance, and work impairment; as itch improved, so too did sleep disturbance and work impairment. When people were treated with abrocitinib, they experienced relief from itch, which improved sleep, which in turn reduced work productivity loss. Larger and longer studies are needed to confirm these results. This analysis further informs the expectations of patients with moderate or severe AD as it relates to progression of symptom relief after treatment with abrocitinib. [ABSTRACT FROM AUTHOR]

Introduction Patients with prurigo nodularis (PN) often report high disease burden with substantial impact on quality of life. Patient Global Impression of Change (PGIC) and Severity (PGIS) are patient self-assessment measures that quantify their experience of disease during treatment. Dupilumab has recently been approved as the first systemic treatment for PN in the US and Europe. Objectives: To evaluate patient-reported global impression of disease severity improvement in dupilumab-treated patients with PN during the LIBERTY-PN PRIME and PRIME 2 trials. Materials & Methods: PRIME and PRIME2 were randomized, double-blind, multicenter, parallel-group, 24-week, phase 3 trials in adults with PN with ≥20 nodules and severe itch, inadequately controlled with topical prescription therapies or for whom these are inadvisable. Patients received 300 mg dupilumab subcutaneously (600 mg loading dose; n = 153) or matched placebo (n = 158) every 2 weeks. In this analysis, data from the two studies were pooled. Patient satisfaction was assessed in the overall placebo group, overall dupilumab-treated group, and those treated with dupilumab who did not achieve the stringent multicomponent endpoint (n = 99) of ≥4-point improvement from baseline in Worst Itch Numerical Rating Scale (WI-NRS, range: 0-10) and an Investigator's Global Assessment PN Stage (IGA PN-S, score range: 0-4) score 0 or 1 (clear or almost clear; ≤5 nodules) at Week (W) 24. Endpoints include proportion of patients achieving: PGIC (range: 0-6) scores of 0 or 1 (very much better or moderately better) at W12, and W24; and PGIS (range: 1-4) score of 1 or 2 (none or mild) at baseline, W12, and W24. Safety was also assessed. Results: Baseline demographic and clinical characteristics were generally similar between groups. In the overall dupilumab and placebo groups, baseline mean (SD) WI-NRS scores were 8.6 (0.9) and 8.4 (1.1), respectively; 32.7% and 34.2% had an IGA PN-S score of 4 (remaining patients had IGA PN-S 3); and mean (SD) PGIS scores were 3.7 (0.5) and 3.7 (0.5) respectively. In dupilumab multicomponent endpoint non-responders, mean (SD) WI-NRS score was 8.6 (0.9). 35.4% and 64.6% had an IGA PN-S score of 4 and 3 respectively; and mean (SD) PGIS score was 3.7 (0.5). At W12, 68.0% vs 38.0% (P < 0.0001 vs placebo) of dupilumab-treated vs placebo-receiving patients achieved PGIC 0 or 1, while 55.6% of dupilumab multicomponent non-responders achieved this endpoint (P = 0.0099 vs placebo). At W24, this increased to 74.5% vs 32.9% (P < 0.0001 vs placebo) of dupilumab-treated vs placebo-receiving patients achieving PGIC 0 or 1, and 61.6% of multicomponent non-achievers (P < 0.0001 vs placebo). At W12, 51.6% vs 22.2% (P < 0.0001 vs placebo) of dupilumab-treated vs placebo-receiving patients achieved PGIS 1 or 2, while 40.4% of multicomponent non-responders achieved the endpoint (P = 0.0027 vs placebo). At W24, 61.4% vs 24.1% (P < 0.0001 vs placebo) of dupilumab-treated vs placebo-receiving patients achieved PGIS 1 or 2, while 44.4% of multicomponent non-responders achieved the endpoint (P = 0.0025 vs placebo). Safety findings were consistent with the known dupilumab safety profile. Conclusions: While not all patients achieved the stringent multicomponent endpoint within the 24-week treatment period during PRIME and PRIME 2 trials, around half of the dupilumab-treated patients still reported significantly more improvement in disease severity and satisfaction with therapy. Overall safety was consistent with the known dupilumab safety profile. [ABSTRACT FROM AUTHOR]

