Special interest groups (SIGs)
SIG1: Novel guideline on prurigo – where are we?
Department of Dermatology, Center for Chronic Pruritus, University Hospital of Münster, Germany
Chronic pruritus in combination with single, and often multiple, symmetrically dispersed, pruriginous nodules, papules and/or plaques are the typical characteristics that distinguish chronic prurigo, a skin condition that was recently designated an own disease entity, from other dermatological diseases. Chronic prurigo (CPG) is known to diminish the quality of life of affected patients, who are known to experience sleep disturbances, social and career-related repercussions and stigmatization as a result of the visible changes to their skin. There are few treatment options available for this treatment refractory disease, although current options focus on breaking the vicious itch-scratch cycle. An international group of experts based in the EU and the USA are working on summarizing contemporary diagnostics and therapies for CPG via a consensus paper/guideline, as such a guide had been lacking until now. The initial consensus meeting was held on August 2019, during which its participants devised recommendations on the clinics of CPG, ranging from its stages and levels of severity to recommendations on various diagnostic steps, including questionnaires, clinical assessments, skin biopsies, physical examinations and laboratory, radiological and microbiological tests. General principles in treatment, topical therapies, physical therapies and multiple classes of systemic therapies are recommended by experts, but evidence in the literature is still low. Recent reviews describe first line therapies such as topical steroids, capsaicin, calcineurin inhibitors, phototherapy and the systemic antihistamine application. Gabapentinoids and immunosuppressants were described as second line therapies. Opioid receptors modulators, interleukin-31 antagonists and neurokinin-1 receptors inhibitors represent current novel therapies; some of them are currently also available in trials. Treatment options for chronic prurigo are limited, but a group of experts is currently working on a first international approach to summarize the evidence and expert opinion in a guidance for diagnostics and therapy.
SIG2: A responder in clinical trials – what is it?
Gil Yosipovitch, MD
Dr Phillip Frost Department of Dermatology and the Miami Itch Center Miller School of Medicine, Miami, FL, USA
Understanding of the issues involved in establishing the amount of change in itch reported by subjects, participating in clinical trials and using standard and clinically meaningful outcome measures may enhance efforts to develop effective treatments for chronic itch. Clinical trials for chronic itch currently use different outcome measures making it difficult to compare efficacy of responders to different treatments. The method determining treatment benefit considered as a statistically significant benefit may be clinically meaningless. Therefore tools to assess efficacy in itch have to primarily focus to what patients experience as a response. We will cover several recent studies examining what is a responder. Currently the most important suggested domains are reductions in worse itch intensity, health related quality of life including physical functioning such as sleep. Whether an outcome measure is clinically meaningful may also be determined by establishing the minimal important difference (MID), which is defined as “the smallest difference in score in the domain of interest that patients perceive as important”.
SIG3: Pediatric itch – how do we assess and unique factors
Suephy C. Chen, MD, MS
Department of Dermatology, Emory University, Atlanta, GA, USA
Formal studies of chronic pruritus in the pediatric population are in their infancy, partly because validated pediatric pruritus measurement tools are lacking. In this presentation, we will review existing tools that can be utilized, including unpublished data from the Study of Kids Itch Severity (SKIS). We will preview the adaptation of the ItchyQoL into the 8-17 year old (TweenItchyQoL), 6-7 year old (KidsItchyQoL), and 4-5 year old (TotsItchyQoL) populations. We will also preview the adaptation of the ItchyQuant, a cartoon annotated numeric rating scale, in these same populations. Lastly, we will present data from SKIS and other published literature regarding predictors of itch quality of life impact and resource utilization.
SIG4: International itch questionnaire – mission impossible?
