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doi: 10.1097/itx.0000000000000058
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Young investigator council (YIC)

YIC1: Developing druggable in-vitro models to combat itch in atopic dermatitis

Hendrik Miessner1,2, Ewan St. John Smith1, Judith Seidel2

1University of Cambridge, Department of Pharmacology, Cambridge, UK,2Beiersdorf AG, Dermatological Skin Care, Berlin, Germany

Introduction: Atopic dermatitis (AD) is a highly prevalent, relapse-remitting, inflammatory skin disease, the hallmark symptom being chronic itch. The origin of chronic itch in AD is not yet fully understood but might be associated with neuronal hyperinnervation and hyperactivity. The underlying signaling of AD itch is thought to be multifactorial, involving various cells, receptors, and mediators, opening the possibility that pathways could be identified and targeted to relieve itch in AD. Therefore, establishing an AD model system to mimic the disease is crucial.

Aim of the Study: The goal is to generate a physiologically relevant, fully humanized model system for AD itch research and drug development.

Results: Human induced pluripotent stem cell-derived sensory neurons (iPSC-SNs) were combined with human primary skin cells to form fully human models. In a contact-independent insert-based format, the impact of factors secreted by skin cells could be observed on the development of sensory neurons underneath. In a further developed, contact-dependent 2.5D format mimicking natural skin innervation, the cell-cell interaction not only permits remote paracrine exchange, but also juxtacrine signaling across gap junctions. Using Ca2+-imaging, iPSC-SNs show response to pruritogens and potentially increased receptor expression in initial functional experiments with the contact-dependent system. In an AD-like setup, different Th2 cytokines could be used to stimulate the coculture systems to mimic the inflamed lesional skin environment.

Conclusion: Alternative human (AD) skin model systems were developed for use with functional assays that promise to be a useful tool in itch research. Also with respect to other (skin) diseases, these models can potentially be utilized to assess the capabilities and differences of control versus disease-related itch signaling of sensory neurons.

YIC2: D1R In the lateral shell of nucleus accumbens encodes the driving force for itch-evoked scratching behavior

Tongyu Liang, Hua Zhou, Yan-Gang Sun

Center for Excellence in Brain Science and Intelligence Technology (Institute of Neuroscience), Shanghai, China

Itch is usually be regarded as an unpleasant sensation that evokes the desire to scratch. Ventral tegmental area (VTA) dopaminergic neurons have been proven to play an essential role in modulating itch signal processing. Dopaminergic projection constitutes the major component of the VTA-Nucleus accumbens (NAc) circuit. However, how the dopamine signals in NAc participated in itch processing remains largely unknown. By recording the dynamics of dopamine release in different sub-regions of the NAc during itch-induced scratching behavior, we found that dopamine signals received by D1 and D2 receptors in the lateral shell (LaSh), rather than the medial shell (MeSh) of the NAc, increased after scratching onset. Moreover, the blockade of D1 receptors, but not D2 receptors in the LaSh impaired pruritogen-induced scratching behavior. To further investigate the coding mechanism of dopamine signals during the itch-scratching cycle, we recorded the dopamine release on D1 receptors of the NAc LaSh while delivering a newly-established optogenetics-based pruritic stimulus with high temporal precision, which was achieved by optogenetic stimulation of spinal itch- selective gastrin-releasing peptide receptor (GRPR) positive neurons. We used collar to block itch-relieving behaviors to better separate different components of itch, including the itch sensory component and itch relief. We found that the dopamine signal on D1 receptors of the NAc LaSh showed increase before the relief of itch sensation and sustained elevated activity during itch stimulation. These data suggest that the dopamine signals received by D1 receptors of the NAc LaSh might encode the driving force for itch-induced scratching, while also holding the capability to process itch relief associated reward. Our study characterized the dopamine dynamics within the NAc, and emphasized a critical role of D1R in the NAc LaSh in regulating the itch- scratching cycle.

YIC3: Neuroimmune mediators of pruritus in scalp psoriatic itch: an immunofluorescent analysis

Leigh Nattkemper1, Zoe Lipman1*, Giuseppe Ingrasci1*, Enrique Loayza2, Claudia Maldonado2, Juan Carlos Garces2, Ahmed Hawash1, Gil Yosipovitch1

1Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery and Miami Itch Center, University of Miami, Miami, FL, USA,2Departamento de Dermatología, Hospital Luis Vernaza, Guayaquil, Ecuador

*Contributed equally

Background: Scalp psoriatic itch is a prevalent yet understudied condition with numerous associated treatment challenges.

Objective: The current study aims to enhance our understanding of scalp psoriatic itch pathophysiology in order to guide current management and identify novel treatment targets.

Methods: Immunohistochemical analysis of known neuroimmune mediators of pruritus was conducted using scalp biopsies from 37 patients (27 with scalp psoriasis, 10 healthy controls).

Results: Intraepidermal nerve fiber (IENF) density and PAR2, TRPV3, TRPM8, and IL-23 expression all significantly differed between scalp psoriasis patients compared to controls and significantly correlated with itch intensity. TRPV1, TNFα, and IL17 expression was increased in psoriasis patients compared to controls but did not correlate with itch intensity.

Limitations: Our study is limited by the small sample size, and the examination of protein expression exclusively through IHC analysis. We also lacked inclusion of non-itchy psoriatic patients, which could have helped differentiate mediators of psoriatic pathology from itch-specific pathology.

Conclusion: Our results are congruent with prior data that scalp psoriasis pathophysiology is largely non-histaminergic and rather, driven by a Type 1 and IL-17 dominant immune response. Additionally, scalp psoriatic itch may have a greater neurological component than previously thought.

YIC4: The delta opioid receptor bidirectionally modulates itch

Kelly Smith, Eileen Nguyen, Sarah Ross

University of Pittsburgh, Pittsburgh, PA, USA

Introduction: Opioids have previously been shown to be important for itch. Both the kappa opioid receptor (KOR) and the mu opioid receptor (MOR) have been implicated in the spinal modulation itch; KOR agonism inhibits itch and MOR agonism elicits itch. Despite the importance of MOR and KOR in itch, no studies have looked at the role of the delta opioid receptor (DOR) in the spinal modulation of itch.

Methods and Results: Using intrathecal DOR agonists (Deltorphin II and SNC80) and antagonists (Tipp Ψ and naltrindole) we found that DOR agonism decreases scratch bouts in response to intradermal chloroquine, while DOR antagonism increases spontaneous scratch bouts. These results show that DOR bidirectionally modulates itch. To begin to uncover the spinal circuitry by which DOR modulation of itch may occur, we used in situ hybridization to look at co-expression of enkephalin (the endogenous ligand for DOR) and NPY (a known population involved in itch inhibition) as well as DOR and KOR. In this experiment we found a 40% overlap between excitatory DOR and excitatory KOR neurons, suggesting a common pathway for the mediation of itch. We also found that all inhibitory enkephalin cells co-expressed NPY, suggesting that NPY expressing neurons may be upstream of DOR neurons.

Conclusions: In this study, we show that DOR expressing neurons bidirectionally modulate itch, and that DOR and KOR are frequently co-expressed. Further, we show that enkephalin is co-expressed on NPY neurons. Taken together, these data raise the possibility that NPY and dynorphin neurons (dynorphin is the endogenous ligand for KOR) may share a common KOR/DOR expressing target in the spinal cord to mediate the inhibition of itch. These findings underscore the importance of DOR in the modulation of itch.

YIC5: Cutaneous transcriptomics identifies fibroproliferative and neurovascular gene dysregulation in prurigo nodularis compared to psoriasis

Zachary A. Bordeaux, Nishadh Sutaria, Martin Alphonse, Varsha Parthasarathy, Junwen Deng, Youkyung S. Roh, Justin Choi, Thomas Pritchard, Shawn G. Kwatra

Johns Hopkins University, Department of Dermatology, Baltimore, MD, USA

Introduction: Prurigo nodularis (PN) is a chronic inflammatory skin disease that is associated with several systemic comorbidities, suggesting dysregulation of cutaneous and systemic inflammatory processes. Th22 and Th17 immune signatures have been identified in PN lesions and psoriasis, highlighting shared gene signatures between PN and psoriasis.

Aim of the Study: To identify novel pathophysiological pathways specific to PN through comparison of lesional and nonlesional skin transcriptomes of PN and psoriasis patients.

Materials and Methods: Lesional and nonlesional biopsies were collected from PN patients without a history of atopy or psoriasis. RNA was extracted, RNA-seq libraries were constructed, and sequencing was performed using Illumina NovaSeq 6000. Psoriasis transcriptomics were obtained from Gene Expression Omnibus, which contained lesional and nonlesional gene expression profiles from psoriasis patients. Lesional samples were compared to their respective matched nonlesional samples. Differentially expressed genes (DEGs) were calculated using the DESeq2 for R version 4.0.5. Gene ontology (GO) enrichment analysis was performed using the GOseq package for R. Based on the top GO categories, pathways were further explored using Gene Set Variation Analysis (GSVA).

Results: 26 PN and 26 psoriasis matched samples were analyzed. 3,775 DEGs were shared by both diseases, and PN had twice as many DEGs as psoriasis. The top GO categories for PN included epithelium development, cell adhesion, and cell-cell signaling, while top categories for psoriasis included cytokine-mediated signaling, Fc receptor signaling, and cellular response to cytokine stimulus. GSVA revealed that PN, but not psoriasis, demonstrated significant upregulation of transforming growth factor beta-induced epithelial to mesenchyme transition (logFC [fold change] 0.44, P=0.001), epidermal acanthosis (logFC 0.61, P<0.001), axon regeneration (logFC 0.46, P=0.011), and vascular endothelial growth factor activity (logFC 0.23, P=0.014).

Conclusion: Patients with PN have upregulation of fibroproliferative, neuropathic, and angiopathic pathways that are distinct from psoriasis.

YIC6: Chronic pruritus represents a major burden in hepatic disorders

Vanessa Karlen1, Miriam Düll1, Marcel Vetter1, Peter Dietrich1,2, Jörg P. Kupfer3, Markus F. Neurath1, Andreas E. Kremer1,4

1Department of Medicine 1, University Hospital Erlangen, Deutsches Zentrum Immuntherapie DZI, Erlangen, Germany,2Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany,3Institute of Medical Psychology, Justus-Liebig-University Giessen, Giessen, Germany,4Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland

Introduction: While previous data show a high prevalence of pruritus in patients with immune-mediated liver disorders, there is only scarce data on pruritus in hepatobiliary diseases in general.

Aim of the Study: This study therefore aims at further investigating the epidemiology, clinical features, and influence on quality of life (QoL) in a large cohort of patients with different liver diseases.

Materials and Methods: We performed a prospective, cross-sectional study in the hepatological outpatient department of the University Hospital Erlangen from August 2020-May 2021. We collected clinical data including characteristics of pruritus (eg, mean/worst itch intensity on a numeric rating scale, NRS) and questionnaires containing the validated scores ItchyQoL and SF12. Statistical analyses were performed using Mann-Whitney-U-test and Spearman’s rank correlation. Data are given as mean±SEM.

Results: Out of 609 patients, 24.1% (N=147) of patients reported on pruritus, of whom 61.9% (N=91) were female and 38.1% (N=56) male. 27.3% (N=166) of patients had liver cirrhosis. Immune-mediated and cholestatic liver diseases presented with 46.3% (N=68) the majority of underlying disorders in the pruritus group. 80.9% (N=119) of pruritic patients reported on chronic itch (duration > 6 wk). 17.7% (N=26) received anti-pruritic therapy, most commonly used were fibrates (30.5%, N=8). Mean and worst itch intensity during the last week were rated at 3.7±0.2 and 4.2±0.3 respectively. The QoL of affected patients quantified by ItchyQoL correlated with mean and worst itch intensity (rs=0.34; P<0.001; r=0.40; P<0.0001). SF-12 analyses exhibited significantly lower median physical (P<0.0001) and mental scores (P<0.01, Mann-Whitney-U-test) in the pruritus group.

Conclusion: Chronic pruritus affected almost every fourth patient with hepatobiliary diseases and chronified in a large number of patients. Our findings underscore to increase awareness of chronic itch in systemic diseases and to study this symptom in clinical trials beyond the classical cholestatic liver disorders.

YIC7: Peripheral signaling pathways of non histaminergic itch in humans

Andrea Fiebig1, Victoria Leibl2, Barbara Namer1

1Research Group Neuroscience, Interdisciplinary Centre for Clinical Research Within the Faculty of Medicine at the RWTH Aachen University, Aachen, Germany,2Institute of Physiology and Pathophysiology, University of Erlangen-Nürnberg, Erlangen, Germany

In the last years agonists of MRGP receptors such as BAM 8-22 and beta-alanine have been extensively scrutinized with respect to itch sensation mainly in cellular approaches and animal models. We set out to investigate the action of BAM 8-22, beta-alanine and cowhage extract in human. We performed psychophysical experiments using two different application modes: intracutaneous injections or focal application via inactivated cowhage spicules and assessment of axon-reflex- erythema as indicator for activation of silent nociceptors (CMi). Single C-fiber responses to BAM 8-22, beta-alanine and cowhage extract were recorded using microneurography. We found that beta-alanine causes the same itch/pain ratio independently of application mode. Injection of Bam 8-22 or Cowhage evoked more pain than focal application. A wide-spread axon- reflex-erythema could be only observed after cowhage injection. Microneurography showed that all tested CM-nociceptors were activated by beta-alanine (n=49). BAM 8-22 activated 85% of CM-nociceptors (total n=39). 29 of 34 beta-alanine responsive CM-nociceptors were also activated by Bam 8-22. CMi-fibers were rarely activated by beta-alanine (one of 11 tested CMi-fibers) and BAM 8-22 activated none of 8 tested CMi-fibers. All very high threshold fibers were activated by BAM 8-22 (n=5) and beta-alanine activated the majority of tested VHT fibers (6 of 7). Injection of cowhage extract activated 10 of 18 CM-fibers and 3 of 12 tested CMi-fibers. In 18% of CM-fibers beta-alanine induced a specific action potential pattern consisting of regular trains of action potentials for few seconds and breaks of 20-60 seconds. Bam 8-22 induced this pattern in 30% of CM-fibers and cowhage extract in 11% of CM-fibers. We conclude that CM-fibers are major players in non-histaminergic itch evoked by beta-alanine and BAM 8-22. Cowhage extract activates CMi-fibers. We propose that a mixture between spatial contrast, population coding and pattern coding leads to the differential sensations of itch versus pain.

YIC8: P-Cresyl sulfate, a gut microbiota-derived metabolite, is associated with itch in psoriasis

Mariusz Sikora

Medical University of Warsaw, Warsaw, Poland

Introduction: p-Cresyl sulfate (pCS), a bacterial metabolite, has been associated with changes in peripheral and central nervous system, endothelial damage and inflammatory responses. A recent study reported that pCS enhance protease-activated receptor-2 expression in vitro and in vivo in keratinocytes, potentially playing an important role in itch pathogenesis. Pruritus is a common and distressing symptom that affects patients with psoriasis. Our previous study showed altered intestinal barrier in psoriasis with subsequent translocation of bacterial metabolites into the systemic circulation. However, the correlation between pCS and pruritus in patients with psoriasis has not been evaluated yet.

Aim of the Study: This study investigated the serum concentration of pCS and its possible correlation with pruritus in patients with psoriasis.

Materials and Methods: Serum pCS concentrations were measured in 40 patients with psoriasis and age-, sex- and BMI-matched healthy controls (n=30) using high-performance liquid chromatography. The characteristic of pruritus was assessed using a visual analog scale (VAS; 0-10).

Results: Serum pCS concentration was significantly higher in patients with psoriasis than in control group (1.93±0.5 vs. 4.35±1.2 ug/mL, P<0.05). In patients with psoriasis, serum pCS concentrations were significantly correlated with VAS (R=0.628; P<0.05). Increasing tertiles of pCS concentrations were associated with itch intensity. Multiple regression analysis revealed pCS as an independent factor associated with pruritus in psoriasis, even after full adjustment for age, psoriasis activity, inflammatory status and renal function.

Conclusion: These findings suggest that serum pCS concentration may be a valuable biomarker of itch in patients with psoriasis. Bacterial metabolites, such as pCS, may be a link between microbiome changes, intestinal barrier damage and pathogenesis of pruritus in psoriasis.

YIC9: Alloknesis and hyperknesis differentiate chronic pruritus entities

Manuel Pereira1, Henning Wiegmann1, Lina Renkhold1, Bettina Pfleiderer2, Claudia Zeidler1, Martin Schmelz3, Konstantin Agelopoulos1, Sonja Ständer1

1Department of Dermatology and Centre for Chronic Pruritus, University Hospital Münster, Münster, Germany,2Institute of Clinical Radiology, Medical Faculty, University of Münster and University Hospital Münster, Münster, Germany,3Department of Anesthesiology and Intensive Care Medicine, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany

Introduction: Neuronal sensitization is a state of augmented responsiveness of neurons to nociceptive and innocuous stimuli. In chronic pruritus (CP) conditions, neuronal sensitization contributes to enhanced itch perception and disease chronicity.

Aim of the Study: To assess neuronal sensitization, alloknesis (ie, perception of itch after non-pruritic stimulation) and hyperknesis (ie, exaggerated response to pruritic stimulation) were tested in patients with CP of neuropathic and inflammatory origin.