Tofacitinib is an oral Janus kinase inhibitor. This post-hoc analysis aimed to investigate the psychometric properties of the Itch Severity Item (ISI), a numeric rating scale from 0 (no itching) to 10 (worst possible itching) for pruritus in psoriasis, and review the effect of tofacitinib on pruritus in patients with psoriasis participating in Phase 3 studies (N = 3,641). The ISI showed high test-retest reliability (intra-class correlation coefficient: 0.84). The clinically important difference was defined as a 1.48-point change, using Patient Global Assessment as an anchor. Mean changes from baseline in ISI scores with tofacitinib were significantly greater than placebo by Day 2 and exceeded the clinically important difference by Week 4 and Week 2 for tofacitinib 5 and 10 mg twice daily, respectively. The sound psychometric properties of the ISI as an assessment tool for pruritus in psoriasis were confirmed. Tofacitinib provided clinically meaningful improvements in psoriatic pruritus versus placebo. [ABSTRACT FROM AUTHOR]

Pruritus persisting for six weeks or longer is considered chronic. It may arise from dermatological, systemic, neurological, psychosomatic or psychiatric conditions or result from a combination of several factors. Due to chronicity processes, such as peripheral and central sensitization, pruritus may persist even after treatment of the underlying cause. Additionally chronic pruritus constitutes often a high burden for the affected patients, who frequently develop associated conditions, such as anxiety, depression or sleep disorders. Owing to the multiple dimensions of chronic pruritus, it presents a diagnostic and therapeutic challenge to the attending physician. The categorization of the condition according to the clinical presentation helps directing the diagnostic and treatment efforts. Therapeutically a step-wise approach should be undertaken. First basic measures, such as the use of emollients for dry skin, topical steroids for inflamed or excoriated skin and antihistamines should be initiated. If the origin underlying the chronic pruritus is found, a causal therapy should be attempted. If no cause is found or a causal treatment is not possible, a symptomatic multimodal therapy with topical and systemic agents is often necessary. With increasing knowledge of the pathophysiological mechanisms underlying chronic pruritus, novel drugs with promising effects are being developed. [ABSTRACT FROM AUTHOR]

Chronic pruritus remains a central societal issue because of its high occurrence and the substantial decrease in quality of life it may cause to affected individuals. Not only dermatological conditions, but also systemic, neurological, or psychiatric diseases may lead to chronic pruritus. Additionally, various underlying conditions may coexist or the cause may be unknown. Due to its heterogeneity, the therapeutic approach is complex and remains a challenge for the clinician. Basic measures such as emollients to avoid xerosis and treatment of the underlying disease should be initiated regardless of the duration of the symptom. Depending on the indication, other topical (e.g., calcineurin inhibitors, topical corticosteroids, capsaicin) and systemic agents (immunosuppressive drugs, gabapentinoids, antidepressants, mu-opioid receptor antagonists) may provide further relief. Additionally, accompanying disorders such as sleep impairment, depression, or anxiety should also be treated. New insights into pathways involved in the development and maintenance of chronic pruritus have led in the past years to the development of a considerable number of novel antipruritic drugs. Several randomized controlled trials have been recently completed or are currently underway testing biological compounds with promising approaches. These include antagonists for nerve growth factor, neuropeptides, histamine 4 receptors, certain interleukin receptors, and opioid receptors. [ABSTRACT FROM AUTHOR]