Elke Weisshaar1, Friederike Dominick1, Andrea W.M. Evers2, Antoinette I.M. van Laarhoven2
1Occupational Dermatology, Department of Dermatology, Ruprecht Karls University Heidelberg, Germany, 2Health, Medical, and Neuropsychology Unit, Faculty of Social and Behavioral Sciences, Leiden Institute for Brain and Cognition (LIBC), Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands
Assessing itch is difficult and remains a great challenge. It is very important to address aspects of itch helping to identify the underlying disease, helping to find the best treatment and addressing the individual patient’s needs. The International Forum for the Study on Itch (IFSI) special interest group on “Questionnaires” aims to propose tools to assess different dimensions of itch and improve patients’ care. After having published a consensus paper, we performed a study that systematically reviewed existing patients’ self-report questionnaires on itch. The databases PubMed, PsycINFO, and CINAHL were systematically searched for any scientific publication describing patients’ self-report questionnaires (≥two items) that assessed itch-related information. Questionnaire content was extracted by two experts considering 14 dimensions of itch that had been predefined by the IFSI Special Interest Group, e.g. duration of itch, itch aggravating or relieving factors, and effects on quality of life. Sixty-two questionnaires were derived 58 included articles that resulted from 5282 records. Measurement properties of the questionnaires were not systematically assessed, because these were regularly not reported in the original publication. Over half of the questionnaires were developed for dermatological diseases, and most were designed for adults. Whereas itch-related disability and itch intensity were frequently asked for, the dimensions affective qualities of itch, coping with itch, response to current itch treatment, and the opinion on the origin of itch were only sparsely included. Within each dimension, heterogeneity in the number and content of the items was high. Future research should aim at selecting adequate and reliable (sub)scales as part of a modular questionnaire system in order to uniformly assess each patient’s demands and, in turn, improve health care. Though there is still a long way to go, the SIG will has taken a great step to reach the goal of creating an International Itch Questionnaire.
SIG5: Chronic pruritus of unknown origin (CPUO): uniform nomenclature and diagnosis as a pathway to standardized understanding and treatment
Gil Yosipovitch1*, Brian S. Kim2–5, Timothy G. Berger6
1Dr Phillip Frost Department of Dermatology and Miami Itch Center, University of Miami, Miller School of Medicine, USA, 2Center for the Study of Itch, Washington University School of Medicine, USA, 3Division of Dermatology, Department of Medicine, Washington University School of Medicine, USA, 4Department of Anesthesiology, Washington University School of Medicine, USA, 5Department of Pathology and Immunology, Washington University School of Medicine, USA, 6Department of Dermatology, University of California, San Francisco, USA
Given the vast number of potential causes and associations of chronic itch, many attempts have been made to define clinical, diagnostic, and therapeutic guidelines for different forms of chronic itch. However, even after exclusion of all currently known chronic itch disorders, many patients suffer from chronic itch of unknown cause. This has been referred to cause chronic idiopathic pruritus, generalized pruritus of unknown origin, and chronic pruritus of unknown origin (CPUO). Given the lack of unified terminology and understanding of this condition, pathways to investigation and treatment have been limited. Herein, we propose the uniform terminology of CPUO and a basic diagnostic work-up recommendation and classification scheme to help more forward our evolving understanding of this highly unmet condition.
SIG6: Sensitive skin: Update of a sensitive issue
Laurent Miseryand the IFSI SIG on sensitive skin
University Hospital of Brest, France
The IFSI SIG on sensitive skin previously defined sensitive skin 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. A new work was done on the pathophysiology and the management of sensitive skin to provide a new position paper. Sensitive skin is not an immunological disorder and is related to alterations of the skin nervous system. Skin barrier abnormalities are frequently associated, but there is no cause and effect relationship. Further studies are needed to better understand the pathophysiology of sensitive skin – as well as the inducing factors. Avoidance of possible triggering factors and the use of well-tolerated cosmetics, especially those containing inhibitors of unpleasant sensations, might be suggested for patients with sensitive skin. The role of psychosocial factors, such as stress or negative expectancies, might be relevant for subgroups of patients.
To date there is no clinical trial supporting the use of topical or systemic drugs in sensitive skin, no study providing data to reach a consensus on sensitive skin management. In general, patients with sensitive skin require a personalized approach, taken into account the various biomedical, neural and psychosocial factors affecting sensitive skin.