Methods: CP Patients with atopic dermatitis (AD, n=33) and brachioradial pruritus (BRP, n=35), and matched healthy controls (HC, n=60) were included. We tested mechanical alloknesis using a cotton swab, chemical hyperknesis upon a skin challenge with cowhage and electrical hyperknesis with transcutaneous electrical stimulation delivering half sine and sine wave pulses in rising intensity. Assessments were performed in pruritic and non-pruritic skin of patients and in non-pruritic skin of HC.

Results: BRP patients perceived itch more often upon stimulation with a cotton swab in pruritic skin compared to AD patients (P=0.03) and HC (P<0.05). Maximal evoked itch by cowhage stimulation at both testing sites was higher in patients compared to controls (P<0.01), while no differences were recorded across patient groups (AD vs. BRP). Upon electrical stimulation, maximal evoked itch was higher in pruritic skin of BRP patients compared to HC (half-sine stimulation: P=0.01; sine stimulation: P=0.02). Electrically evoked pain was higher in BRP patients compared to AD patients and controls.

Discussion: BRP patients show more often alloknesis in pruritic skin compared to AD patients and HC, while hyperknesis was elicited in both patient groups with different stimulation modalities. Induction of alloknesis and hyperknesis differed according to skin status (pruritic vs. non-pruritic). These data argue for varying degrees of neuronal sensitization according to CP origin and skin status.

YIC10: Experiencing itch via the rubber hand illusion

Antoinette van Laarhoven1, Judy Veldhuijzen1, Chris Dijkerman2

1Leiden University, Leiden, The Netherlands,2Utrecht University, Utrecht, The Netherlands

Touch can be perceived as itch as a result of sensitization processes. It has however, barely been investigated how psychological processes can lead to non-itchy stimuli being perceived as itchy. The aim of the present study was to investigate whether healthy individuals can feel itch upon and after mechanical stimulation when they have the illusion that an itch stimulus is applied. Thirty-six female healthy volunteers were tested, in a within-subjects design, using a rubber hand illusion paradigm with a right-handed rubber arm. Ownership over the rubber arm (ie, as if the rubber arm was the participant’s) was first induced by simultaneously stroking both the rubber arm and the hidden participant’s right arm with brushes. The itch-provoking substance cowhage was rubbed for 45 s onto the left arm of the participant, followed by a 2:15 min follow-up period with cowhage remaining on the arm. A similar ownership induction followed, succeeded by rubbing cowhage onto the rubber arm simultaneously with rubbing without cowhage on the hidden participant’s right arm. Levels of evoked itch were assessed on a numeric rating scale from 0 (no itch at all) to 10 (worst itch imaginable) every 15 s. Average itch perceived during the 45-seconds of rubbing (primary outcome) and during follow-up were statistically compared with 0 in one-sample t-tests. During the RHI, the average evoked itch differed significantly from 0 during both the rubbing and follow-up phase. The illusion that an itch stimulus is applied can induce itch. Although the average levels of itch were low, this study demonstrates that the RHI paradigm is suitable to study the role of psychological factors in itch origination.

Special Interest Groups (Sigs)

SIG1: What are good and weak instruments in itch assessment?

Christian Apfelbacher1, Janine Topp2, Sonja Ständer3, Matthias Augustin2, Christine Blome2

1Institute of Social Medicine and Health Economics, Otto von Guericke University Magdeburg, Magdeburg, Germany,2Institute for Health Services Research in Dermatology and Nursing (IVDP), German Center for Health Services Research in Dermatology (CVderm), University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany,3Department of Dermatology, Center for Chronic Pruritus, University Hospital of Münster, Münster, Germany

Introduction: Pruritus as a subjective sensation needs to be assessed from the patients’ perspective. Various patient-reported outcome measures have been developed, but they vary in underlying constructs and their clinimetric performance. Guidance is needed regarding the choice of instrument.

Aims: We aimed to systematically review the literature pertaining to validation studies of pruritus-specific patient-reported outcome measures. The methodological quality of validation studies was assessed based on the COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) checklist and the measurement properties of patient-reported outcome measures were evaluated.

Results: The Medline literature search (1965-2019) yielded 41 studies evaluating 38 different measures. Outcome measures were mapped to one of three constructs where possible: pruritus intensity, pruritus severity, pruritus-specific health-related quality of life. The COSMIN rating revealed mixed results with deficiencies in methodological quality of many studies across all constructs. Aggregated ratings for single outcome measures did not exceed a moderate evidence level. The most appropriate pruritus severity measure was the “Itch Severity Scale”. “Itchy Quality of Life” and the disease-specific “Uremic Pruritus in Dialysis Scale” achieved most promising results considering the construct pruritus-specific health-related quality of life. For pruritus intensity, nine different measures PERFORMED SIMILARLY WELL. THESE WERE mostly versions of the Numerical Rating Scale (NRS) - 11 and the Visual Analogue Scale (VAS), differing in recall period and addressing mean or worst itch.

Conclusion: Future validation studies should focus on rigorous methodological quality and thorough reporting of methodology. Particular focus should be put on under-investigated measurement properties, including content validity, responsiveness, measurement error, and cross-cultural validity, with content validity being the most important MP.

SIG2: ITCHYQOL – What is new?

Claudia Zeidler

Department of Dermatology and Centre for Chronic Pruritus, University Hospital Münster, Münster, Germany

Introduction: Chronic pruritus can severely impair the quality of life. To improve the measurement of the effects of chronic pruritus on quality of life. Chen et al developed a pruritus-specific instrument called ItchyQoL. The ItchyQoL consists of 22 items and has a recall period of seven days. A total score and three further subscores for “Symptom”, “Function” and “Emotion” can be calculated from these items.

Material and Methods: In order to assess the psychometric properties of ItchyQoL 551 patients with chronic pruritus completed the patient reported outcome measure. Item characteristic curves and confirmatory factor analyses were carried out. Afterswards a Rasch analysis for the modifed ItchyQoL assessed the mean fit residuals in addition to the assumptions of unidimensionality and local independence.

Results: Using CTT an excellent structural validity in the modified version with three possible answers was shown. The overall fit to the Rasch model was adequate.

Conclusions: A modified version with a response categories from a 5-point to a 3-point scale is more valid. We therefore suggest to modify the ItchyQoL.

SIG3: Scratch assessment

Brian Kim

Washington University School of Medicine, St. Louis, MO, USA

Itching is a subjective sensation that is currently captured by patient-reported tools such as the numerical rating scale (NRS) itch score. While the NRS has proven useful for measuring chronic itch severity and measuring response to treatments in clinical trials, weaknesses include its subjective nature, inability to distinguish different kinds of itch, and limited utility in children and those with cognitive impairment. Herein, we describe a new wireless and touchless technology called Emerald which employs radiofrequency signals and machine learning to measure itch objectively, accurately, and in a three-dimensional manner. We speculate Emerald’s utility in unveiling previously unrecognized forms of itch and their associated comorbidities.

SIG4: Pruritus in chronic kidney disease: what is new?

Thomas Mettang

Kidney Center Wiesbaden, Wiesbaden, Germany

Many patients are suffering from advanced chronic kidney disease (CKD) worldwide with about 6 Mio patients being on dialysis in 2019. Uremic pruritus is quite frequent in patients with end-stage renal disease and underestimated as a major contributor to patients’ suffering. Uremic Pruritus (UP) is still an unresolved clinical and pathophysiological problem which has a significant negative impact on patients’ quality of life. According to the current pathophysiological approaches different treatment modalities have been investigated. Referring to the Calcium-Phosphate hypothesis one meticulous study tried to enlighten the downstream mechanism of uremic itch after an subcutaneous injection of calcium-phophate-cristalls in mice identifying IL-6, ERK (Extracellular signal-regulated) and Brutons Kinase (BTK) as signal-transducing factors. In line with these results another study documented the success of calcium-lowering treatment with sodium thiosulfate in patients suffering from UP. Focusing on opioid-receptor derangements as a main reason for UP a polish group could demonstrate a significant epidermal reduction in kappa-opiod-expression in Pat. with UP compared to dialysis patients not complaining about itch. Recently a landmark study on treatment of UP with the peripherally active kappa-opiod-agonist Difelikefalin (Df) was published (KALM-1-Study). 24-hour worst-itch-sensation could be lowered significantly more effective by treatment with Df in patients with moderate to severe UP than with placebo. No significant side effects of treatment with Df were observed. Since many years UVB phototherapy is utilized to reduce itch in patients with UP. However in recent years its use has been withheld in many cases due to a feared carcinogenic effect. A large Taiwanese study now stated that ultraviolet B phototherapy did not increase the risk of skin cancer, non-melanoma skin cancer or cutaneous melanoma.

SIG5: Clinically meaningful itch change in chronic kidney disease associated pruritus

Sonja Ständer1, Margaret Vernon2, Catherine Munera3, Robert H. Spencer3, Frédérique Menzaghi3

1Center for Chronic Pruritus, Department of Dermatology, University Hospital Münster, Germany,2Evidera, Bethesda, MD, USA,3Cara Therapeutics, Stamford, CT, USA

The Numerical Rating Scale (NRS) ranging from 0 (no itching) to 10 (worst imaginable itching) is currently the most commonly used primary endpoint in clinical trials assessing the anti-pruritic effect of novel therapies. Though it is validated for chronic pruritus, data on the performance of NRS in chronic kidney disease associated pruritus are rare. Especially the magnitude of the reduction that is clinically meaningful to the patients was unknown. To address this, a secondary analysis of data pooled across treatment groups from a phase 2, multicenter, double-blind, randomized, placebo-controlled study (NCT02858726) was performed with the aim to determine the magnitude of change required for a meaningful reduction in itch intensity on the Worst Itch NRS (WI-NRS) in hemodialysis patients with moderate-to-severe pruritus. The study showed a significant reduction of itch intensity and an improvement of itch-related quality of life (QoL) for the selective kappa opioid receptor agonist difelikefalin over placebo. Itch intensity and QoL scores were collected over an eight week treatment period. Secondary outcomes comprised a Patient Global Impression of Change (PGI-C; seven categories ranging from “very much improved” to “very much worse”), Patient Global Impression of Worst Itch Severity (PGI-S; 0 (none) to 4 (very severe)), Skindex-10 and 5-D itch QoL questionaires. The threshold for meaningful reduction of WI-NRS was estimated using anchor- and distribution-based methods consistent with FDA guidance. A total of 174 hemodialysis patients were included, who were predominantly male (60%) and African American (59%) with a median (range) age of 59 (26-84) years and history of chronic itching for 4.4 years. The baseline WI-NRS mean was 6.8; distribution-based estimates, considered to provide lower boundaries of meaningful change thresholds, ranged from −0.67 to −1.78 points. In the primary anchor analysis, mean changes in WI-NRS ranged from −2.26 to −3.41 points with large effect sizes (Cohen’s d >1.0) associated with a priori definitions of a clinically important improvement measured by the PGI-C. This analysis demonstrated that a reduction of ≥3 points on the WI-NRS marks an appropriate threshold for defining a clinically meaningful change in pruritus in patients with CKD-aP.

SIG6: Relationship between sensitive skin and environmental factors

Laurent Misery

Department of Dermatology, Brest University Hospital, Brest, France

Sensitive skin is 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”. Meta-analyses on the role of environmental factors on sensitive skin found that cosmetics was the main factor. Other factors were wet air, air conditioning, temperature variations, heat, water, pollution, dry air, cold, wind, sun and emotions. However, all studies were based on the subject's opinions. Few exposure studies were performed and showed that subjects with sensitive skin more frequently use hair dyes or hair conditionners. New exposure are needed.

SIG7: An international study of experiences, needs and preferences of healthcare professionals regarding the psychological assessment and treatment of patients with chronic itch

Andrea M. Evers1, Sonja Ständer2, Jörg P. Kupfer3, Elke Weisshaar4, Christina Schut3, Gil Yosipovitch5, Sylvia van Beugen1, Gudrun Schneider6

1Leiden University, Leiden, The Netherlands,2Department of Dermatology, Center for Chronic Pruritus, University Hospital of Münster, Münster, Germany,3Institute of Medical Psychology, Justus-Liebig-University Giessen, Giessen, Germany,4University Hospital Heidelberg, Occupational Dermatology, Department of Dermatology, Heidelberg, Germany,5Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery and Miami Itch Center, University of Miami, Miami, FL, USA,6Psychosomatic Medicine and Psychotherapy, Department for Mental Health, University Hospital Münster, Münster, Germany

Introduction: Although healthcare professionals such as dermatologists generally recognise the importance of psychological factors in the management of chronic itch, scarce research in small samples in individual countries shows that they have limited time and knowledge to manage these problems. Insights into the needs, experiences and preferences of healthcare professionals could aid in determining focus points to support the needs of healthcare professionals and improve patient care.

Aims: This international study aims to obtain an overarching view of the experiences, needs and preferences of healthcare professionals regarding psychological assessment and treatment of patients with chronic itch.

Results: Preliminary results were based on 95 participants (54% female) from 32 countries. Most participants were dermatologists (74%). Healthcare professionals with clinical and/or research experience in psychological assessment/treatment of chronic itch (ie, 76% of participants) most often recommended the use of questionnaires to assess quality of life (81% of participants), distress, anxiety and/or depression (71%), itch severity and intensity (69%) and other physical symptoms (49%). The psychologist/psychotherapist was most commonly recommended for treatment of patients with chronic itch and other problems such as severe itch-scratch problems, clinical depression/anxiety or somatic symptom disorder. The most suggested kind of psychological treatment is dependent on the disorder (ie, habit reversal training for patients with severe itch-scratch problems; cognitive behavioral therapy and relaxation training for depression, anxiety or somatic symptom disorder). The vast majority of participants (ie, 82%) indicated a need for more education on psychological assessment and treatment of patients with chronic itch.

Conclusion: This study gives insight into current practices regarding psychological assessment and treatment in clinical practice and highlights the broad recommendation of questionnaires for psychological assessment and the high self-reported need for additional education in healthcare professionals. Offering online education is recommended to support this need and potentially improve patient care.

Lectures

Invited Lectures

OP1: Bernhard LectureWhat I have learned from three decades of being a student of itch

Alan Fleischer

University of Cincinnati, USA

Introduction: When I began my exploration into itch and its management in the clinical environment, little was known about mechanisms, measurement and therapy.

Aims: This brief overview will help identify some of the major milestones achieved in my career by many of the members of the International Forum for the Study of Itch.

Results: Major advances have been made into the neuroanatomy and physiology, psychological contribution, itch measurement and identified treatments.

Conclusions: With advances already achieved, we are now in a better position to continue to advance the field.

OP2: KURAISHI Lecturepursuit of itch from an environmental perspective

Hiroyuki Murota

Department of Dermatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

Management of the causal factor of chronic itch is important to achieve long-term control. Itch frequently occurs in response to environmental stimuli, especially those that cause heat or warmth. Noxious heat stimuli can lead to itch, and changes in the temperature of the skin’s surface can augment it. Heat-provoked itch is sometimes intractable to existing treatments. Recent studies of the receptors associated with itch in response to noxious heat stimuli contribute to a much better understanding of the process. From a clinical perspective, a warm sensation is a major provocative factor for patients with atopic dermatitis. The accumulation of artemin in the dermis of lesional skin provides a pathological mechanism for heat-provoked itch. As artemin is induced in the epidermis via continuous activation of aryl hydrocarbon receptors, environmental pollutants caused by dioxins may contribute to the development of alloknesis. Another contributing factor to heat-provoked itch is sweat. To study the mechanism of sweat-mediated exacerbation, we focused on the dynamics of sweat in the sweat gland and its properties. Interestingly, sweat gland leakage into surrounding tissue was involved in the mechanism of the rapid, tingling itch sensation in response to warmth. This leakage was mainly due to a marked reduction in claudin-3 expression in the sweat glands of atopic dermatitis lesions or to histamine exposure. Metabolomic analysis revealed increased glucose in the sweat metabolites of patients with atopic dermatitis, and the sweat glucose levels significantly correlated with disease severity. Further investigation using a disrupted skin barrier animal model revealed that early-stage skin barrier recovery was impaired by a glucose concentration similar to that of atopic dermatitis sweat, implying that sweat glucose may exacerbate itch by interfering with skin barrier recovery in patients with severe symptoms. It can be said that I have acquired these data by being fortunate enough to meet wonderful friends. I will continue to investigate itch from the perspective of a dermatologist.

OP3: Animal models of itch: descending modulation

Earl Carstens

Department of Neurobiology, Physiology and Behavior, University of California, Davis, USA

Introduction: Pruriceptor afferents activate a spinal itch-signaling pathway that is modulated segmentally and probably also suprasegmentally. Pain varies with expectation, stress and other factors that also influence itch. Pain variability is mediated by neurons in the rostral ventromedial medulla (RVM) that modulate spinal nociceptive transmission.

Aims: To determine if itch transmission is also affected by the descending pain-modulatory pathway.

Results: Scratching behavior requires the parabrachial nucleus, and is facilitated by neurokinin-1 receptor (NK-1R)-expressing neurons in the midbrain periaqueductal gray via a synapse in RVM. RVM neurons also express NK-1R and many coexpress GABA. Chemogenetic activation of RVM NK-1R-expressing neurons inhibited pruritogen-evoked scratching behavior with little effect on pain. Microinjection of substance P in RVM also suppressed scratching and facilitated pronociceptive RVM ON-cells. Optotagging revealed that most ON-cells express NK-1R, while 50% of antinociceptive OFF-cells were inhibited by optogenetic activation. Chemogenetic activation of RVM neurons that express the G-protein-coupled estrogen receptor (GPER) also inhibits acute and chronic itch behavior. It is unknown if RVM neurons coexpress NK-1R and GPER. Chemogenetic activation of ventrolateral brainstem GABAergic neurons that coexpress prodynorphin also suppressed acute itch behavior.