Currently valid itch intensity scales, such as the visual analogue scale (VAS), are indispensable, but they can be influenced by the patient's overall health status. The aim of this study was to evaluate the reliability and validity of the Dynamic Pruritus Score (DPS), a new instrument comparing reduction in current pruritus with a defined earlier time-point. Eighty-one randomly selected adults (50 females, mean age 53.9 years) recorded their pruritus at visit 1 and repeatedly at visit 2 on the DPS, VAS, numerical rating scale, and on health status questionnaires (EuroQol; EQ-5D), skin-related quality of life (Dermatology Life Quality Index; DLQI), anxiety and depression (Hospital Anxiety and Depression Scale; HADS) and patient benefit (Patient Benefit Index; PBI). Intraclass correlation showed high reliability for both DPS and VAS (r > 0.9, p < 0.001), while the DPS has shown higher concurrent validity (rDPS to PBI = 0.570; p < 0.001). The DPS can then be considered an alternative instrument to the VAS for assessment of pruritus in adults. Further research is needed to confirm these results with a more representative sample size. [ABSTRACT FROM AUTHOR]

Patients with chronic pruritus may develop scratchinduced lesions with elevated borders and central necrosis. This so-called umbilicated type of prurigo (UP) is rare and is assumed to develop preferentially in the context of metabolic diseases. The aim of this study was to characterize UP in its clinical and histological dimension. Demographic and clinical data were collected from 23 patients with UP. Intensive light microscopical analysis of biopsied lesions was performed. Statistical comparison with previous results for prurigo nodularis (PN) showed that UP is clearly a subtype of PN. In addition, clinical and microscopic features of epidermal perforation identical to those in acquired reactive perforating dermatosis (ARPD) were observed. Hence, we suggest that ARPD is identical to UP and is therefore a subtype of PN. We assume that reduced wound healing capacities due to underlying systemic disorders, particularly diabetes mellitus and uraemia, underlie the pathomechanism of development of umbilicated skin lesions with a perforating aspect. [ABSTRACT FROM AUTHOR]

Chronic pruritus is a complex multifactorial symptom associated with many different diseases that represents a diagnostic and therapeutic challenge for physicians. In order to better manage chronic pruritus, a detailed medical history, individualized diagnostic procedures and treatment approaches are necessary. Treatment should not only take itch into consideration, but also scratching-induced skin lesions and accompanying disorders such as anxiety, depression and insomnia. Various standardized questionnaires and scales have been developed to assist in the characterization and assessment of these parameters. Monodimensional scales (e.g. the visual analogue scale) represent a simple method for assessing pruritus intensity and are frequently used; however, they can easily be confounded and may indicate the level of satisfaction regarding the medical care provided rather than the itch course. The Dynamic Pruritus Score and Itch-Free Days questionnaire enable a closer assessment of patient responses to treatment. Because chronic pruritus has the potential to greatly impact the quality of life, it is important that physicians recognize it as a major issue. The Dermatology Quality of Life Index is an instrument that is used in a variety of dermatological conditions, but may be unsuitable for measuring pruritus of extracutaneous origin. The ItchyQol is a tool designed specifically for those suffering from pruritus. Additional tools, such as the Hospital Anxiety and Depression Scale, take psychiatric comorbidities into consideration. Recommendations from European (EADV-based Task Force Pruritus) and international (International Forum for the Study of Itch) expert groups focusing on assessment instruments for chronic pruritus are also provided in this article. [ABSTRACT FROM AUTHOR]

This study was a prospective, parallel-group, randomized, double-blind, vehicle-controlled, multi-centre clinical trial to compare the efficacy of topical sertaconazole 2% cream with vehicle in reducing chronic pruritus in subjects with atopic dermatitis, and to assess its safety and local tolerability. A total of 70 subjects applied either of the 2 treatments twice daily for a period of 4 weeks on affected, itchy skin areas. Treatment efficacy was evaluated primarily considering the item itch intensity on a 5-point verbal rating scale. Insomnia, state of atopic dermatitis (Scoring Atopic Dermatitis; SCORAD), quality of life and therapy benefit were also assessed. No significant difference between active treatment and vehicle was found at any of the time-points for any of the investigated parameters. Under the experimental conditions of the study, sertaconazole 2% cream did not exert anti-pruritic effects that were better than vehicle in subjects with atopic dermatitis who had chronic pruritus. [ABSTRACT FROM AUTHOR]

The complex nature and difficult-to-establish aetiology of chronic pruritus (CP) makes it challenging to provide medical care for patients with CP. This challenge can only be met with a multidisciplinary approach. The first multidisciplinary Itch Centre in Germany was established at the University of Münster in 2002 to meet the needs of this patient population. More than 2,500 outpatients and 400 inpatients are diagnosed and receive treatment each year. To ensure evidence-based medical care, an electronic system for medical documentation and patient-reported outcomes was established. Automated data transfer to a research database enables comprehensive data analysis. Our translational research has characterized peripheral and central itch mechanisms, provided novel clustering of CP patients, and identified novel target-specific therapies (e.g. neurokinin 1 receptor-antagonist). The multidisciplinary approach, combined with basic, clinical and translational research, enables comprehensive medical care of patients as well as implementation of high-quality experimental and clinical studies. [ABSTRACT FROM AUTHOR]

Sensitive skin is a frequent complaint in the general population, in patients, and among subjects suffering from itch. The International Forum for the Study of Itch (IFSI) decided to initiate a special interest group (SIG) on sensitive skin. Using the Delphi method, sensitive skin was defined as "A syndrome defined by the occurrence of unpleasant sensations (stinging, burning, pain, pruritus, and tingling sensations) in response to stimuli that normally should not provoke such sensations. These unpleasant sensations cannot be explained by lesions attributable to any skin disease. The skin can appear normal or be accompanied by erythema. Sensitive skin can affect all body locations, especially the face". This paper summarizes the background, unresolved aspects of sensitive skin and the process of developing this definition. [ABSTRACT FROM AUTHOR]

Severe persistent pruritus is a common, but incompletely characterized, complication of hydroxyethyl starch (HES) infusion. This retrospective study aimed to assess HES-induced pruritus by electron microscopic findings, pruritus characteristics, and response to stimuli, and to determine the impact of HES dosage, molecular weight and substitution. Seventy patients with electron microscopy-proven HES-induced pruritus were included. HES-laden vacuoles were observed in skin macrophages of all patients. The median latency between HES exposure and pruritus onset was 3 weeks, and the median duration of pruritus was 6 months. Pruritus was severe, or very severe, in 80% of patients. Mechanical stimuli triggered pruritus in 74% of patients. Although the median cumulative dose of HES was 300 g, 15% of patients developed pruritus after only 30 g. There were no significant differences between HES 130/0.4 and HES 200/0.5 in pruritus latency, duration or severity. HES-induced pruritus thus may occur at any dose, molecular weight or substitution. [ABSTRACT FROM AUTHOR]

Chronic pruritus is a common symptom and there is an urgent need to test new anti-pruritic substances in highquality clinical trials. However, no widely accepted standardized and validated method for objectively measuring pruritus is yet available. A special interest group of the International Forum for the Study of Itch has been established to assess scoring methods and questionnaires for use in clinical trials. This paper presents our current recommendations. The set of measures we recommend includes pruritus intensity scales, instruments for assessment of scratch lesions, chronic pruritus course, quality of life and patient benefitsen. [ABSTRACT FROM AUTHOR]

Chronic pruritus ( CP) is a frequent symptom in the general population; in 8% of all patients, it has a neuropathic origin. CP is of neuropathic origin when nerve fiber damage is responsible for the symptom. The damage can be caused by compression or degeneration of the nerve fibers in the skin or extracutaneous in peripheral nerves or the central nervous system. There are significant differences in the pathogenesis and in the clinical presentation of neuropathic CP. Localized neuropathic CP such as brachioradial pruritus or notalgia paresthetica are due to a circumscribed nerve compression and are often limited on the corresponding dermatome. In contrast, generalized neuropathic CP, as in small fiber neuropathies, may be associated with a systemic or metabolic underlying disease. It is not always easy to establish the diagnosis because a variety of diseases can be responsible for this type of CP. The present study shows an overview of possible diseases, diagnostic tools, and the relevant therapy strategies. [ABSTRACT FROM AUTHOR]