Conclusions: Like pain, itch is subject to descending modulation from the brainstem. ON-cells appear to have opposing effects on pain compared to itch.

OP4: Representation of itch perception in the primary somatosensory cortex

Xiao-Jun Chen1,2, Yan-He Liu1,2, Ning-Long Xu1,2,3, Yan-Gang Sun1,3,*

1Institute of Neuroscience, State Key Laboratory of Neuroscience, Center for Excellence in Brain Science & Intelligence Technology, Chinese Academy of Sciences, Shanghai, China,2University of Chinese Academy of Sciences, Beijing, China,3Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, China

*Corresponding author

Multiple cortical areas including primary somatosensory cortex (S1) are activated during itch signal processing, yet cortical representation of itch perception remains unknown. Using a novel miniature two-photon microscopic imaging in free-moving mice, we investigated the coding of itch perception in S1. We found that a subpopulation of S1 pyramidal neurons encoded itch perception, as defined by immediate subsequent scratching behaviors. The itch-induced scratching behavior could be well predicted by the activity of a fraction of layer 2/3 pyramidal neurons. With a newly established optogenetics-based pruritic stimulation that well mimicked chemical itch, we found that itch-coding S1 neurons exhibited a near “all-or-none” response pattern at the stimulus intensity at the threshold of itch perception, further demonstrating the activity pattern of S1 representing itch perception. Our study established new paradigms and revealed the neural mechanism underlying itch perceptual coding in S1, thus paving the way for studying cortical representation of itch perception at the single-neuron level in freely moving animals.

OP5: Activation of mast-cell-expressed mas-related G-Protein-coupled receptors drives non-histaminergic itch

James Meixiong1, Michael Anderson1, Nathachit Limjunyawong1, Mark F. Sabbagh1, Eric Hu1, Madison R. Mack2, Landon K. Oetjen2, Fang Wang2, Brian Kim3, Xinzhong Dong4

1Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA,2Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO, USA; Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA,3Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO, USA; Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA,4Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Mast cells are skin-resident immune cells that are key effectors of pathological itch. Millions of people suffer itch from various conditions such as urticaria or hives, food allergy, drug hypersensitivity reactions, and allergic contact dermatitis (ACD). Classically, this itch is believed to arise from IgE-dependent mast cell release of histamine. However, numerous reports have demonstrated that antihistamines are ineffective at treating various types of pathological itch. Our current study puts forth a novel paradigm of mast cell activation independent of IgE. We employed mouse genetics, behavior, and in vivo calcium imaging of the dorsal root ganglia (DRG) to investigate the role mast cell receptors MrgprB2 and MRGPRX2 play in chronic mast cell-associated itch. We show, for the first time, that MrgprB2 activation of mast cells elicits non-histaminergic itch. Using in vivo DRG imaging, we demonstrated that IgE activation of mast cells actuates a different neuronal pattern compared to MrgprB2 activation (ie, histamine-sensitive vs. insensitive neurons, respectively). This is the first study to visualize the activation of sensory neurons in vivo by direct activation of mast cells in the skin. We determined activation of mast cells via MrgprB2 induces itch distinct from canonical IgE mast-cell activation by preferentially releasing tryptase rather histamine. MrgprB2-triggered itch is not alleviated by histamine receptor antagonists, similar to the observed ineffectiveness of antihistamines in many allergic itch disorders in patients. We also showed that MrgprB2/X2 contribute to ACD itch, a disorder that affects millions of people annually via allergens such as poison ivy, nickel, perfumes, topical antibiotics, etc. MrgprB2 deficiency decreased itch in multiple ACD models and we showed there was significant increases in mast cell number and levels of MRGPRX2 ligand in human skin samples of ACD. This suggests MRGPRX2 could be a promising target for therapeutic intervention for the broad disease category of ACD.

OP6: Endogenous pruritogens and potentiators of chronic itch

Pang-Yen Tseng, Mark Hoon

Molecular Genetics Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA

Introduction: Chronic itch is a major health concern for many inflammatory skin conditions. Despite the clinical need, the molecular and cellular processes underlying this condition are poorly understood.

Aims: We investigated the potential peripheral pathways for potential endogenous pruritogens and potentiators of pruritus in inflammatory skin diseases.

Results: We identified potential mediators of itch in atopic dermatitis (AD) and psoriasis from human dermal transcriptomic data. These agents, beta-defensin (DEF103B) and oncostatin M (OSM), were validated in mouse models of itch and in in vitro assays. Results from these studies show that mechanistically OSM potentiates responses of itch-neurons while DEF103B directly activates MRGPRX1 in these neurons.

Conclusion: OSMR and MRGPRX1 receptor antagonism may be a rational targets for the treatment of psoriasis and AD.

OP7: Skin microbiome and itch

Hei Sung Kim

Incheon St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea

Itch is an unpleasant sensation that emanates primarily from the skin. The chemical mediators that drive neuronal activity originate from a complex interaction between keratinocytes, inflammatory cells, nerve endings and the skin microbiota, relaying itch signals to the brain. Stress also exacerbates itch via the skin-brain axis. Recently, the microbiota has surfaced as a major player to regulate this axis, notably during stress settings aroused by actual or perceived homeostatic challenge. The routes of communication between the microbiota and brain are slowly being unraveled and involve neurochemicals (ie, acetylcholine, histamine, catecholamines, corticotropin) that originate from the microbiota itself. By focusing on itch biology and by referring to the more established field of pain research, this talk will focus on the possible means by which the skin microbiota contributes to itch.

OP8: 3D Skin imaging in itch

Hong Liang Tey

National Skin Centre, Singapure

Introduction: The pathogenesis of chronic itch is not well-understood, and there is no good treatment for chronic pruritus of unknown origin (CPUO), especially one that addresses the underlying cause.

Aims: To elucidate the pathogenesis of itch using 3D ex vivo and in vivo skin imaging in patients with chronic pruritus.

Methods and Results: We performed whole-tissue imaging using optical clearing and 3D imaging to visualize the cutaneous nervous system in ex vivo skin of healthy individuals and patients with chronic pruritic dermatoses. We found a significant reduction of intra-epidermal nerves in chronic itch. This suggests to us that the primary pathology of chronic itch does not lie the nerves and the reduction of the itch-transmitting intra-epidermal nerves is likely a secondary phenomenon. We proceeded to investigate other cutaneous components in chronic itch, using 3D in vivo time-lapsed imaging and ex vivo immunofluorescence studies. We identified pathologies in the sweat apparatus, and instituted treatments targeting this etiology for patients with chronic pruritus of unknown origin. Results of our 6.5-year observational study revealed significant reduction of itch in two-thirds of the patients and the treatments were safe. Further ways to improve the response rate will be explored during the presentation. We will further present ways in which optical clearing and 3D imaging can improve the management of cutaneous basal cell carcinomas, through improving sensitivity in the identification of nervous infiltration and determining clearance of surgical excision margins.

Conclusion: We identified a significant reduction of intra-epidermal nerves in chronic itch and this is likely a secondary phenomenon. We identified pathologies in the sweat apparatus in patients with chronic pruritus of unknown origin and instituted new treatments targeting this etiology, which have been observed to be safe and effective.

OP9: S1PR3 plays a key role in S1P-evoked itch

Rose Z. Hill1, Takeshi Morita1, Ziad Rifi1, Cliff Vuong1, Diana Bautista1,2

1Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA,2Helen Wills Neuroscience Institute, University of California, Berkeley, CA, USA

Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that is associated with a variety of skin disorders, including psoriasis (Checa et al, 2015; Myśliwiec et al, 2016), atopic/allergic contact dermatitis (Kohno et al, 2004; Sugita et al, 2010), and scleroderma (Castelino and Varga, 2014), as well as neuropathic pain (Patti et al, 2012; Janes et al, 2014) and other inflammatory disorders (Rivera et al, 2008; Chiba et al, 2010; Tränkner et al, 2014; Donoviel et al, 2015; Roviezzo et al, 2015). We set out to examine the roles of S1P in acute and chronic itch in mice. We found that S1P triggers itch and pain in a dose-dependent manner via S1PR3. Neuronal imaging and electrophysiological experiments revealed that S1P signals via S1PR3 and TRPA1 in a subset of pruriceptors, and via S1PR3 and TRPV1 in a subset of heat nociceptors. In behavioral assays, S1P-evoked acute itch was selectively lost in mice lacking TRPA1, while S1P-evoked acute pain and was selectively lost in mice lacking TRPV1. Finally, we examined the role of S1P signaling in imiquimod model of psoriasis, and found that loss of S1PR3 significantly attenuates scratching behaviors. Our findings show that S1P/S1PR3 signaling is a key mediator of acute and chronic itch and suggest that S1PR3-specific antagonists may be effective in combating itch associated with inflammatory skin diseases.

OP10: New treatments for itch

Gil Yosipovitch

Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery and Miami Itch Center, University of Miami, Miami, FL, USA

A new exciting era of antipruritic drugs is quickly approaching, presenting targeted treatments for patients suffering from chronic itch of different types. A summary of new and emerging treatments for pruritus will be discussed. Conditions such as CKD itch have for the first time a labeled indication with a kappa opioid agonist and Prurigo Nodularis an itchy condition associated with multiple skin diseases will have specific anti pruritic drugs. New topicals include drugs targeting neural receptors in the skin such as TRPV3 channels and alpha 2 adrenegeric agonists as well as drugs targeting the neural immune axis such as as JAK/Stats inhibitors and phospodiestarase inhibitors. Systemic drugs such as oral kappa opioids and mu antagonists show promising results as well as Mrgprs antagonists with specific anti itch effect in conditions such as hepatic itch and C kit inhibitors for chronic urticaria have a great potential. New treatments for cholestatic itch using kappa opioids and new bile acid absorbers as well as biologics such as IL 31 inhibitors and targeting IL 4 and IL13 and JAK Stats and Tyrosine Kit inhibitor provide promising results for indications beyond atopic eczema. With development of new targets, clinicians can obtain a greater arsenal of treatment for their patients, to successfully treat them and improve their quality of life.

OP11: Prurigo update 2021

Sonja Ständer

Center for Chronic Pruritus, Department of Dermatology, University Hospital Münster, Germany

Chronic prurigo is a persistent and burdenful neuroinflammatory dermatosis associated with severe itching, permanent scratching behavior and diverse comorbidities. Chronic nodular prurigo (prurigo nodularis) is the dominant phenotype of chronic prurigo and comprises 70% of patients. Prurigo affects all races, sex, and all ages with preference of females above age of 60 years. Children are rarely affected. Epidemiological studies are infrequent and report different prevalence depending on method and population included. Recently, prurigo-specific instruments for physician-documentation have been validated. Prurigo can thus be documented by an investigator global assessment (IGA) ranging from 0 (mild prurigo; no nodules) to 4 (severe prurigo; over 100 nodules). The validated investigator questionnaire Prurigo Activity and Severity Score (PAS) assesses several parameter of the disease such as type, number, and distribution of pruriginous lesions, proportion of pruriginous lesions with excoriations and proportion of healed lesions. Itch intensity is monitored best with validated instruments such as the numerical rating scale (NRS). The health-related quality of life can be documented either by Dermatology Life Quality Index (DLQI) or the itch-specific ItchyQol. A close neuroimmune communication is discussed as pathophysiological mechanism with abundant presence of Th1, Th2 and Th22 cells. Especially Th2 cytokines including interleukin (IL) 4 and IL31 are abundantly present in pruriginous skin. IL 4 and IL31 have prominent roles; the latter not only enhancing the inflammation, but also leading to epidermal hyperplasia and fibrosis of the collagen tissue. Next to IL31, also upregulated periostin might promote fibrosis formation by releasing IL31 from various immune cells. Nerve fiber dysfunction and pathological neuroanatomy maintained pruritus and the inflammation. A laddered approach to treat patients is recommended by the first international guideline on diagnostic and therapy of prurigo. Fortunately, clinical trials are currently performed with opioid modulators as well as IL4 and IL31 receptor antibodies being investigated for their antipruritic effect in prurigo.

OP12: Future perspectives in experimental itch research

Brian Kim

Washington University School of Medicine, St. Louis, MO, USA

The discovery of new pruriceptive pathways in the peripheral and central nervous systems have greatly informed new paradigms of not only itch sensation but somatosensory function in general. Herein, we highlight big questions that will continue to change our understanding of itch as a broader paradigm of sensation through new multiomic, optogenetic, and machine learning-based approaches.

OP13: Future perspectives in clinical itch research

Adam Reich

Department of Dermatology, Institute of Medical Sciences, Medical College of Rzeszow University, Rzeszów, Poland

Itch is defined as an unpleasant subjective sensation which provokes a desire to scratch. It is probably the most common symptom in dermatological diseases which significantly impacts the patients’ quality of life. For centuries people tried to alleviate itch using various treatment modalities, but they frequently were ineffective. However, in recent years, a significant progress has been done in the understanding of pruritus pathogenesis which enabled development of new drugs and new treatment strategies for pruritus. Several new molecules are being developed or are in advanced clinical trials, showing very promising results, such as nemolizumab, vixarelimab, or nalbuphine, why others have been demonstrated as less efficacious, such as serlopitant. Conducting clinical trials not only provides data on new drugs effectiveness, but also forces validation of old or development of new instruments to properly assess pruritus severity. Thus, recent years brought several new scales for pruritus measurement. Due to its interdisciplinary nature, patients with pruritus often require multidisciplinary support and care. To optimize current treatment strategies, there is a need to organize a network of centers of excellence dealing with patients suffering from itch on the pattern on UCARE network in urticaria.

Sponsored Lectures

OP14: Nemolizumab results in rapid improvement of pruritus, sleep, and quality of life in patients with prurigo nodularis

Sonja Ständer

Center for Chronic Pruritus, Department of Dermatology, University Hospital Münster, Germany

Introduction: Patients with prurigo nodularis (PN) have intensely itchy nodular skin lesions, a markedly impaired quality of life and frequent sleep deprivation. Nemolizumab is an investigational first-in-class humanized monoclonal antibody directed against the IL-31RA that blocks IL-31 signaling. This paper will present the outcome of the 12-week randomized, double-blind, placebo-controlled phase 2 trial of nemolizumab in PN and will give an update on the ongoing phase 3 studies.

Methods: Patients enrolled into the phase 2 study had moderate-to-severe PN with lesions on upper limbs and ≥20 nodules on the body and severe pruritus (peak pruritus numerical rating scale [PP-NRS] ≥7 over the previous week, scale 0-10). Nemolizumab 0.5 mg/kg was administered subcutaneously at baseline, week 4, and week 8, and safety assessments were performed through week 18.

Results: A total of 70 patients were randomized (nemolizumab n=34, placebo n=36) and baseline PP-NRS was 8.4 in both groups. The groups were comparable in baseline itch, but there were more patients with severe disease (IGA 4) in the nemolizumab group (18 (53%) vs. 14 (39%) in placebo group). Baseline sleep disturbance NRS [SD-NRS] was 7.4 and 6.8 in the nemolizumab and placebo group, respectively. Within 48 hours reduction of itch in patients treated with nemolizumab was significantly greater than in patients receiving placebo (PP-NRS −19.5% vs. −5.8%, respectively, P=0.014). A significant difference between nemolizumab and placebo in the response criteria for itch (PP-NRS ≥4) was achieved at day 3 (23.5% vs. 0%, P<0.001) and was sustained throughout the study. A significant difference in SD-NRS response ≥4 was reported within 48 hours (−8.8% vs. 0% with placebo, P=0.037). Benefits were sustained throughout the study period. Significantly more patients achieved improvement of skin inflammation expressed by an Prurigo Activity Scale 75% and IGA success (clear and almost clear) with nemolizumab compared with placebo.

Outlook: Three phase 3 studies with an enrolment target of 540 patients are ongoing: Two randomized double-blind placebo-controlled studies with flat dosing based on body weight (30 mg for <90 kg or 60 mg every 4 weeks for ≥90 kg) over 16 and 24 weeks respectively and a 64-week long-term extension study.

Conclusion: Compared with placebo, nemolizumab showed a rapid and significant improvement in pruritus, a significant improvement in sleep and QoL and a significantly greater reduction in skin lesions. Results from ongoing large pivotal phase 3 studies with nemolizumab are awaited.

OP15: CLE-400: A novel potential topical treatment for chronic neuropathic itch

Johanna Schumann, Elanite Caspi, Dorit Mimrod, Yael Rosen, Erez Koren, Mark Zamansky, Elena Kagan, Orna Goren

Clexio Biosciences, Petach Tikva, Israel

Neuropathic itch develops in normal skin as a symptom of central or peripheral nervous system disorders. Itch severities are similar to itch caused by classic pruritic dermal or systemic diseases but there are no approved therapies for the condition. CLE-400 is a gel of detomidine being developed for the topical treatment of neuropathic itch. Detomidine is a potent α2-adrenergic receptor agonist. Detomidine also activates histamine-4 and somatostatin-4 receptors and their expression have been confirmed in pig skin. Together, these targets suggest that CLE-400 may have a multimodal mechanism-of-action leading to inhibition of neural signalling from the skin to the brain. Topical administration of CLE-400 was evaluated in the validated chloroquine-induced pruritus mouse model: CLE-400 was administered topically once daily for 5 days, followed by chloroquine challenge. Application of CLE-400 significantly reduced scratching behaviour at all 3 tested doses when compared to placebo. CLE-400 effect was also evaluated in a peripheral neuritis trauma pig model of chronic neuropathic pain induced by partial sciatic nerve ligation, where it was applied on the leg innervated by the injured nerve. CLE-400 demonstrated a dose-dependent analgesic effect, as well as reductions in spontaneous pain behaviour and mechanical allodynia. These results support the hypothesis of the peripheral activity of CLE-400 in inhibiting neuronal signalling, leading to alleviation of sensory symptoms of chronic neuropathic conditions, including neuropathic pain and itch. A Phase 1 single-ascending-dose study demonstrated safety and PK profiles that support further development of CLE-400, and support once daily administration. Preliminary results from an ongoing multiple-ascending-dose study are also supportive. A Phase 2 proof-of-concept study in patients suffering from Brachioradial Pruritus is planned to start in H1-2022. Based on publically available data, this is the first investigational study in BRP. Treatment of additional conditions involving chronic itch and pain may be evaluated in subsequent studies.

OP16: The engineering fabric utilizes the regulatory functions of sweating: Comfiknit

Andrea Chan

Wealthy Step International Limited, Hong Kong, China

Introduction: A microbial balanced environment is essential to maintain healthy skin, and therefore improve the self-management of medical skin conditions such as Atopic Dermatitis (AD). A balanced skin condition can be achieved by: (1) maintaining our skin surface in a suitable temperature; (2) keeping our skin dry but moisturized; (3) maintaining our skin’s pH value between pH 4.5-6; and (4) keeping our skin from potential allergen. Clothing is a significant element because it touches our skin all the time. The choice of clothing becomes an important part of the AD self-management to reduce possible skin irritation. A suitable clothing choice should have the functions that resemble the roles of sweating so it can fill in the roles of sweating when it is not functioning properly.

Aims: Design clothing with features that utilize the regulatory functions of sweating: (1) maintain suitable skin temperature; (2) keep skin dry but moisturized; (3) with a pH value between 4.5-6; (4) non-allergic.

Results: Comfiknit is an engineered fabric with a unique layered structure and special knitting properties. Comfiknit has the following features: (1a) It keeps our skin at a suitable temperature via evaporative cooling, if we sweat. (1b) It can be constructed with different levels of thermal conductivity according to seasonal change by adjusting the moisture content of a fabric through its intelligent design. (2) It manages sweat by having the ability to dry quickly through its unique layered structure. (3) It keeps our skin’s pH balance by using Poly Lactic Acid (PLA) as one of the major textile materials and as the next-to-skin fabric layer because PLA has a pH value of 5.5, similar to the natural skin pH value. Furthermore, PLA, a common material used in surgery, is also hypoallergenic, so it will not cause skin irritation. (4) It prevents salt residue staying on our skin surface because it absorbs sweat due to the unique layering structure and special knitting properties, so sweat can be evaporated through the garment rather than on skin surface, reducing skin irritation when wearing the clothing for a long period of time.

Conclusion: Wearing suitable clothing that addresses the needs to stabilize skin condition during seasonal change can be a solution to reduce skin irritation and improve skin management. The innovative structure and special knitting properties of Comfiknit address these needs for patients with medical skin condition during seasonal change from summer to winter, leading to an improved life quality with reduced pain and discomfort.

OP17: Translating itch biology to new therapies

Brian Kim

Washington University School of Medicine, St. Louis, MO, USA

Emerging innovations in itch neurobiology, coupled with new understanding of the neuroimmune circuitry underlying chronic itch, have rapidly informed and advanced novel therapeutics for chronic pruritus. Herein, we describe new approaches to treat different for forms of chronic itch including atopic dermatitis, chronic pruritus of unknown origin, prurigo nodularis, and uremic pruritus. In addition to blocking key pruriceptive signals, we present new data on how modulation of mu and kappa opioid pathways represent novel itch-suppressive therapies.

OP18: Measurement of nocturnal scratching in children with atopic dermatitis using the itch tracker app

Shigetoshi Kobayashi

Department of Pediatrics, Teikyo University School of Medicine, Tokyo, Japan

Itch and scratch are the major symptoms of atopic dermatitis (AD), which cause sleep disorders and significantly reduce the patient's quality of life. Scratching worsens the skin condition which in turn triggers another scratching, leading to a vicious cycle known as the itch-scratch cycle. Itch is usually assessed by subjective measures such as the Visual Analogue Scale (VAS), but this is difficult in children. In order to properly treat itching in pediatric patients with AD, an objective method to evaluate itching or scratching movement is needed. Itch Tracker is a smartwatch application with a unique algorithm that analyzes acceleration data from the Apple Watch. It is capable of measuring nocturnal scratching movement and has been demonstrated to have high sensitivity and positive predictive value in the assessment of nighttime pruritus in adult AD patients. In this study, to investigate the usefulness of this application in children, we measured nocturnal scratching movements in 9 children (5 AD patients and 4 non-AD controls, aged 10-16 years) using Itch Tracker. The duration of the scratching movement of AD patients was significantly longer than that of non-AD controls. In addition, the number of scratching movement of AD patients was significantly higher than that of non-AD controls. These two parameters also showed the strong positive correlation with Eczema Area and Severity Index (EASI) in AD patients. These results suggest that the Itch Tracker is a simple tool for objective assessment of scratching movement and is expected to be applied to the evaluation of disease activity in pediatric AD patients.

View Point Session

OP19: What I miss in itch research – basic scientist perspective

Martin Schmelz

Department Experimental Pain Research Mannheim, Heidelberg University, Mannheim, Germany

Before starting to name shortcomings of the research field it is important to highlight the key achievements of basic itch research in the last decade: when considering the enormous head start of pain research it is amazing that basic itch research has managed to surpass the pain field in the molecular characterization of primary afferents, spinal cord processing of itch and central connectivity. The single most important factor for this unique success in my opinion is the value of scratch behavior as biomarker for itch intensity. In contrast, evoked pain behavior or measures of ongoing pain in experimental animals does not provide the same level of information and does not cover supra-threshold encoding. Thus, we have to concede that basic itch research has performed extremely well in characterizing mediators and neuronal populations involved in itch processing. When focusing on aspects that still need improvement it is mainly successful translation: this obviously includes translation from acute to chronic itch, from rodent to human, and from evoked to disease-related itch. Species differences between human and rodent pruriceptor and nociceptor populations are currently being investigated. A more complex problem is the translation of “natural” activation patterns of nociceptors and pruriceptors as compared to optogenetically induced synchronized activity or temporal discharge profiles induced via designer receptors exclusively activated by designer drugs (DREADDs). The challenge here is that in addition to specificity based on the genetic tools, the temporal activation patterns need to be considered as the acute short-lasting activation might facilitate itch induction whereas tonic discharge might be required for spinal itch processing. In summary, basic itch research has pioneered characterization of spinal and brain circuits crucial for itch processing. The key challenges from my perspective are successful translation concerning species, temporal aspects, and disease entity.

OP20a: What I miss in itch research –clinician’s perspective

Asit Mittal

Department of Dermatology RNT Medical College, Udaipur, India

Although there has been impressive advancement in our understanding of chronic itch, both at basic sciences level and in Clinic, a few things that still bother me as clinician when I see a patient of chronic itch in my clinic. I will share here. Itch measurement in clinic is still a major challenge. There are no totally objective tools available. Various quality of life questionnaires do not capture all dimensions of chronic itch in all populations. This is one area where more research is needed. Workup of generalized Pruritus without skin lesions remains a challenge in clinic. Comprehensive screening can be quite expensive for these patients. There is a lack of consensus for optimal screening approach. There are no systemic therapies approved for itch specifically. Most clinicians still use antihistamines as one size fit all treatment for all itches even though most of chronic itches seen in clinic are non histaminergic. This needs to be addressed. Number of other systemic therapies that include SSRIs, Opioid agonists/antagonists, TCIs, and Gabaergics, Naltrexone all have strong rationale and are supposed to work in different chronic itches, but there are lack of well designed studies to convince clinician about their definite role in managing itches. More research should also be directed in finding effective topical medications for managing itch. Number of newer molecules such as IL31 R inhibitors, NK antagonists, Opioid agonist/antagonist are under phase 2/3 trials. Even if these newer molecules make their way in the market, cost of their therapy will not allow their routine use in clinic particularly in places/countries where patients have to pay from their pockets (No insurance). There is a need for a strong cost-effective treatment approach. Psychological factors are important in all kinds of itches, more research should be put into neurobiological mechanism and psychological determinants and psychological intervention in the treatment of chronic itch, the therapeutic potential of heat, cold, light, other natural products in tackling chronic itch should also be explored more.

OP20b: A clinician’s perspective: opportunities/knowledge gaps

Timothy Berger

Department of Dermatology, University of California, San Francisco, California, USA

Pruritus is driven by inflammation and sensed by specific neural pathways. Patients would benefit from more knowledge in both of these aspects of pruritus. Immunology of Pruritus: 1. Skin biopsies: On routine biopsies be able to determine: cytokine profiles (IL-36), cell populations, 2. Regulatory T cells, unstudied? 3. Better animal models, 4. Think outside the box: skin Na+ and Th2 (skin sodium elevated in AD but not psoriasis), 5. Barrier: Outside-In, 6. Genetics: Larger data bases. For psoriasis researchers to discover 60+ “psoriasis genes” > 10,000 patients were genotyped, 7. Complex model systems: Immune cells and nerves, 8. Why does Th2 system continue to exist? It’s not just parasites. Neurobiology: 1. Why does neural degeneration cause pruritus? (aging population, DM, SFN), 2. Circadian Rhythm and itch (itch and sleep), 3. Where and how is itch sensed? New Neural receptors (potential targets), 4. Neural-immune/Nerve-Nerve crosstalk (IL-31, neuropeptides), 5. Relevance of nerve recruitment, polymodal nerves in chronic itch/sensitization, 6. Sympathetic nervous system and pruritus, 7. Genetics: My Hypothesis: there will be at least 3 types of genetic diseases implicated in pruritus/eczemas: a. Barrier (Filaggrin), b. Immune (IL4, 13, 31 etc) c. Neural (???). Let’s take a Global Perspective: 1. Better classification/definition of itching conditions: Sonja S. and PN; Dan Butler and Itch in the Elderly, 2. More international cooperation/studies: Aquagenic pruritus in Nigeria (20 % of young males!!); Lichenoid Reactions: Indian dermatologists can teach us a lot, 3. Healthcare disparities-their role in pruritus, 4. Itch and Climate Change-What will we see in the future? Clinicians need to provide scientists with more carefully characterized pruritus patients and scientists need new methods to investigate these well defined subtypes of pruritic conditions.

OP21: What I miss in itch research – the patient perspective

Wendy Smith Begolka

National Eczema Association, Novato, CA, USA

The patient perspective and answers to questions patients most often ask are poorly represented in research. Patients and caregivers have identified itch as the most problematic eczema symptom, and immediate and sustained relief of itch as the most important result that an eczema treatment should provide. To make research more patient-centric, reseachers should consider questions that have practical implications to self-care and the medical treatment of the itch of eczema, as well as harness real-world data collected from patients. While much has been learned about this burdensome symptom and its multidimensional impacts, as new eczema therapies emerge, it will be essential for future research to investigate how the burden of itch is changing, for who, and with what approaches, in order to drive future innovation and appreciation of this significant health issue. The National Eczema Association’s new app and research registry EczemaWise (eczemawise.org) is collecting patient-reported data, including data related to itch, to support patient care and shared decision making today as well as future research advances in itch and other areas of eczema-related investigation.

Posters

P1: Itch in esthetic dermatology - what is known?

Radomir Reszke, Jacek C. Szepietowski

Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Wroclaw, Poland

Introduction: Itch is a multifactorial symptom occurring due to diverse cutaneous and systemic conditions. Notably, itch may also appear as a consequence of various medical and cosmetic procedures (often referred to as esthetic dermatology procedures). This is especially important, as with the growing number of esthetic procedures worldwide, physicians and other medical specialists will encounter more patients with adverse events, including itch.

Aim of the Study: To review the available literature on the occurrence of itch associated with the most common procedures used in esthetic medicine.

Results: There are multiple esthetic procedures/modalities which were reported to cause itch in the literature, including peelings, laser therapy, injections of fillers, injections of platelet-rich plasma (PRP), various skin grafts, but also tattoos or permanent make-up. Itch may appear as an isolated sensation or together with the development of cutaneous lesions. Moreover, certain procedures are frequently associated with the development of itch which may be anticipated. Conversely, itch may also denote a possibility of secondary infections, eg. fungal.

Conclusion: Itch is an important symptom associated with many esthetic procedures. It is necessary to raise awareness of this issue both in practitioners and their patients.

P2: Safety and effectiveness of dupilumab treatment for moderate-to-severe atopic dermatitis in Korean patients: a real-world retrospective analysis

Hanjae Lee, Bo Ri Kim, Kyu Han Kim, Dong Hun Lee, Jung Im Na

Seoul National University Bundang Hospital, Seoul, National University College of Medicine, Seoul, South Korea

Background: The use of dupilumab is growing exponentially worldwide, the importance of reporting/sharing the accumulating experience with dupilumab in clinical practice cannot be stressed enough.

Objectives: We aimed to assess the efficacy and safety of dupilumab in Korean patients with moderate-to-severe AD in real clinical practice.

Methods: We retrospectively reviewed the clinical findings of patients diagnosed with moderate-to-severe AD who were administered dupilumab at Seoul National University Hospital or Seoul National University Bundang Hospital during August 2018-October 2019.

Results: Among the 40 patients identified, most were men (n=29, 72.5%), and the mean age was 30.9 years. Most had AD since infancy or childhood (n=35, 87.5%), and concurrent histories of other atopic disorders were common with 18 (43.9%) patients with allergic rhinitis and 12 (29.3%) patients with asthma. We observed excellent overall treatment efficacy with the mean EASI score decreased from 28.2 to 3.2 at week 52. Notably, the therapeutic effect was maintained despite the considerable number of patients requiring an increase in treatment intervals due to the financial burden in a real clinical setting. Seven of the 40 patients (17.5%) reported 9 adverse events in total. Conjunctivitis was the most frequent adverse event (6 [15%]).

Conclusion: Our study confirms the therapeutic efficacy of dupilumab in real clinical practice in a setting where an increase in the treatment interval was frequently required.

P3: Itch in multiple sclerosis

Giuseppe Ingrasci1, Leticia Tornes2, Andrew Brown2, Kottil Rammohan2, Jeffrey Hernandez2, Gil Yosipovitch1

1University of Miami, Department of Dermatology and Cutaneous Surgery, Miami, FL, USA,2University of Miami, Department of Neurology and Multiple Sclerosis, Miami, FL, USA

Introduction: Multiple Sclerosis (MS) is an autoimmune demyelinating inflammatory disease of the CNS. Few anecdotal case reports and case series have documented itch in MS patients. The current estimated prevalence of pruritus in MS is 4.5%. However, little is known about itch experienced by patients with MS as there are no large-scale studies of itch in this patient population.

Aims: This cross-sectional study sought to determine the prevalence, characteristics, and quality of life impacts of itch in MS patients. It also aimed to determine associations between itch severity with MS-specific review of symptoms and to determine if affected itchy areas were associated with dermatomal areas of T2 hyperintense lesions found on recent MRI imaging studies.

Materials/Methods: Patients with an established MS diagnosis were asked to participate and describe their current symptoms. Those who had itch in last two months were given the Standardized Itch Questionnaire and ItchyQol forms. The NRS was used to rate the itch intensity (range 0 to 10). All patients’ medical records were reviewed for MS-specific review of symptoms, neurologic examination findings, comorbid conditions, and most recent MRI imaging findings. T-tests were used to compare numerical parameters between itch- and non-itch-groups. Categorical variables were compared using Chi-square or Fisher’s Exact tests.

Results: Of the 72 total MS patients, 27 patients (37.5%) reported experiencing itch associated with their disease. Anxiety, depression, heat sensitivity, paroxysmal cramps or spasms were significantly more common in MS patients with itch than without. In 75% of cases, itch was localized to a dermatomal region innervated by T2 hyperintensity on MRI.

Conclusions: Localized itch is more common in MS patients than in the general population. Their itch is linked to their disease severity and is often localized to dermatologic areas innervated by hyperintense lesions on MRI.

P4: The association of chronic pruritus with patients’ quality of life: a cross-sectional study

Zoe Lipman1, Qai Ven Yap2, Leigh Nattkemper1, Gil Yosipovitch1

1Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery and Miami Itch Center, University of Miami, Miami, FL, USA,2Department of Biostatistics, Yong Loo Lin School of Medicine, Singapore, Singapore

In this study, we aimed to examine how demographics and itch characteristics (intensity, duration, frequency, and diagnosis category) impact patients' quality of life (QoL). A cross-sectional survey was administered to patients with chronic pruritus at Itch Centers in the Department of Dermatology at the University of Miami and at Temple University from 2015 to 2020. Survey data included demographics, clinical diagnoses, itch intensity [numerical rating scale, 0-10], itch characteristics, and the ItchyQoL survey. Gender significantly impacted QoL, with females displaying higher overall, symptom, and emotional scores while males displayed more impaired functioning. All racial/ethnic groups were associated with a change in symptom QoL, whereas only African Americans and Middle Easterners had decreased overall QoL. Greater itch history lengths were found to decrease QoL in all domains. Increasing daily itch episodes were associated with increased ItchyQoL scores in all domains, specifically those with >2 episodes per day. Itch intensity weakly correlated with ItchyQoL scores in all domains. Gender, age, and length of itch history did not independently associate with itch intensity. Multivariate regressions revealed significant impacts of gender, itch frequency, and length of itch history for overall, symptom, functioning, and emotional QoL. Our results demonstrate that different etiologies of itch can similarly decrease QoL. Rather, decreased QoL may have a greater association with female gender, length of itch history and frequency of itch episodes. We hope that this data raises awareness of the various items that may influence patients’ QoL.