Modern genetic approaches in animal models have unveiled novel itch‐specific neural pathways, emboldening a paradigm in which drugs can be developed to selectively and potently target itch in a variety of chronic pruritic conditions. In recent years, kappa‐opioid receptors (KORs) and mu‐opioid receptors (MORs) have been implicated in both the suppression and promotion of itch, respectively, by acting on both the peripheral and central nervous systems. The precise mechanisms by which agents that modulate these pathways alleviate itch remains an active area of investigation. Notwithstanding this, a number of agents have demonstrated efficacy in clinical trials that influence both KOR and MOR signalling. Herein, we summarize a number of opioid receptor modulators in development and their promising efficacy across a number of chronic pruritic conditions, such as atopic dermatitis, uremic pruritus and beyond. [ABSTRACT FROM AUTHOR]

Abstract: Pruritus is an unpleasant sensation leading to the desire to scratch. It is the most common symptom in dermatology, and various skin and systemic diseases can be associated with the presence of itching. Pruritus may also be provoked by numerous drugs. Although the exact epidemiologic data are still absent, it is generally accepted that elderly people frequently suffer from pruritus, and the problem of itching in this population remains a challenge for clinicians. The elderly often complain of numerous comorbidities that complicate the determination of the cause of pruritus, as well as its treatment. Physical and mental deprivation may complicate proper assessment of pruritus severity and negatively impair compliance with complex antipruritic therapies. Taking also into account heterogeneity of possible causes of pruritus, every patient with pruritus must be handled individually, regarding the diagnostic procedures and antipruritic therapy. [ABSTRACT FROM AUTHOR]

Background: Documenting quality of life (QoL) in routine medical care and using it both for treatment and for clinical research is not common, although such information is absolutely valuable for physicians and patients alike. We therefore aimed at developing an efficient method to integrate quality of life information into the clinical information system (CIS) and thus make it available for clinical care and secondary use. Methods: We piloted our method in three different medical departments, using five different QoL questionnaires. In this setting we used structured interviews and onsite observations to perform workflow and form analyses. The forms and pertinent data reports were implemented using the integrated tools of the local CIS. A web-based application for mobile devices was developed based on XML schemata to facilitate data import into the CIS. Data exports of the CIS were analysed with statistical software to perform an analysis of data quality. Results: The quality of life questionnaires are now regularly documented by patients and physicians. The resulting data is available in the Electronic Health Record (EHR) and can be used for treatment purposes and communication as well as research functionalities. The completion of questionnaires by the patients themselves using a mobile device (iPad) and the import of the respective data into the CIS forms were successfully tested in a pilot installation. The quality of data is rendered high by the use of automatic score calculations as well as the automatic creation of forms for follow-up documentation. The QoL data was exported to research databases for use in scientific analysis. Conclusion: The CIS-based QoL is technically feasible, clinically accepted and provides an excellent quality of data for medical treatment and clinical research. Our approach with a commercial CIS and the web-based application is transferable to other sites. [ABSTRACT FROM AUTHOR]

Background: Documenting quality of life (QoL) in routine medical care and using it both for treatment and for clinical research is not common, although such information is absolutely valuable for physicians and patients alike. We therefore aimed at developing an efficient method to integrate quality of life information into the clinical information system (CIS) and thus make it available for clinical care and secondary use. Methods: We piloted our method in three different medical departments, using five different QoL questionnaires. In this setting we used structured interviews and onsite observations to perform workflow and form analyses. The forms and pertinent data reports were implemented using the integrated tools of the local CIS. A web-based application for mobile devices was developed based on XML schemata to facilitate data import into the CIS. Data exports of the CIS were analysed with statistical software to perform an analysis of data quality. Results: The quality of life questionnaires are now regularly documented by patients and physicians. The resulting data is available in the Electronic Health Record (EHR) and can be used for treatment purposes and communication as well as research functionalities. The completion of questionnaires by the patients themselves using a mobile device (iPad) and the import of the respective data into the CIS forms were successfully tested in a pilot installation. The quality of data is rendered high by the use of automatic score calculations as well as the automatic creation of forms for follow-up documentation. The QoL data was exported to research databases for use in scientific analysis. Conclusion: The CIS-based QoL is technically feasible, clinically accepted and provides an excellent quality of data for medical treatment and clinical research. Our approach with a commercial CIS and the web-based application is transferable to other sites. [ABSTRACT FROM AUTHOR]