P5: Racial differences in dysregulation of the renin-angiotensin-aldosterone system in patients with prurigo nodularis

Nishadh Sutaria, Melika Marani, Justin Choi, Youkyung S. Roh, Varsha Parthasarathy, Junwen Deng, Zachary A. Bordeaux, Martin Alphonse, Shawn G. Kwatra

John Hopkins University, School of Medicine, MD, USA

Introduction: Prurigo nodularis (PN) has a strong association with kidney disease. The mechanism of this association and its racial disparities are unclear but may be linked to the renin-angiotensin-aldosterone system (RAAS).

Aims of the Study: To characterize the role of the systemic and cutaneous RAAS in PN patients stratified by race.

Materials and Methods: We conducted a cross-sectional analysis of renal comorbidities in PN using TriNetX, a global health research network providing access to medical records. Epidemiological findings provided the basis for translational studies on plasma and skin biopsy samples from PN patients stratified by race. Plasma and skin biopsies were also collected from a cohort of PN patients and healthy controls. Plasma was assayed for angiotensinogen and RNA-sequencing was performed on skin specimens to identify dysregulated RAAS genes. Ingenuity Pathway Analysis (IPA) on was performed on transcriptomic data to identify dysregulated pathways. All analyses were stratified by race to determine racial differences in RAAS dysregulation.

Results: PN was associated with stages 1-5 of chronic kidney disease (CKD), end-stage renal disease, nephritic syndrome, nephrotic syndrome, glomerular disease, and tubulointerstitial disease, but the associations were significantly stronger in black patients. Compared to controls, CKD progression was faster (HR 2.88, 95% CI: 1.01–8.26) only in black PN (10-year survival: 63.5% black vs. 85.5% white). Translational studies showed that plasma angiotensinogen was dysregulated (P<0.001) only in black PN patients. Cutaneous transcriptomic analysis of genes related to the renin-angiotensin-aldosterone system (RAAS) and IPA analysis revealed considerable dysregulation in PN lesions with greater dysregulation in black patients.

Conclusion: The systemic and cutaneous RAAS are dysregulated in PN patients and may explain PN’s association with renal comorbidities. Higher incidence and severity of renal disease in black PN patients may be explained by greater RAAS dysregulation.

P6: CD26/DPPIV Regulates mechanical alloknesis at the periphery

Eriko Komiya1, Mitsutoshi Tominaga1, Ryo Hatano2, Takumi Itoh2, Kotaro Honda1, Sumika Toyama1, Yayoi Kamata1, Haruna Otsuka2, Kei Onuma2, Chikao Morimoto2, Kenji Takamori1,3

1Juntendo Itch Research Center (JIRC), Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, Japan,2Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, Japan,3Department of Dermatology, Juntendo University, Urayasu Hospital, Japan

Introduction: Mechanical alloknesis is itch hypersensitivity caused by normally innocuous mechanical stimuli. We recently discovered the involvement of CD26/DPPIV enzyme in the regulation of psoriatic itch. This enzyme exerts its biological activity by processing various substances including neuropeptides. However, the role of CD26/DPPIV in alloknesis remains unclear.

Aim of the Study: To investigate the regulatory mechanism of CD26/DPPIV in alloknesis.

Materials and Methods: Innocuous mechanical stimuli using von Frey filaments was applied to the rostral back of CD26/DPPIV knockout (CD26KO) mice or wild-type mice 30 times in 5-sec intervals. The number of scratching responses was taken as the alloknesis score (alloknesis assay). Immunohistochemical and behavioral pharmacological analyses were performed to examine the physiological activities of CD26/DPPIV or endomorphins (EMs), endogenous agonists of mu-opioid receptors.

Results: The alloknesis score in CD26KO mice was significantly higher than that in wild-type mice. When recombinant DPPIV or mu-opioid receptor antagonist was injected intradermally, the alloknesis score in CD26KO mice significantly decreased, whereas mutant DPPIV without enzyme activity had no effect. We next focused on endomorphins (EMs, EM-1 and EM-2), which are endogenous ligands for the mu-opioid receptor and substrates for the DPPIV enzyme. Intradermal injection of EM-1 or EM-2 to wild-type mice induced alloknesis, while the recombinant mixture of DPPIV- digested EM fragments did not. We found that EMs were located in keratinocytes and peripheral neurons. Behavioral analyses revealed that EMs evoked mechanical alloknesis more than chemical itch, whereas beta-endorphin, another MOR ligand, elicited chemical itch more potently than mechanical alloknesis.

Conclusion: Our data suggest that CD26/DPPIV negatively regulates alloknesis through DPPIV enzymatic degradation of cutaneous EMs.

P7: Performance of itchyqol-mini in routine dermatologic care

John Monroe1, Fatema Esaa2, Suephy C. Chen3, Julie Ryan Wolf4

1University of Rochester, Rochester, NY, USA,2University of Rochester School of Medicine & Dentistry Rochester, NY, USA,3Duke University, Durham, NC, USA,4University of Rochester Medical Center, Rochester, NY, USA

Introduction: Itch is a multidimensional symptom of dermatologic disease associated with significant impairment of health-related quality of life (QoL). The ItchyQoL-mini (IQM), a shortened version of the ItchyQoL (IQ), could be used to monitor itch burden in clinical care.

Aim of the Study: This study compared the use of the IQM to the IQ in routine dermatologic care.

Materials and Methods: A retrospective study of itch-specific PROs [IQM, IQ, and Itch Numerical Rating Scale (NRS)] administered on tablets during routine dermatologic care (n=1907 clinic visits). The IQM (3 items) and IQ (22 items) measured impact of itch on QoL, on a 5–point scale (1=Never; 2=Rarely; 3=Sometimes; 4=Often; and 5=All of the time), in three subscales (Symptom, Function, Emotion). Itch NRS was used for itch severity grouping (mild=1-3, moderate=4-6, severe=7-10). Statistical analyses were performed at 0.05 significance level using JMP15 Pro.

Results: Majority of patients were Caucasian (81%) females (60%) with mean age of 49 years. Itch was reported for 974 visits, with severe itch reported for 27% of visits. The highest itch severity (Itch NRS) was reported for Pruritus (n=32; 6.7), Atopic Dermatitis (n=27; 6.1), Rash/Skin Eruption (n=62; 5.7), Dermatitis (n=110; 5.3), and Psoriasis (n=121; 5.0). IQM duration was less than IQ (39.5 vs. 167.1 seconds, P<0.001). IQM strongly correlated with IQ (r=0.879, P<0.001; α=0.917). Overall, IQM scores were higher than IQ scores (2.86±1.15 vs. 2.40±0.97, P<0.001). For visits with the highest itch severity, Black patients reported significantly greater itch burden compared to white patients (IQM Total: 3.93±1.02 vs. 3.22±1.15, P=0.004).

Conclusions: IQM is a valid instrument to measure the burden of itch during routine dermatologic care. The itch burden was significantly greater in Black patients than white patients with chronic skin disease.

P8: Real-world data on the role of peripheral blood laboratory testing in prurigo nodularis: a multicenter cohort study

Junwen Deng1, Varsha Parthasarathy1, Melika Marani1, Nishadh Sutaria1, Zachary A. Bordeaux1, Thomas K. Le1, Kevin Lee1, Waleed Adawi2, Sylvie Gabriel3, Rajeev Chavda3, Shawn G. Kwatra1

1Johns Hopkins University, Department of Dermatology, School of Medicine, Baltimore, MD, USA,2Eastern Virginia Medical School in Norfolk, VA, USA,3Galderma GBU in La Tour-de-Peilz, Switzerland

Introduction: The recommended diagnostic workup of prurigo nodularis (PN) involves blood testing for systemic comorbidities, but laboratory dysregulation in PN have yet to be quantified using real-world data.

Aim of the Study: To examine the laboratory alterations in PN and identify appropriate tests for diagnostic workup.

Materials and Methods: PN patients ≥18 years were identified with ≥2 diagnostic codes for PN (ICD-10 L28.1) from 2015-2021 using TriNetX, a global research network encompassing medical records from 170 healthcare organizations. Patients were age-, sex-, race-, and BMI-matched to controls without any dermatitis diagnoses. Laboratory results within 1 month of diagnosis were only considered. P-values were adjusted using the Benjamini-Hochberg method for multiple hypothesis testing with an a priori alpha of 0.05.

Results: We identified 11,716 PN patients and 12,639,847 controls. Demographics after matching included mean age of 45.9 (±16) years, 59.9% female, 65.2% white, and 19.6% black race. Compared to controls, PN had higher mean absolute lymphocyte count (6.5±40.2×103/μL vs. 2.7±8.4×103/μL, P=0.0002), eosinophil percentage (3.3±3.5% vs. 2.5±2.1%, P<0.0001), and monocyte percentage (8.5±3.1% vs. 8.2±2.9%, P=0.001) on complete blood count. On comprehensive metabolic panel, PN had higher glucose (120.4±63.6 mg/dL vs. 110.8±45.4 mg/dL, P<0.0001), blood urea nitrogen (19.5±14.8 mg/dL vs. 16.7±9.7 mg/dL, P<0.0001), creatinine (1.6±4.4 mg/dL vs. 1.1±1.9 mg/dL, P<0.0001), alkaline phosphatase (107.0±92.9 U/L vs. 84.5±64.2 U/L, P<0.0001), and lower estimated glomerular filtration rate (73.1±31.4 mL/min/1.73 m2 vs.81.6±25.1 mL/min/1.73 m2, P<0.0001). PN also had higher triglycerides (172.4±380.4 mg/dL vs. 127.4±82.2 mg/dL). Coagulation studies revealed higher prothrombin time (16.3±8.2sec vs. 14.2±5.8sec, P<0.0001) and activated partial thromboplastin time (35.7±15.6sec vs. 32.5±11.5sec, P=0.002). Finally, PN patients had higher hemoglobin A1c (7.0±2.1% vs. 6.3±1.5%, P<0.0001), erythrocyte sedimentation rate (35.4±30.9 mm/hr vs. 28.3±27.2 mm/hr, P=0.017), and greater presence of hepatitis C antibodies (P=0.01).

Conclusion: Blood laboratory testing reveals dysregulation of endocrine, immune, hepatic, renal, hemostatic, and metabolic axes in PN, which is consistent with current knowledge of comorbidities associated with PN.

P9: Risk of hematological malignancy in patients with undifferentiated pruritus: a multicenter cohort study

Junwen Deng1, Nishadh Sutaria1, Waleed Adawi2, Abhishek Gami1, Varsha Parthasarathy1, Thomas K. Le1, Zachary A. Bordeaux1, Shawn G. Kwatra1

1Johns Hopkins University, Department of Dermatology, School of Medicine, Baltimore, MD, USA,2Eastern Virginia Medical School in Norfolk, VA, USA

Introduction: Pruritus is common among patients with hematologic malignancies (HMs). However, the risk of HM among patients with pruritus is not established. Additionally, the diagnostic utility of serum lactate dehydrogenase (LDH), frequently ordered to assess malignancy in pruritic patients, remains uncertain.

Aim of the Study: To determine the risk of a future HM and the diagnostic utility of LDH in patients with undifferentiated pruritus.

Materials and Methods: A population-level analysis from 2002-2020 was conducted with TriNetX, a global health research network encompassing 69 million patients. Patients were identified using ICD-10 code L29.9 (undifferentiated pruritus), excluding patients with chronic pruritic dermatoses or systemic disease-associated pruritus. Patients were age-, sex-, race-, BMI-, and smoking/alcohol status-matched to controls without diagnosis of pruritus. Diagnostic codes prior to the introduction of ICD-10 were mapped using SNOMED-CT and General Equivalence Mappings. P-values were adjusted for multiple hypothesis testing using the Benjamini-Hochberg method.

Results: 327,502 patients with undifferentiated pruritus and 8,934,671 controls were identified. Pruritic patients had highest risk of HM within 12 months of initial diagnosis, including increased risk of Hodgkin’s lymphoma (relative risk [RR] 4.42, 95% confidence interval [CI] 2.83-6.88), non-Hodgkin’s lymphoma (RR 2.35, 95% CI 1.96-2.82), multiple myeloma (RR 2.38, 95% CI 1.66-3.41), lymphocytic leukemia (RR 1.47, 95% CI 1.07-2.02), myeloid leukemia (RR 2.56, 95% CI 1.79-3.67), monoclonal gammopathy (RR 1.90, 95% CI of 1.55-2.32), and myelodysplastic syndrome (RR 1.74, 95% CI 1.14-2.64). Beyond the first 12 months, the risk of HM becomes comparable to controls. Pruritic patients had higher serum LDH (297.55±310.9 units/liter) compared to controls (255.51±223.73 units/liter), but LDH >250 units/liter did not confer a higher risk of developing HM in either group.

Conclusion: The risk of HM in patients with undifferentiated pruritus is highest only within the first 12 months of diagnosis, and LDH has limited diagnostic utility in these patients.

P10: Racial disparities in incident comorbidities and mortality in patients with prurigo nodularis: a multi-center cohort study

Varsha Parthasarathy1, Nishadh Sutaria1, Junwen Deng1, Thomas K. Le1, Zachary A. Bordeaux1, Kevin Lee1, Melika Marani1, Waleed Adawi1, Madeline Richard1, Sylvie Gabriel2, Rajeev Chavda2, Shawn G. Kwatra1

1Johns Hopkins University, Department of Dermatology, Baltimore, MD,2Galderma Prescription GBU, La Tour-dePeilz, Switzerland

Introduction: Prurigo nodularis (PN) is an inflammatory skin disease characterized by pruritic, hyperkeratotic nodules. PN is associated with racial and ethnic differences in presentation; however, limited information is known on the variation of associated systemic diseases and health care outcomes.

Aims: To identify racial and ethnic differences in incident comorbidity outcomes, healthcare utilization, and mortality of PN patients.

Materials and Methods: We used TriNetX, a health research network containing approximately 64 million patient records across 45 worldwide organizations. PN patients with ≥2 diagnosed instances of ICD-10 code L28.1 were age-, sex-, and race-matched to non-pruritic controls without PN. P-values were adjusted for multiple hypotheses using the Benjamini-Hochberg method.

Results: A total of 22,858 PN patients were identified from 1995-2020. Overall, PN was associated with all 36 incident diseases examined, most strongly with psychotic disorders [RR (relative risk) 3.68, 95% confidence interval (CI): 3.11-4.36], HIV [RR 3.5, 95% CI: 2.25-5.47], liver cirrhosis [RR 3.44, 95% CI: 2.89-4.10], and chronic viral hepatitis [RR 3.42, 95% CI: 2.78-4.21]. Black patients had the highest RR for 16 diseases, Asian patients for 14 diseases, and White patients for 6 diseases. PN patients also had more ambulatory visits [70.39±0.95 vs. 34.82±0.43, P<0.001], ER visits [4.71±0.15 vs. 2.99±0.09, P<0.001], and inpatient visits [9.37±0.30 vs. 5.85±0.17, P<0.001] than controls. Black PN patients had the highest number of ambulatory, ER, and inpatient visits overall. Finally, PN patients had higher mortality rates than controls [HR (hazard ratio) 1.70, 95% CI: 1.51-1.91, P<0.001]. Black PN patients had the highest mortality [HR 2.07, 95% CI: 1.64–2.61], followed by White [HR 1.74, 95% CI: 1.52-2.00] and Hispanic patients [HR 1.62, 95% CI: 1.03–2.54].

Conclusions: There are racial disparities in PN comorbidities, healthcare utilization, and mortality. These findings suggest a possible role of race in the presentation and severity of PN.

P11: Sleep disturbance in adults with prurigo nodularis is associated with increased C-reactive protein levels: a multicenter cohort study

Varsha Parthasarathy1, Kevin Lee1, Junwen Deng1, Nishadh Sutaria1, Thomas K. Le1, Zachary A. Bordeaux1, Melika Marani1, Waleed Adawi1, Madeline Richard1, Rajeev Chavda2, Sylvie Gabriel2, Shawn G. Kwatra1

1Johns Hopkins University, Department of Dermatology, Baltimore, MD, USA,2Galderma Prescription GBU, La Tour-dePeilz, Switzerland

Introduction: Prurigo nodularis (PN) is an inflammatory skin disease associated with a significant reduction in quality of life. The relationship between PN and sleep comorbidities remains understudied.

Aims: To examine the burden of sleep conditions in PN and associate findings with systemic inflammatory markers.

Materials and Methods: We used TriNetX, a healthcare research network of electronic medical records from approximately 73 million patients. PN patients were identified as having ≥2 diagnosed instances of ICD-10 code L28.1, and were age, race, and sex-matched to non-pruritic controls. P-values were adjusted for multiple hypotheses using the Benjamini-Hochberg method.

Results: A total of 73,181 PN patients were identified. After matching, the cohort mean (±SD) age was 54 (±15.4) years and 52.7% female. Relative to controls, PN patients had an increased risk of developing general sleep disorders [relative risk (RR) 1.47, 95% confidence interval (95% CI) 1.42-1.52], sleep apnea [RR 1.59, 95% CI 1.52-1.66], obstructive sleep apnea [RR 1.61, 95% CI 1.54-1.69], insomnia [RR 1.37, 95% CI 1.29-1.45], hypersomnia [RR 1.47, 95% CI 1.32-1.64], sleep-related movement disorders [RR 1.36, 95% CI 1.17-1.58], restless legs syndrome [RR 1.45, 95% CI 1.28-1.65], and unspecified sleep disorders [RR 1.20, 95% CI 1.06-1.35]. PN patients had higher mean C-reactive protein (CRP) than controls (12.7 mg/L vs. 7.6 mg/L, P<0.0001), and PN patients with sleep disorders had higher CRP than PN patients without sleep disorders (16.2 mg/L vs. 10.6 mg/L, P<0.0001). PN patients with sleep disorders were more likely to experience myocardial infarction [RR 1.60, 95% CI 1.38-1.85], cerebral infarction [RR 1.77, 95% CI 1.52-2.07], and peripheral vascular disease [RR 1.82, 95% CI 1.66-2.00] than PN patients without sleep disorders.

Conclusions: PN is associated with an increased risk of developing sleep disorders. Sleep disorders in PN are associated with higher risk of cardiovascular outcomes, likely contributing to the systemic inflammatory impact of PN.

P12: Improvement in sleep quality from reduction of itch intensity in patients with moderate-to-severe pruritus undergoing hemodialysis

Rebecca S. Ahdoot1, Kamyar Kalantar-Zadeh1, Kieran McCafferty2, Sebastian Walpen3, Thilo Schaufler3, Isabelle Morin3, Warren Wen4, Frédérique Menzaghi4, Sonja Ständer5

1Department of Medicine, Division of Nephrology Hypertension and Kidney Transplantation, University of California Irvine (UCI), Orange, CA, USA,2Barts Health NHS Trust, London, UK,3Vifor Pharma Group, Zurich, Switzerland,4Cara Therapeutics, Stamford, CT, USA,5Center for Chronic Pruritus, University of Münster, Münster, Germany

Introduction: Chronic kidney disease-associated pruritus (CKD-aP) is a common condition in patients with CKD undergoing hemodialysis (HD). Night-time pruritus may be a particularly burdensome symptom: In CKD- aP patients this results in poor sleep quality, an important marker of worse health-related quality of life (QoL). In phase 3 trials in patients with moderate-to-severe CKD-aP, difelikefalin (an investigational, peripherally restricted kappa-opioid receptor agonist), demonstrated significant improvements in itch intensity versus placebo at week 12, and improvements in sleep quality and itch-related QoL.

Aim of the Study: To evaluate the impact of reduced itch intensity on sleep quality among HD patients treated with difelikefalin or placebo in the KALM-1 and KALM-2 Phase 3 clinical trials.

Materials and Methods: This post-hoc analysis used pooled data for all patients. Improvement from baseline to week 12 in itch intensity was evaluated by weekly mean of the 24-hour Worst Itching Intensity Numerical Rating Scale (WI-NRS) score (range 0 [no itch] to 10 [worst itch imaginable]). Change in sleep quality was assessed by the 5-D Itch scale sleep disability question (1 [never affects sleep] to 5 [delays falling asleep and frequently wakes me up at night]). Spearman’s correlation analysis was performed.

Results: Patients with a clinically meaningful (≥3-point) reduction in WI-NRS score had significantly greater improvements in mean 5-D Itch sleep disability question score (−1.5 vs. −0.6 for <3-point WI-NRS score reduction; P<0.0001) from baseline to week 12 (n=709). A moderate correlation was observed between WI-NRS and 5-D Itch sleep disability question scores at week 12 (r=0.499, 95% confidence interval 0.442, 0.552). A significant improvement was also observed at the first assessment of sleep quality (4 wk) for patients with a ≥3-point (vs. <3-point) reduction in WI-NRS score (−1.2 vs. −0.4, P<0.0001, n=761).

Conclusion: Reduction of itch intensity correlates with improvement in sleep quality in HD patients.

P13: Psychosocial burden of itch in patients with basal cell carcinoma

Aleksandra A. Stefaniak, Iwona Chlebicka, Łukasz Matusiak, Jacek C. Szepietowski

Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Wroclaw, Poland

Introduction: Itch related to BCC was first described 13 years ago; however, its frequency, pathophysiology, management, and impact on life quality was never fully established.

Aim of the Study: This study aimed to analyze the psychosocial burden of patients with BCC and the influence of itch on patient life quality.

Materials and Methods: 180 consecutive patients with histologically confirmed BCC were included in the study. Maximal itch intensity from the last 3 days and from the beginning of the disease was assessed with Numerical Rating Scale (NRS) and 4-Item Itch Questionnaire (4IIQ). Quality of life was assessed with the 36-item Short-Form Health Survey (SF-36), Dermatology Life Quality Index (DLQI), 6 Item Stigmatization Scale (6-ISS), and Beck Depression Inventory (BDI).

Results: Mean DLQI in the study group was 2.0±2.0, while mean SF-36 was 71.38±15.77 points. The intensity of itch assessed with 4IIQ correlated negatively with SF-36 (R=–0.48, P=0.003). 16.34% of patients may be threatened with the co-existence of depression measured with BDI.

Conclusion: Itch presence and intensity may significantly affect the quality of life among the affected subjects with BCC.

P14: Is basal cell carcinoma an itchy tumor? clinical characteristics of itch in basal cell carcinoma

Aleksandra A. Stefaniak, Iwona Chlebicka, Łukasz Matusiak, Jacek C. Szepietowski

Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Wroclaw, Poland

Introduction: In common knowledge, basal cell carcinoma (BCC) is known to be asymptomatic, but in clinical practice, some patients complain of itching. Despite the frequency of this tumor, data on frequently encountered dermatologic symptoms, including itch, are still emerging.

Aim of the Study: This study aimed to assess the prevalence and clinical characteristics of itch in patients with histologically confirmed BCC.

Materials and Methods: The study group comprised of 180 consecutive subjects with BCC. Detailed information on demographics, clinical history, and physical findings were obtained. Various clinical features of itch were recorded. The intensity of itch was assessed with the Numerical Rating Scale (NRS) and 4-Item Itch Questionnaire (4IIQ). Moreover, detailed data regarding clinical features of itch including anatomical location, quality, descriptors, and the most common factors responsible for its aggravation or alleviation were obtained.

Results: Localized itch during the time of tumor development was present in 31.1% (56/180) of patients and during the last three days in 41 patients (71.4%). 48.2% experienced itching a few times per week, while the remaining subjects experienced itching every day (21.4%) or at least a few times per month (10.7%). The mean maximal intensity of the itch during the disease was 3.4±1.8 points, and during the last 3 days was 3.1±1.2 points (NRS), indicating moderate itch intensity. Usually, itch was not accompanied by other unpleasant cutaneous sensations (48.2%). Less commonly, it was described as stinging (10.7%), burning (8.9%), or tingling (7.1%).

Conclusion: Itch related to BCC is a moderately frequent, although seemingly underestimated problem among patients. It should be highlighted that more than 20% of patients reported that itching occurs constantly, every day.

P15: Characteristics of itch in pediatric population with diabetes mellitus type I

Aleksandra A. Stefaniak1, Agnieszka Zubkiewicz-Kucharska2, Łukasz Matusiak1, Anna Noczyńska2, Jacek C. Szepietowski1

1Department of Dermatology, Venereology and Allergology, Wrocław Medical University, Wroclaw, Poland,2Department of Endocrinology and Diabetology for Children and Adolescents, Wroclaw Medical University, Wroclaw, Poland

Introduction: Diabetes mellitus and its complications are a growing problem worldwide, with type 1 diabetes (DM1) reported being one of the most common medical conditions in school-age youth. There is a paucity in studies concerning cutaneous manifestations in children and adolescents with DM1.

Aim of the Study: This study aimed to investigate the prevalence of itch, to provide itch characteristics and explore the potential underlying causes.

Materials and Methods: The study group comprised of 100 children with DM1. Intensity of itch was assessed with Numerical Rating Scale (NRS) (maximal itch intensity during the last 3 d and 24h) and 4-Item Itch Questionnaire (4IIQ). Data regarding various clinical features of itch were obtained. The Children’s Dermatology Life Quality Index (CDLQI) was applied to assess life quality impairment. Skin dryness was assessed clinically and with corneometric assessment. Neurologic examination was done according to the guidelines of the American Diabetes Association.

Results: Among 100 studied patients, 22 subjects (22%) reported itch during the course of the disease, while 12 of them had itch present during the last three days. The mean maximal intensity of the itch during the last 3 days in NRS was as 5.9±3.0 points and last 24 h 5.0±3.8 points, indicating moderate itch intensity. The mean 4IIQ score was 6.7±3.5 points. Skin xerosis was more advanced in children with itch compared with those without itch (P<0.01). Intensity of itch (both NRS last 3 d and NRS last 24 h) correlated positively with life quality impairment (R=0.7; P=0.015 and R=0.8, P=0.002, respectively).

Conclusion: Itch as a moderately frequent symptom in children with DM1 and skin dryness may play a role in the pathogenesis of itch in this population.

P16: Clinical characteristics of itch in adult patients with type II diabetes

Aleksandra A. Stefaniak1, Piotr K. Krajewski1, Dorota Bednarska-Chabowska2, Grzegorz Mazur3, Jacek C. Szepietowski1

1Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Wroclaw, Poland,2Department of Angiology, Hypertension, and Diabetes, Wroclaw Medical University, Wroclaw, Poland,3Department of Internal Medicine, Occupational Diseases and Hypertension, Wroclaw Medical University, Wroclaw, Poland

Introduction: Itch is a common and distressing symptom occurring not only in dermatological conditions but also in chronic systemic diseases. In diabetes underlying pathophysiology, course of the disease, coexisting comorbidities, and medications – all tend to predispose patients to develop itch.

Aim of the Study: This study aimed to assess the frequency and exact characteristics of itch in adult patients with diabetes mellitus type II.

Materials and Methods: The study group comprised of 109 consecutive subjects with DM2 diagnosed according to internationally accepted criteria. Detailed information on demographics, clinical history, and physical findings were obtained. Various clinical features of itch were recorded. The intensity of itch was assessed with the Numerical Rating Scale (NRS) and 4-Item Itch Questionnaire (4IIQ). Moreover, detailed data regarding clinical features of itch including anatomical location, quality, descriptors, and the most common factors responsible for its aggravation or alleviation were obtained.

Results: Itch during DM2 was present in 35.8% (n=39) of patients, and during the time of examination (point prevalence) in 36 patients (33%). 26.3% (n=10) of patients experienced generalized itch and 30.8% (n=12) patients stated, that itch occurs constantly, every day. The mean maximal intensity of the itch during the last 3 days in NRS was as 6.3±2.2 points and last 24 h 4.9±2.5 points, indicating moderate itch intensity. The mean 4IIQ score was 8.1±3.5 points. Usually, itch was accompanied by burning sensations (38.5%) followed by pinching (30.8%), tingling (28.2%), stinging, and tickling (both 12.8%).

Conclusion: Based on our results, more than one-third of patients with DM2 suffer from itch. More than 25% of them experience itch constantly, every day.

P17: Observed and projected prevalence of prurigo nodularis in a commercially and medicare-insured U.S. population

Shawn G. Kwatra1, Jorge Puelles2, Oth Tran3, Matthew Brouillette3, Timothy Lillehaugen3, Sylvie Gabriel2

1Johns Hopkins University, School of Medicine, Baltimore, MD, USA,2Galderma S.A., La Tour-de-Peilz, Vaud, Switzerland,3IBM Watson Health, Cambridge, MA, USA

Introduction: Prurigo nodularis (PN) is a rare, debilitating, chronic inflammatory skin condition characterized by severe itch. Prevalence estimates of PN in the U.S. are limited.

Aim of the Study: This study sought to evaluate the real-world prevalence of PN in a population of commercially and Medicare-insured individuals in the U.S.

Materials and Methods: A cross-sectional sample was identified using IBM MarketScan Commercial and Medicare Supplemental claims databases. Patients were required to have ≥2 diagnoses for PN (ICD-10-CM code L28.1) ≥30 days apart between 1/10/2015 and 31/12/2019 and continuous enrollment in the 12 months prior to the cross-sectional date (31/12/2019). The period prevalence rate of PN was estimated by dividing the number of patients with PN in the cross-sectional sample by the total number of individuals in the MarketScan databases. Prevalence was standardized to the U.S. population by multiplying person-level national weights created using age, sex, and census division from the American Community Survey matched to individuals in the MarketScan Research Databases. Demographics at the cross-sectional date were reported.

Results: 6,003 eligible PN patients were identified (mean age=54.7, 54.8% female) with 48.1% residing in the South region). PN affects an estimate of 52.9 per 100,000 people in the entire U.S. employer- and Medicare- insured population. Specifically, it affects an estimate of 28.7 per 100,000 people in employer-insured population and 127.1 per 100,000 people in Medicare-insured population. By applying the prevalence rate of 52.9 per 100,000 people to the entire U.S. population, 170,803 individuals were estimated to have PN.

Conclusions: This real-world data analysis provides the latest estimate of prevalence of patients diagnosed with PN in the U.S., confirming it as a rare disease, given diagnosed prevalence falls below the 200,000-person threshold established by the 1983 Orphan Drug Act.

P18: Suspicious skin picking disorder in psoriasis and atopic dermatitis patients: a single-center cross-sectional study in China

Yanjiao Ju, Mufeng Li, Zhiqiang Xie

Peking University Third Hospital, Peking, China

Introduction: Scratching/skin picking is common in chronic itch diseases, but excessive skin picking behaviors in dermatological patients has not been fully studied.

Aim of the Study: To evaluate the occurrence of suspicious skin picking disorder in atopic dermatitis (AD) and psoriasis patients.

Materials and Methods: From January 2018 to December 2020, a structured questionnaire including demographic characteristic, the Skin Picking Scale (SPS, SPS,measure for the assessment of skin picking, score ≥7 is highly suspected to have skin picking disorder, which also known as self-injurious skin picking) and Numerical Rating Scale (NRS, assement of itch degree) was administered to AD and psoriasis patients visiting our dermatology clinic.

Results: A total of 122 AD patients and 216 psoriasis patients were enrolled in the study. The mean SPS score among patients with AD was 8.69±4.93 points (range 0–24), whereas psoriasis patients scored significantly lower (4.59±5.34, P < 0.0001). The results indicate self-injurious skin picking disorder (SPS ≥7) in 64.8% of AD patients and 28.7% of psoriasis patients. Severity of itch (NRS) correlated significantly with the SPS scores both in AD and Psoriasis patients (r=0.535, P < 0.0001 and r=0.502, P < 0.0001, respectively). Besides, what we should pay attention to is that 9 atopic dermatitis patients and 4 Psoriasis patients with mild itching (NRS < 4) but suspicious skin picking disorder (SPS ≥7).

Conclusion: Excessive skin picking is more common in AD patients. Attention should also be paid to atopic dermatitis and psoriasis patients who have non or mild-pruritic skin picking for they may suffer from suspicious skin picking disorder.

P19: Voluntary movement may be involved with a large part of provoking itch: what we learned from adult case with atopic dermatitis accompanied by amyotrophic lateral sclerosis

Tatsushi Kiyohara1, Takayasu Fukutome1, Hiroyuki Murota2

1National Hospital Organization Nagasaki Kawatana Medical Center, Nagasaki, Japan,2Nagasaki University, Graduate School of Biomedical Sciences, Nagasaki, Japan

Fifty-two years old female with atopic dermatitis had been treated with topical corticosteroids since age of 20 years old, and has been suffered from moderate disease with intense itch. At the age of 47, she had moderate to severe erythema with lichenification and lichenoid dermatitis with seropapules on both her trunk and extremities. She developed amyotrophic lateral sclerosis (ALS) on 1 year before the first visit of our dermatology clinic. At her initial consultation, she was loss of both coordination and voluntary movement, but maintained normal skin sensation. She had mild atopic dermatitis scored 0.7 by EASI despite use of simplified treatment like moisturizers. It was noteworthy that itch intensity disappeared as ALS became more advanced although her perception was kept in normal range. We anticipated that voluntary movement may largely involved in the etiology of itch in atopic dermatitis.

P20: Do patients with chronic itch avoid itchy pictures?

Putu Gita Nadinda1, Antoinette van Laarhoven1, Andrea M. Evers1, Joyce Maas2, Sylvia van Beugen1

1Leiden University, Leiden, The Netherlands,2Tilburg University, Tilburg, The Netherlands

Introduction: Research has shown that itch may be influenced by underlying automatic processes such as avoidance and attention. Both patients with chronic itch and their significant others tend to be more intolerant of itchy cues which may lead to avoidance. However, research on itch related avoidance is lacking, and results on attentional biases towards itch stimuli are mixed.

Aims: This study investigated whether patients with psoriasis and their significant others tend to avoid itch related pictures and display more attention towards itch related words compared to healthy controls.

Materials and Methods: An approach-avoidance task and a modified Stroop task for itch were administered to three participant groups: patients with psoriasis (n=50), their significant others (n=50), and controls from the general population (n=50).

Results: Preliminary analyses indicate that approach-avoidance responses do not differ between patients with psoriasis, their significant others, and healthy controls (P=0.47). However, participant’s reaction times were generally slower in response to itch pictures compared to neutral pictures (P < 0.001) and were faster to push (avoid) than to pull (approach) pictures (P < 0.001). Furthermore, participants were generally slower in naming itch related words, than neutral words (P <0.001) in the Stroop task but there was no difference in reaction times between groups (P=0.60).