Background: Chronic pruritus is a global clinical problem with a high impact on the quality of life and lack of specific therapies. It is an excruciating and frequent symptom of e.g. uncurable renal, liver and skin diseases which often does not respond to conventional treatment with e.g. antihistamines. Therefore antipruritic therapies which target physiological mechanisms of pruritus need to be developed. Substance P (SP) is a major mediator of pruritus. As it binds to the neurokinin receptor 1 (NKR1), we evaluated if the application of a NKR1 antagonist would significantly decrease chronic pruritus. Methods and Findings: Twenty hitherto untreatable patients with chronic pruritus (12 female, 8 male; mean age, 66.7 years) were treated with the NKR1 antagonist aprepitant 80 mg for one week. 16 of 20 patients (80%) experienced a considerable reduction of itch intensity, as assessed by the visual analog scale (VAS, range 0 to 10). Considering all patients, the mean value of pruritus intensity was significantly reduced from 8.4 VAS points (SD±1.7) before treatment to 4.9 VAS points (SD±3.2) (p,0.001, CI 1.913-5.187). Patients with dermatological diseases (e.g. atopic diathesis, prurigo nodularis) had the best profit from the treatment. Side-effects were mild (nausea, vertigo, and drowsiness) and only occurred in three patients. Conclusions: The high response rate in patients with therapy refractory pruritus suggests that the NKR1 antagonist aprepitant may indeed exhibit antipruritic effects and may present a novel, effective treatment strategy based on pathophysiology of chronic pruritus. The results are promising enough to warrant confirming the efficacy of NKR1 antagonists in a randomized, controlled clinical trial. [ABSTRACT FROM AUTHOR]

Abstract: Background and objectives: The most abundant malignant brain tumor in human is glioblastoma and patients with this type of tumor have a poor prognosis with high mortality. Glioblastoma are characterized particularly by fast growth and a dependence on blood vessel formation for survival. Cannabinoids (CBs) inhibit tumor growth by inducing apoptosis of tumor cells and impairing tumor angiogenesis. The distribution of CB1 and CB2 receptors in glioblastoma and associated endothelial vessels is still unknown. Methods: Tissue samples were collected consecutively after neurosurgery of 19 patients suspected glioblastoma and examined immunohistochemically for CB1 and CB2 receptor expression. Vessel endothelial cells of the sections were immunocytochemically identified by using a primary antibody against PECAM-1. Double labelling was performed for CB receptors and endothelial cells of the vessels by DAPI staining. Results: In endothelia of control tissue, about 24% and 45% of the cells were positive for CB1 and CB2 receptors. In glioblastoma endothelial cells, CB1 and CB2 receptors were present in about 38% and 54% of the cells respectively. In comparison to CB1, an elevated CB2 receptor expression was identified in glioblastoma. Conclusions: The abundant expression and distribution of CB2 receptors in glioblastoma and particularly endothelial cells of glioblastoma indicate that impaired tumor growth in presence of CB may be associated with CB2 activation. Selective CB2 agonists might become important targets attenuating vascular endothelial growth factor (VEGF) signalling and thereby diminishing neoangiogenesis and glioblastoma growth. [Copyright &y& Elsevier]