Conclusion: The findings suggest that neither patients, nor their significant others have the tendency to avoid itch related stimuli as compared to controls. Furthermore, patients and their significant others did not display more attention towards itch-related words than controls. A general effect of prioritizing (action against) itch related stimuli compared to neutral stimuli was found in all participants. More research on itch related avoidance and attention may reveal possible mechanisms to target in treatments for chronic itch.

P21: Uraemic pruritus in dialysis patient (UP-DIAL): Polish version of multidimensional 14-item questionnaire

Karolina Świerczyńska1, Piotr K. Krajewski1, Radomir Reszke1, Magdalena Krajewska2, Surapon Nochaiwong3,4, Rafał Białynicki-Birula1, Jacek C. Szepietowski1

1Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Wroclaw, Poland,2Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wroclaw, Poland,3Department of Pharmaceutical Care, Pharmacoepidemiology and Statistics Research Center (PESRC), Faculty of Pharmacy, Chiang Mai, Thailand,4Chiang Mai University, Chiang Mai, Thailand

Introduction: Uraemic pruritus (UP) is one of the most common dermatological symptoms associated with chronic kidney disease. Although the problem bothers approximately 40% of patients undergoing haemodialysis, it appears to be markedly underestimated by the clinicians. Various instruments describing itch are in use, however only recently a specific instrument for uraemic itch – Uraemic Pruritus in Dialysis Patient (UP-Dial) – questionnaire has been created.

Aim of the Study: To create and to validate the Polish language version of the UP-Dial questionnaire.

Materials and Methods: The process of translation and validation was carried out according to international standards. The instrument was validated on a group of 30 patients on maintenance haemodialysis. All respondents were perceiving ureamic pruritus and completed the questionnaire twice with a 3–7 days’ interval. Furthermore, for convergent validity, the subjects were asked to assess their itch with the Numerical Rating Scale (NRS), 4-Item Itch Questionnaire (4IIQ) as well as ItchyQoL questionnaire.

Results: Newly created Polish version of the UP-Dial questionnaire showed very good internal consistency – Cronbach α coefficient was 0.90 for total score. The intraclass correlation coefficient (ICC) was also very high – 0.90 and confirmed good reproducibility of the tool. Moreover, UP-Dial showed strong correlation with NRS (r=0.74, P < 0.01), 4IIQ (r=0.82, P < 0.01) and ItchyQoL (r=0.88, P < 0.01).

Conclusion: The Polish version of the UP-Dial questionnaire showed high internal reliability, validity and reproducibility. Having a Polish language version of this multidimensional instrument will enable its use in daily clinical practice to characterize UP and can be of help in evaluation of the effects of applied itch therapy.

P22: Probing the cellular basis of kappa opioid receptor inhibition of itch

Tayler Sheahan, Allison Manalo, Louis Fanien, Sarah Ross

University of Pittsburgh, Pittsburgh, PA, USA

Introduction: The kappa opioid receptor (KOR, encoded by Oprk1) is an extremely attractive target for the treatment of chronic itch. The KOR agonist nalfurafine is currently used to treat chronic itch associated with kidney and liver disease in Japan, with additional KOR agonists in development for atopic dermatitis and neuropathic itch.

Aims: Despite the clinical promise of these agonists, the cellular basis of KOR inhibition of itch remains unknown. Previous work from our lab demonstrated KOR inhibition of itch occurs – at least in part – at the level of the spinal cord, raising the question: which spinal neurons underlie KOR inhibition of itch? We are addressing this fundamental gap in knowledge through a combination of genetic, behavioral, and molecular approaches.

Methods, Results, & Conclusions: First, we used an Oprk1-Cre allele to selectively express excitatory chemogenetic tools in Oprk1 spinal neurons and found that chemogenetic activation of Oprk1-Cre spinal neurons potentiated itch behaviors. Next, we visualized Oprk1-Cre spinal neurons using viral labeling and discovered that Oprk1-Cre is expressed in local interneurons, as well as spinal projection neurons that target brainstem and thalamic structures that are critical for the supraspinal processing of itch. We then used fluorescent in situ hybridization to determine the molecular identity of Oprk1 spinal neurons. We show that Oprk1 is expressed within a heterogenous population of spinal neurons, primarily including those that express the neuropeptide substance P, which is known to trigger itch behavior. Finally, we genetically delete Oprk1 from these subsets of spinal neurons to test their necessity in KOR inhibition of itch. Notably, these data are the first in-depth look into the cellular basis of spinal KOR inhibition of itch and provide fundamental mechanistic insights into KOR agonists that are clinically effective in alleviating chronic itch. Supported by NIH grants F32NS110155 (TDS) and R01NS0967905 (SER).

P23: Variability of pruritogen in inbred scratching behavior in inbred mouse strain

Yanbin Zhang

Anesthesiology, University Clinic Erlangen, Erlangen, Germany

One previous studies tested the effect of the pruritogens histamine and chloroquine (Green, Young et al 2006) in eleven inbred mouse strains and identified resistant and sensitive strains. Here we used 7 common pruritogens and measured respective dose-response relationships in the resistant C3H/HeJ and the sensitive C57BL/6J strain to find out if resistance to itch in C3H/HeJ is restricted to histamine and chloroquine and/or depends on the effective dose and is a general trait in C3H/HeJ. Four concentrations of the pruritogens were injected in the range of 0.3, 1, 3 and 10 fold in the nuchal fold and scratching behavior was recorded for 30 minutes after injection. The mice received bilateral implantation of mini-magnets in the hindpaws. Scratching behavior was analyzed automatically in single cages placed within a magnetic coil. A software was then used to record and extract the scratch events from the gap-free recordings of the mouse behavior. Apparently, resistance to pruritogens is a general phenotype of the C3H/HeJ strain and extends to all pruritogens tested, histamine, chloroquine, LPA, trypsine, SLIGR, LPA and serotonine. In contrast, C57BL/6J were highly sensitive to all pruritogens and displayed an inverted U-shaped dose-response curve as previously found for histamine chloroquine. Comparable scratch responses were observing for the 0.3 fold concentration of the pruritogen in C57BL/6J whereas C3H/HeJ required the 10-fold concentration. The general resistance to pruritogens and the low level of scratching behavior found in the C3H/HeJ strain may provide an interesting model for the study of the heritability of itch and is accompanied in C3H/HeJ with a higher sensitivity in assays of nociception (Mogil, Wilson et al 1999).

P24: Itch in renal transplant recipients: prevalence, intensity and clinical characteristics

Piotr K. Krajewski1, Piotr Olczyk2, Magdalena Krajewska2, Wojciech Krajewski3, Jacek C. Szepietowski1

1Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Wroclaw, Poland,2Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wroclaw, Poland,3Department and Clinic of Urology, Wroclaw Medical University, Wroclaw, Poland

Introduction: End stage renal disease-associated chronic itch (ESRDCI) is a common burden affecting up to 35% of patients treated with hemodialysis. Kidney transplant (KTx) is believed to be the best renal replacement therapy leading to the elimination of ESRDCI.

Aim of the Study: The study was undertaken to characterize and assess the prevalence of itch among patients after renal transplantation.

Methods: Between October 2019 and January 2020 we have analyzed data of 197 patients, 121 males (61.4%) and 76 females (38.6%), aged 54.5±13.6 years old. The data collection was performed with specially designed questionnaire. Worst itch after renal transplantation was assessed with the use of numeral rating and visual rating scale and 4-Item Itch Questionnaire. Moreover, previous 3-days itch was evaluated.

Results: The patients suffered from chronic renal disease for 20.2±12.3 years, mean time of the pre-transplant dialysis was 2.6±2.4 years and the mean time after the KTx was 8.0±6.5 years. The itch was present in 38.6% of the patients during the hemodialysis and in 73.7% of them ceased completely after the successful transplantation. Moreover, only in 2.63% of the cases there was no improvement. Nevertheless, the itch was reported in 42 (21.3%) renal transplant recipients (RTR) and in 22 (52.4%) of them it appeared after transplantation. The majority of patients suffering from itch were women (54.8%). Itch in the last free days was reported in 21 patients. Itch worst severity, assessed with numerical rating scale (NRS), was at 6±2.2 points, indicating moderate itch. In most cases (57.1%) itch affected multiple body areas.

Conclusion: Our analysis on representative patients’ population indicates that itch after KTx is an important problem. Moreover, it is worth noticing, that more than half of the RTR did not suffer from itch during dialysis.

P25: Health care workers suffer frequently from face mask-associated itch

Piotr K. Krajewski, Łukasz Matusiak, Marta Szepietowska, Rafał Białynicki-Birula, Jacek C. Szepietowski

Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Wroclaw, Poland

Introduction: Face mask use has increased significantly due to the COVID-19 pandemic. Health care workers (HCW) wear masks for prolonged periods of time and are prone to its adverse effects. Very little is known about face masks associated itch.

Aim of the Study: The aim of this study was to assess the prevalence and, intensity and clinical characteristics of itch related to the use of face masks by the HCW during the COVID-19 pandemic.

Methods: A questionnaire was created and tested among HCW in Dermatology Department of Wroclaw Medical University. All of the important domains were taken in consideration and used for the developing of the survey. The questionnaire was afterward uploaded with the use of Google® Forms and send among HCW in the whole country. Data was collected in 7 days, between 1.10.2020 and 7.10.2020. For a control group, a similar technique was used to create an online questionnaire, adjusted for student population.

Results: A total of 1156 HCW have completed the survey. Among them, 31.6% (365) reported suffering from itch associated with face mask use. Itch was more frequent among females. Moreover, subjects who reported sensitive skin, atopic predispositions and facial dermatoses tended to report itch more frequently. The wort itch in the previous seven days, assessed with numeric rating scale (NRS) was 4.6± 2.0 points. The itch prevalence increased along with the time of face mask use, being at 34.6% among those who wore masks more than 4 hours. HCW reported itch significantly more frequently than students.

Conclusion: Face mask associated itch is a frequent problem among HCW in COVID-19 pandemic. Itch sensation may cause scratching which may decrease necessary protection during pandemic.

P26: “AP-short”: is the new patient-reported outcome measure able to detect the underlying origin of aquagenic pruritus?

Claudia Zeidler, Sonja Ständer

Center for Chronic Pruritus, Department of Dermatology, University Hospital Münster, Münster, Germany

Introduction: Aquagenic pruritus (AP) is a rare condition characterized by itch without visible skin lesions evoked by contact with water. It is associated with haematological diseases such as polycythemia vera, but it can also be idiopathic. A premonitory occurrence of AP has been described - therefore, it is recommended to monitor patients with AP closely.

Material and Methods: The study consisted of three parts. In part 1, 77 patients with AP (34 with a haematological disease) completed the newly developed questionnaire “AP-short” as part of a validation study. Based on a logistic regression model and a multivariate analysis a score differentiating between AP caused by haematological diseases and AP of other origins was developed. In part 2, 76 other patients with AP (37 with a haematological disease) completed the “AP-short” in order to test the sensitivity and specificity of the score. In part 3, 26 patients who had already participated in part 1 without any evidence for a haematological disease completed the AP-short again after three years.

Results: Retest reliability was shown to be (almost) perfect with a Cohen’s kappa value of 0.842. The score was able to differentiate between patients with and without a haematological disease with a sensitivity of 97.3% and a specificity of 79.5%. Five patients without any evidence of a haematological condition who achieved a score indicating the presence of a haematological disease in part 1, indeed developed a haematological disease within the three years between these observations.

Conclusion: Due to its high sensitivity, the “AP-short” is a useful diagnostic tool. The specificity close to 80% can be classified as good. Additionally the “AP-short” showed predictive value in identifying patients developing haematological disease; patients who achieve a score indicating the presence of a haematological disease should be monitored more closely.

P27: Frequency and characteristics of pruritus in patients with monoclonal gammopathy: a case-control study

Cécile Devergne1, Helene Kerspern2, Florence Poizeau3, Jean-Richard Eveillard4, Jean-Luc Carré2, Laurent Misery1, Christelle Le Gall-Ianotto5, Emilie Brenaut1

1Department of Dermatology, Brest University Hospital, Brest, France,2Department of Biochemistry and Pharmaco-Toxicology, Brest University Hospital, Brest, France,3Department of Dermatology, Rennes University Hospital, Rennes, France,4Department of Haematology, Brest University Hospital, Brest, France,5University of Brest, Laboratoire Interactions Epitheliums Neurones (LIEN), Brest, France

Serum protein electrophoresis (SPEP) is the exam to diagnose monoclonal gammapathies (MGs). It is recommended in laboratory screening for chronic pruritus (CP). However, no study about the association of CP and MGs has been performed. The aim of our study was to determine the frequency of CP in patients with MGs in comparison with controls with normal SPEP results. A monocentric, observational, case-control study was conducted. Patients were selected on the basis of SPEP results performed at the University Hospital of Brest. Cases were selected on monoclonal protein rates. Controls were selected if they had normal SPEP results, and matched with cases on age and sex. Patients answered a questionnaire about the presence of pruritus and its characteristics. One hundred forty-one cases and 141 controls answered the questionnaire with a respective response rate of 48% and 50%. Each group was composed of 46% women, with a mean age of 71 years±10.4. There were 45 MG of undetermined significance (MGUS), 63 myelomas and 33 Waldenström’s macroglobulinema. CP without any skin disease was more frequently observed in cases (22.7%) than in controls (8.5%). The difference was significant (OR 2.46 [1.14-5.32], P-value 0.023). The intensity of CP was severe for 65.5 % of cases. Pruritus was triggered by contact with water in only 4 cases (12.9%). The mean 5-D itch scale score was 11.0±5.9. The mean ItchyQol score was 38.7±18.2. In multivariate analysis, multiple myeloma was less associated with pruritus (OR 0.31 [0.11-0.83], P-value 0.02) than MGUS and Waldenström’s macroglobulinemia. Our study highlighted that CP is 2.5 times more frequent in MGs than in controls. Its intensity is severe. It is not an aquagenic pruritus contrary to myeloproliferative disorders. Thus, SPEP is useful in the check-up to find the aetiology of unexplained CP.

P28: Use of cosmetic products in real life by women with sensitive skin: exposure study and comparison with controls

Cecile Legeas1, Pauline Nezet2, Laurent Misery1, Alain-Claude Roudot2, Anne-Sophie Ficheux2, Emilie Brenaut1

1Department of Dermatology, Brest University Hospital, Brest, France,2University of Brest, Laboratoire Interactions Epitheliums Neurones (LIEN), Brest, France

Sensitive skin is a syndrome manifested by the occurrence of abnormal sensations (tingling, burning, pain, pruritus, tingling). A recent meta-analysis showed that the most frequently reported trigger was the use of cosmetics. The aim of this study was to compare the use of cosmetics in women with sensitive skin with controls. Women aged 18 to 65 years, without facial dermatosis, with or without sensitive skin, were recruited. They completed the Sensitive Scale 10 (SS-10) and questionnaire about their cosmetic habits. They brought personal products used on the face for analysis of the composition and the amount used per application. 160 women were included, with a mean age of 41 years. Two groups were created: the “non-sensitive skin”: the 25% of women with the lowest SS-10 scores and the “sensitive skin” group: the 25% of women with the highest scores. The number of products used daily was similar in both groups. Women with sensitive skin used liquid soap significantly more frequently than those without sensitive skin (70% vs. 43%, P=0.01). Women with sensitive skin used twice as much moisturizer per application as women without sensitive skin: 511 µg±438 µg versus 290 µg±203 µg (P=0.039). The only difference in composition of the products concerned phenoxyethanol, which was more often present in the moisturizer of women without sensitive skin (P=0.007). Women with sensitive skin were more likely to buy products for “sensitive skin”, and products from pharmacies than from supermarkets. The causal relationship between the use of cosmetic products and sensitive skin cannot be established. Subjects with sensitive skin look for products that improve skin sensitivity. Phenoxyethanol was found less frequently in the creams of women with sensitive skin. A limitation of the analysis is the impossibility of knowing the concentration of ingredients in cosmetic products.

P29: Is it possible to differentiate sensitive skin from normal skin?

Cecile Legeas1, Misery Laurent1, Joachim Fluhr2, Alain-Claude Roudot3, Anne-Sophie Ficheux3, Emilie Brenaut1

1Department of Dermatology, Brest University Hospital, Brest, France,2Department of Dermatology, Charité Universitätsmedizin, Berlin, Germany,3University of Brest, Laboratoire Interactions Epitheliums Neurones (LIEN), Brest, France

Sensitive skin is commonly assessed on the basis of self-reports from patients, and sometimes questionnaires such as the sensitive scale are used. However, the severity of sensitive skin follows a continuum from the absence of sensitive skin to very sensitive skin. Until now, however, it has been difficult to diagnose sensitive skin as a distinct condition. The aims of this study were to compare subjects with and without sensitive skin and to propose diagnostic criteria for sensitive skin. 160 women between 18 and 65 years old were included, with and without sensitive skin and without any associated facial dermatosis. After a clinical examination, the subjects answered different questionnaires on the presence of sensitive skin, its characteristics (SS-10 score) and its impact on quality of life (BoSS score). The mean age was 41 years old. 55% of participants declared having “very sensitive” or “sensitive” skin. Two groups were formed: the 40 women with the lowest SS-10 scores and the 40 women with the highest SS-10 scores. The sensitive skin group had a lighter phototype and more often had combination or dry skin than the non-sensitive skin group. In the sensitive skin group, the participants mainly experienced skin irritability (100%), tautness (97.5%), discomfort (90%) and redness (90%). A positive and statistically significant correlation was observed between the SS-10 score and the BoSS score. According to the ROC curve, a SS-10 cut-off value of 12.7 can be used to detect sensitive skin (with a sensitivity of 72.4% and specificity of 90.3%). Based on the results of this study, we propose that a score greater than 13 out of 100 on the SS-10 can be used as a threshold to diagnose sensitive skin, and that a score lower than 5 out of 100 can be used to exclude the diagnosis of sensitive skin.