Pruritus is an unpleasant sensation that leads to scratching. In addition to several diseases, the administration of drugs may induce pruritus. It is estimated that pruritus accounts for approximately 5% of all skin adverse reactions after drug intake. However, to date there has been no systematic review of the natural course and possible underlying mechanisms of drug-induced pruritus. For example, no clear distinction has been made between acute or chronic (lasting more than 6 weeks) forms of pruritus. This review presents a systematic categorization of the different forms of drug-induced pruritus, with special emphasis on a therapeutic approach to this side-effect. [ABSTRACT FROM AUTHOR]

According to epidemiological studies, up to 50% of adults report facial sensitivity with various distinctive symptoms, such as prickling, burning, tingling, pain or itching. This is termed sensitive skinand represents a syndrome of physiological reactions rather than a disease entity. In this review, we discuss the currently available literature on this syndrome and describe the possible underlying neuronal pathomechanisms. The sensory receptors expressed on unmyelinated nerve fibres and keratinocytes involved in nociception, such as TRPV1 and endothelin receptors, are hypothesized to play a role in the induction of sensitive skin. Furthermore, we discuss the role of neurotrophins and the influence of stress on sensitive skin. [ABSTRACT FROM AUTHOR]

Chronic pruritus is difficult to treat and requires the evaluation of new therapeutic modalities. We initiated an open-labelled, two-arm prospective, proof-of-concept study applying two selective serotonin re-uptake inhibitors on a long-term basis. Paroxetine and fluvoxamine were tested in a total of 72 pruritic patients (27 men, 45 women, age range 28-88 years, mean age 59.2 years). The reduction in pruritus was evaluated by analysis of visual analogue scores and determination of the maximal antipruritic effect (maximal percentual reduction in pruritus). Forty-nine of 72 patients (68.0%) experienced a weak (n=9), good (n= 16) or very good (n =24) antipruritic effect. Statistical analysis proved the efficacy of paroxetine and fluvoxamine with no significant difference. The best response was observed in patients with pruritus due to atopic dermatitis, systemic lymphoma and solid carcinoma. Chronic scratch lesions healed completely in 14/31 patients and partially in 17/31 patients. Adverse drug effects were observed in 70.8% of patients, resulting in discontinuation of treatment in 18 patients. These results support previous reports of high antipruritic potency of selective serotonin re-uptake inhibitors, which are a good alternative treatment modality in chronic pruritus. This should be confirmed in future double-blind studies. [ABSTRACT FROM AUTHOR]

Chronic pruritus of any origin is a frequent discomfort in daily medical practice, and its therapy is challenging. Frequently, the underlying origin may not be identified and symptomatic therapy is necessary. Conventional treatment modalities such as antihistamines often lack efficacy, and hence new therapeutic strategies are necessary. The neuronal mechanisms underlying chronic pruritus have been partly identified during the past years and offer new therapeutic strategies. For example, mast cell degranulation, activation of neuroreceptors on sensory nerve fibres and neurogenic inflammation have been identified to be involved in induction and chronification of the symptom. Accordingly, controlling neuroreceptors such as cannabinoid receptors by agonists or antagonists showed high antipruritic efficacy. Pruritus is transmitted to the central nervous system by specialized nerve fibres and sensory receptors. It has been demonstrated that pruritus and pain have their own neuronal pathways with broad interactions. Accordingly, classical analgesics for neuropathic pain (gabapentin, antidepressants) also exhibit antipruritic efficacy upon clinical use. In summary, these recent developments show that highlighting the basis of pruritus offers modern neurophysiological and neurochemical therapeutic models and the possibility to treat patients with refractory itching of different origin. [ABSTRACT FROM AUTHOR]

Chronic itch is a common and distressing symptom that arises from a variety of skin conditions and systemic diseases. Despite this, there is no clinically based classification of pruritic diseases to assist in the diagnosis and cost-effective medical care of patients with pruritus. The proposed classification focuses on clinical signs and distinguishes between diseases with and without primary or secondary skin lesions. Three groups of conditions are proposed: pruritus on diseased (inflamed) skin (group I), pruritus on non-diseased (non-inflamed) skin (group II), and pruritus presenting with severe chronic secondary scratch lesions, such as prurigo nodularis (group lII). The next part classifies the underlying diseases according to different categories: dermatological diseases, systemic diseases including diseases of pregnancy and drug-induced pruritus, neurological and psychiatric diseases. In some patients more than one cause may account for pruritus (category "mixed") while in others no underlying disease can be identified (category "others"). This is the first version of a clinical classification worked out by the members of the international Forum for the Study of itch. it is intended to serve as a diagnostic route for better evaluation of patients with chronic pruritus and aims to improve patients' care. [ABSTRACT FROM AUTHOR]

Switch to Itch - The many novel facets of pruritus research Itch is one of the most important physiological senses in human beings and brings attention to the skin during transient or self-removable contact with plants or insects. We are aware that there are many aspects of itch in particular chronic itch that we did not cover but we hope that this special edition will serve as an eye opener to this evolving field. [Extracted from the article]

Summary: Background:: Cannabinoid receptors mediate the psychopharmacological action of marijuana and have been localized in the central and peripheral nervous system as well as on cells of the immune system. Objective:: Up to now, two cannabinoid receptors (CB1 and CB2) have been cloned and recent studies on animal tissue gave evidence for the presence of cannabinoid receptors in the skin. Methods:: In the present immunohistochemical investigation we determined the precise localization of CB1 and CB2 in sections of human skin and in one case of mastocytosis. Results:: CB1 and CB2 immunoreactivity was observed in cutaneous nerve fiber bundles, mast cells, macrophages, epidermal keratinocytes, and the epithelial cells of hair follicles, sebocytes and eccrine sweat glands. In epidermal keratinocytes, hair follicle and sebaceous glands, CB1 and CB2 were distributed in a complementary fashion. Double-immunostaining with an anti-CGRP antibody suggested the presence of cannabinoid receptors on small afferent peptidergic nerves. Conclusion:: The abundant distribution of cannabinoid receptors on skin nerve fibers and mast cells provides implications for an anti-inflammatory, anti-nociceptive action of cannabinoid receptor agonists and suggests their putatively broad therapeutic potential. [Copyright &y& Elsevier]

Ständer S, Moormann C, Schumacher M, Buddenkotte J, Artuc M, Shpacovitch V, Brzoska T, Lippert U, Henz BM, Luger TA, Metze D, Steinhoff M. Expression of vanilloid receptor subtype 1 in cutaneous sensory nerve fibers, mast cells and epithelial cells of appendage structures. The vanilloid receptor subtype 1 (VR1)/(TRPV1), binding capsaicin, is a non-selective cation channel that recently has been shown in human keratinocytes in vitro and in vivo. However, a description of VR1 localization in other cutaneous compartments in particular cutaneous nerve fibers is still lacking. We therefore investigated VR1 immunoreactivity as well as mRNA and protein expression in a series ( n = 26) of normal ( n = 7), diseased ( n = 13) [prurigo nodularis (PN) ( n = 10), generalized pruritus ( n = 1), and mastocytosis ( n = 2)], and capsaicin-treated human skin ( n = 6). VR1 immunoreactivity could be observed in cutaneous sensory nerve fibers, mast cells, epidermal keratinocytes, dermal blood vessels, the inner root sheet and the infundibulum of hair follicles, differentiated sebocytes, sweat gland ducts, and the secretory portion of eccrine sweat glands. Upon reverse transcriptase-polymerase chain reaction and Western blot analysis, VR1 was detected in mast cells and keratinocytes from human skin. In pruritic skin of PN, VR1 expression was highly increased in epidermal keratinocytes and nerve fibers, which was normalized after capsaicin application. During capsaicin therapy, a reduction of neuropeptides (substance P, calcitonin gene-related peptide) was observed. After cessation of capsaicin therapy, neuropeptides re-accumulated in skin nerves. In conclusion, VR1 is widely distributed in the skin, suggesting a major role for this receptor, e.g. in nociception and neurogenic inflammation. [ABSTRACT FROM AUTHOR]