P30: Sensitive scalp: a possible association with the use of hair conditioners

Cecile Legeas1, Laurent Misery1, Alain-Claude Roudot2, Anne-Sophie Ficheux2, Emilie Brenaut1

1Department of Dermatology, Brest University Hospital, Brest, France,2University of Brest, Laboratoire Interactions Epitheliums Neurones (LIEN), Brest, France

Sensitive scalp is defined by the occurrence of unpleasant sensations (tingling, burning, pain, pruritus, pins and needles) triggered by stimuli that should not cause such sensations. Cosmetics could be triggers or aggravators. The aim was to include women between 18 and 65 years old, without scalp dermatosis, with or without sensitive scalp. After a dermatological examination, the participants completed the Sensitive Scale, the 3S and the Burden of Sensitive Skin (BoSS). Their use of scalp cosmetics was recorded. 133 women were included, with a mean age of 41 years. 5% reported having a very sensitive scalp, 25% sensitive, 38% slightly sensitive and 32% not sensitive. The mean 3S score (0-20) was 3.7±1.6 in the highly sensitive scalp group, 3.6±2.1 in the sensitive group, 1.2±1.2 in the slightly sensitive group and 0.1±0.4 in the non-sensitive group. Two groups were analyzed: the 56 subjects with a sensitive scalp (3S≥2 score) and the 56 subjects with no 3S score. In the sensitive scalp group, 89% had itching, 45% tingling, 27% tightness. No parameter (hormonal status, smoking, age, phototype, BMI) was correlated with the 3S score. The presence of a sensitive scalp was correlated with the presence of sensitive skin. The amount of conditioner used per application was significantly higher in the sensitive scalp group than in the non-sensitive scalp group, respectively 5.48±5.87 grams versus 2.88±3.75 (P=0.03). Sensitive scalp is a common problem that can impact on quality of life. In this study, the systematic dermatological examination allowed the inclusion of only women without dermatosis, according to the definition of sensitive skin. Itching was the main symptom of sensitive scalp. The only difference in cosmetic use was the amount of conditioner used, significantly higher in the sensitive scalp group.

P31: Causes of pruritus in patients treated with immune checkpoint inhibitors for melanomas or skin carcinomas

Nadia Salinas, Emmanuel Nowak, Maxime Etienne, Delphine Legoupil, Maxime Fouchard, Emilie Brenaut, Laurent Misery

Centre Hospitalier Régional et Universitaire de Brest (CHRU de Brest), Brest, France

Background: Pruritus is a frequent adverse event during the use of immune checkpoint inhibitors (ICIs), with a frequency estimated to be between 11 and 47%. The underlying causes remain poorly understood.

Objectives: The main goal was to search for putative causes of pruritus occurring in patients treated with ICIs for melanomas and cutaneous carcinomas. Other objectives were to assess the association between the occurrence of pruritus and survival and between the occurrence of pruritus and other adverse events.

Methods: A monocentric retrospective descriptive study was performed using data for patients treated with ICIs (nivolumab, pembrolizumab, ipilimumab, cemiplimab) between August 2010 and November 2019.

Results: A total of 181 patients were included (mean age: 69 y). Pruritus was reported by 25 patients (13.8%). We were able to determine three subgroups of pruritus causes under ICI use: pruritus directly related to immunotherapy, pruritus indirectly related through other pruritus-inducing side effects and pruritus unrelated to ICIs. In 6/25 patients, no more specific cause of pruritus was found at the onset of pruritus or in their backgrounds, other than ICI use.

Limitations: The study has some limitations due to its unicentric and retrospective design.

Conclusion: Pruritus was found in 25/181 patients in this series; only in 6/25 patients no potential cause other than ICI could be found, and pruritus was not associated with differences in survival.

P32: Characterization of molecular targets to mediate skin itch and inflammation

Anita Jäger

Merck KGaA

In the treatment of individuals with sensitive and psoriatic skin a number of inflammation and itch related molecular and cellular targets have been identified but many of these have yet to be characterized. In this study we present two potential targets in skin, that can be linked to the inflammation and itch cycle. An enzyme responsible for converting inactive cortisone to active cortisol used to transmit signals downstream. The activation of a receptor correlates with promoting inflammation, and the perception of itch and pain in skin. In this study, both targets have been investigated based on their involvement in inflammation. The role of both identified targets were characterized based on the secretion of inflammation cytokine- IL6, IL-8, and TNF- alpha, as well as proliferation and simulated wound healing capabilities of skin cells. It was found, that through treating skin cells with molecules able to inhibit inflammatory pathways resulting in the reduction of inflammatory signaling molecules secreted by skin cells and increases their proliferative capacity. Therefore, with these molecular targets and their associated pathways show therapeutic potential and can be mitigated via small molecules. This research can be used for further studies in inflammation and itch pathways and can help to treat the pathological symptoms.

P33: Efficacy of treatments for cholestatic pruritus: a systemic review and meta-analysis

Charles Dervout1, Nicholas Boulais2, Thomas Barnetche3, Jean-Baptiste Nousbaum4, Laurent Misery1, Emilie Brenaut1

1Department of Dermatology, Brest University Hospital, Brest, France,2University of Brest, Laboratoire Interactions Epitheliums Neurones (LIEN), Brest, France,3Department of Rheumatology, FHU ACRONIM, Bordeaux University Hospital, Bordeaux, France,4Department of Gastroenterology, Brest University Hospital, Brest, France

Cholestatic itch is a disabling symptom that may be secondary to hepatobiliary diseases. The wide variety of underlying causes makes it difficult to reach a consensus on treatment. The objective was to carry out a systematic review of the literature and a meta-analysis on the efficacy of the treatments for cholestatic pruritus.

Methods: The review focussed on articles identified by the search algorithm “(hepatitis OR cholestatic OR liver) AND (pruritus OR itch) AND (management OR treatment OR treatments)” in PubMed and the Cochrane Library, over the period 1975-2019. Of the 2264 articles identified, 93 were selected for the systematic review and 14 for the meta-analysis. Some treatments act by reducing the levels of pruritogens in the enterohepatic cycle: cholestyramine (3 studies), inhibitors of the ileal bile acid transporter (IBAT) (4), and biliary drainage (10). Others modify the metabolism or secretion of these pruritogens: ursodeoxycholic acid (15 studies), rifampicin (8), S-adenosylmethionine (7), and fibrates (3). Finally, others act on pruritus pathways: opioid receptor agonists and antagonists (14), ondansetron (5), and sertraline (4). Albumin dialysis (MARS) is also a possible treatment (10). It is difficult to identify and recommend one treatment over the other because of various heterogeneities: in the inclusion criteria, the endpoint and the type of study. Only 14 studies were included in the meta-analysis because of the small number of randomized studies using the VAS. Cholestatic pruritus is difficult to treat. Current recommendations suggest step-by-step management. Patients who do not respond to treatments should be included in clinical trials or try experimental approaches.

P34: Chronic pruritus in the absence of skin disease: a retrospective study of 197 French inpatients

Marine Robert1, Laurent Misery1,2, Emilie Brenaut1,2

1Department of Dermatology, Brest University Hospital, Brest, France,2University of Brest, Laboratoire Interactions Epitheliums Neurones (LIEN), Brest, France

Chronic pruritus (CP), lasting for at least 6 weeks, may be secondary to a skin disease or can occur without skin damage. The causes of CP without any skin disease are numerous and include systemic (such as hepatic, renal, haematological, endocrine, and iatrogenic), psychogenic, neuropathic and idiopathic causes. The check-up for CP includes a clinical examination, several biological and radiological examinations as a first step, and other examinations depending on the findings. Our aim was to analyse the causes of CP in our cohort of patients, its characteristics, the results of the check-up as well as the treatments and their effectiveness. A descriptive, retrospective study was performed in our dermatology department, including all patients hospitalized for the check-up of their CP, between 2008 and 2018. A total of 197 patients with CP were included, with a mean age of 66.7 years (19-97) and 50.8% men. Scratching lesions were present in 65.5% of patients. The main causes identified were psychogenic pruritus (41.1% of patients) and neuropathic (36.5%), endocrine (12.2%), haematological (9.6%) and iatrogenic (7.1%) causes. The cause remained unknown in 20.8% of patients. Only one aetiology of CP was identified in most patients (69.5%), but sometimes 2 aetiologies (18.3%) or more (12.2%) were identified. Aetiological treatment was often ineffective. Concerning symptomatic treatments, emollients were prescribed for 40.6% of patients and topical steroids for 20.3%. Among systemic treatments, gabapentinoids (33%), antidepressants (27.4%) and antihistamines (25.3%) were prescribed. The efficacy was rarely complete. The retrospective and monocentric nature of the study was a limitation because of possible recruitment bias and incomplete data. The main causes of CP were psychogenic and neuropathic pruritus in our patients. Aetiological treatment was often ineffective, and symptomatic treatments had moderate efficacy.

P35: Oral difelikefalin reduces pruritus in atopic dermatitis

Brian Kim1, Masato Tamari1, Lydia Zamidar1, Kristine Nograles2, Catherine Munera2, Joana Goncalves2, Emma Guttman-Yassky3, Mark Lebwohl3

1Washington University School of Medicine, St. Louis, MO, USA,2Cara Therapeutics, Stamford, CT, USA,3Icahn School of Medicine at Mount Sinai, New York, NY, USA

Introduction: Difelikefalin (DFK), a selective kappa-opioid receptor (KOR) agonist, is being developed for chronic pruritic conditions.

Aim of the Study: A mouse model of atopic dermatitis (AD) evaluated DFK effects on itch; a phase 2 study assessed DFK in AD patients.

Materials and Methods: A mouse model of topical MC903-induced AD-like disease was employed in which mice were treated with DFK (0.5 mg/kg) intraperitoneally BID. Scratching was measured on days 0, 4, 8, and 12. A phase 2, multicenter, randomized, double-blind study enrolled adults with AD and moderate-to-severe pruritus. Patients received PBO or oral DFK (0.25, 0.5, or 1.0 mg) BID for 12 weeks. Primary and key secondary endpoints, respectively: change from baseline and ≥4-point improvement in weekly mean Itch Numerical Rating Scale (I-NRS) at week 12. A subgroup analysis based on lesional severity was conducted.

Results: Single-cell RNA-sequencing revealed expression of Oprk1 (gene encoding KOR) on mechanosensory Aβ neurons. DFK directly activated large-diameter sensory neurons and promoted rapid itch reduction. In the clinical study, 401 patients were randomized (~64% had mild-to-moderate AD [body surface area <10%]). In the overall population, the treatment difference in I-NRS mean change between the combined DFK group (all doses) and PBO was −0.43 at week 12 (P=0.144). In patients with mild-to-moderate AD, a significant difference in I-NRS mean change from baseline was observed at week 12 (−0.75) for DFK versus PBO (P=0.036); a greater proportion of patients achieved ≥4-point improvement in I-NRS. Most commonly reported adverse events with DFK were abdominal pain, nausea, dry mouth, headache, dizziness, and hypertension.

Conclusion: The anti-pruritic effect of DFK was observed in an AD mouse model. DFK substantially reduced itch severity in patients with mild-to-moderate AD and was well tolerated. These findings support the role of DFK as a neuromodulatory agent for itch-predominant AD.

Author Index

A

Adawi, Waleed

Agelopoulos, Konstantin

Ahdoot, Rebecca S.

Alphonse, Martin

Anderson, Michael

Apfelbacher, Christian

Augustin, Matthias

B

Barnetche, Thomas

Bautista, Diana

Bednarska-Chabowska, Dorota

Berger, Timothy

Beugen, Sylvia van

Białynicki-Birula, Rafał

Blome, Christine

Bordeaux, Zachary A.

Boulais, Nicholas

Brenaut, Emilie

Brouillette, Matthew

Brown, Andrew

C

Carré, Jean-Luc

Carstens, Earl

Caspi, Elanite

Chan, Andrea

Chavda, Rajeev

Chen, Suephy C.

Chen, Xiao-Jun

Chlebicka, Iwona

Choi, Justin

Cole, Emily F.

D

Deng, Junwen

Dervout, Charles

Devergne, Cécile

Dietrich, Peter

Dijkerman, Chris

Dong, Xinzhong

Düll, Miriam

E

Ebata, Toshiya

Esaa, Fatema

Etienne, Maxime

Eveillard, Jean-Richard

Evers, Andrea M.

F

Fanien, Louis

Ficheux, Anne-Sophie

Fiebig, Andrea

Fleischer, Alan

Fluhr, Joachim

Follansbee, Taylor

Forbes, Bill

Fouchard, Maxime

Fukutome, Takayasu

G

Gabriel, Sylvie

Gami, Abhishek

Garces, Juan Carlos

Goncalves, Joana

Goren, Orna

Guttman-Yassky, Emma

H

Hatano, Ryo

Hawash, Ahmed

Hernandez, Jeffrey

Hill, Rose Z.

Honda, Kotaro

Hoon, Mark

Hu, Eric

I

Ingrasci, Giuseppe

Irie, Hiroyuki

Itoh, Takumi

J

Jäger, Anita

Ju, Yanjiao

K

Kagan, Elena

Kalantar-Zadeh, Kamyar

Kamata, Yayoi

Karlen, Vanessa

Kerspern, Helene

Kim, Bo Ri

Kim, Brian

Kim, Hei Sung

Kim, Kyu Han

Kiyohara, Tatsushi

Kobayashi, Shigetoshi

Komiya, Eriko

Koren, Erez

Krajewska, Magdalena

Krajewski, Wojciech

Krajewski, Piotr K.

Kremer, Andreas E.

Kupfer, Jörg P.

Kwatra, Shawn G.

L

Laarhoven, Antoinette van

Le Gall-Ianotto, Christelle

Le, Thomas K.

Lebwohl, Mark

Lee, Dong Hun

Lee, Hanjae

Lee, Kevin

Legeas, Cecile

Legoupil, Delphine

Leibl, Victoria

Lerner, Ethan

Li, Mufeng

Liang, Tongyu

Lillehaugen, Timothy

Limjunyawong, Nathachit

Lipman, Zoe

Liu, Yan-He

Loayza, Enrique

M

Maas, Joyce

Mack, Madison R.

Manalo, Allison

Maldonado, Claudia

Marani, Melika

Matusiak, Łukasz

Mazur, Grzegorz

McCafferty, Kieran

Meena, Manju

Meeuwis, Stephanie

Meixiong, James

Menzaghi, Frédérique

Mettang, Thomas

Metz, Martin

Miessner, Hendrik

Mimrod, Dorit

Misery, Laurent

Mittal, Asit

Monroe, John

Morimoto, Chikao

Morin, Isabelle

Morita, Takeshi

Munera, Catherine

Murota, Hiroyuki

N

Na, Jung Im

Nadinda, Putu Gita

Namer, Barbara

Nattkemper, Leigh

Neurath, Markus F.

Nezet, Pauline

Nguyen, Eileen

Nochaiwong, Surapon

Noczyńska, Anna

Nograles, Kristine

Nousbaum, Jean-Baptiste

Nowak, Emmanuel

O

Oetjen, Landon K.

Olczyk, Piotr

Onuma, Kei

Otsuka, Haruna

P

Parthasarathy, Varsha

Pereira, Manuel

Pfleiderer, Bettina

Poizeau, Florence

Pritchard, Thomas

Puelles, Jorge

R

Rammohan, Kottil

Reich, Adam

Renkhold, Lina

Reszke, Radomir

Richard, Madeline

Rifi, Ziad

Ringkamp, Matthias

Robert, Marine

Roh, Youkyung S.

Roudot, Alain-Claude

Rosen, Yael

Ross, Sarah

Ryan Wolf, Julie

S

Sabbagh, Mark F.

Salinas, Nadia

Schaufler, Thilo

Schmelz, Martin

Schumann, Johanna

Schut, Christina

Seidel, Judith

Sheahan, Tayler

Shiratori-Hayashi, Miho

Sikora, Mariusz

Smith, Kelly

Smith Begolka, Wendy

Spencer, Robert H.

St. John Smith, Ewan

Ständer, Sonja

Stefaniak, Aleksandra A.

Sun, Yan-Gang

Sutaria, Nishadh

Świerczyńska, Karolina

Szepietowska, Marta

Szepietowski, Jacek C.

T

Takamori, Kenji

Tamari, Masato

Tey, Hong Liang

Tominaga, Mitsutoshi

Topp, Janine

Tornes, Leticia

Toyama, Sumika

Tran, Oth

Tseng, Pang-Yen

V

Veldhuijzen, Judy

Vernon, Margaret

Vetter, Marcel

Vuong, Cliff

W

Walpen, Sebastian

Wang, Fang

Weisshaar, Elke

Wen, Warren

Wiegmann, Henning

X

Xie, Zhiqiang

Xu, Ning-Long

Y

Yap, Qai Ven

Yosipovitch, Gil

Z

Zamansky, Mark

Zamidar, Lydia

Zeidler, Claudia

Zhang, Yanbin

Zhou, Hua

Zubkiewicz-Kucharska, Agnieszka

Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The International Forum for the Study of Itch.