SIG7: Special interest group “psychological factors in itch”: Update and new initiatives
Andrea W.M. Evers1, Jörg Kupfer2
1Leiden University, The Netherlands, 2Giessen University, Germany
Recently, the new initiative of a SIG group on “Psychological factors in itch” was launched as part of ISFI. The goal of this special interest group is to examine the role of psychological factors in itch and to develop new assessment and treatment options for patients with acute and chronic itch. Psychological factors include the role of cognitive, emotional and behavioral responses to itch, that are triggered by individual (e.g. personality characteristics) and environmental (e.g. chronic stress) factors and are mediated by neurobiological pathways (e.g. brain-skin axis). General themes that are possibly relevant for this SIG are: (1) Psychological determinants of itch and its measurements (e.g. itch cognitions), (2) Psychological treatments of itch (e.g. cognitive behavior therapy focusing on itch), (3) Psychoneurobiological mechanisms of itch (e.g. brain-skin axis mediators). Ongoing projects and future initiatives will be discussed during the meeting.
Hot off the bench: Latest news by young investigators
OP1: Dissecting the role of neurokinin-1 receptor spinal neurons in itch
Tayler D. Sheahan, Michael C. Chiang, Justin A. Chestang, Sarah E. Ross
Pittsburgh Center for Pain Research and Department of Neurobiology, University of Pittsburgh, PA, USA
Neurokinin-1 receptor (NK1R) antagonists have recently emerged as effective treatments for a variety of chronic itch conditions. However, the site and mechanism of action of NK1R antagonists within the nervous system remains unclear. Preclinical NK1R antagonist and NK1R spinal neurotoxic ablation studies suggest that the clinical anti-pruritic effects of NK1R antagonists may be mediated by NK1R spinal neurons. However, interpretation of ablation studies is limited by ambiguities in the time course, specificity, and extent of neuronal death. As further dissection of the role of NK1R neurons in itch spinal circuitry has been stymied by a lack of genetic tools to label discrete subpopulations of spinal neurons, we recently developed an NK1R-CreER mouse line to study the anatomy and function of NK1R spinal neurons. Using this novel genetic tool, we first demonstrate that NK1R-CreER is expressed in local interneurons as well as spinal projection neurons that target brainstem structures known to modulate itch, such as the lateral parabrachial nucleus and periaqueductal gray. Next, we show that chemogenetic activation of NK1R-CreER spinal neurons potentiates chloroquine-induced itch, highlighting that NK1R neurons are involved in processing of itch within the spinal cord. Lastly, we use electrophysiology and calcium imaging to tease apart NK1R neuron spinal circuitry and characterize their physiological responses to pruritogens. Taken together, these studies suggest that clinically effective NK1R antagonists are likely to act (at least in part) by inhibiting NK1R within the spinal cord. This observation could allow for optimization of therapeutic interventions for chronic itch. Supported by T32NS086749 and F32NS110155 to TDS and R01NS096705 to SER.
OP2: Selective nerve fiber activation in patients with chronic generalized pruritus
Manuel P. Pereira1, Konstantin Agelopoulos1, Johannes Köllner1, Gitta Neufang2, Martin Schmelz3, Sonja Ständer1
1Department of Dermatology and Center for Chronic Pruritus, University Hospital Münster, Germany, 2Research & Development, Beiersdorf AG, Hamburg, Germany, 3Department of Anesthesiology and Intensive Care Medicine, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany
Central sensitization is responsible for augmenting pain in chronic pain states, manifesting clinically as hyperalgesia, allodynia and temporal or spatial summation. Analogous mechanisms are believed to play a role in the chronicity of pruritic conditions, in which hyperknesis and alloknesis are the clinical expression of central sensitization. We compared 79 patients with generalized chronic pruritus (CP) of different origins (atopic dermatitis, n=19; chronic pruritus on non-lesional skin, n=45; chronic nodular prurigo, n=15) and 54 healthy controls (HC) in regard to pruritus intensity and evoked sensory qualities after peripheral electrical stimulation at 5 Hz as a surrogate for C-fiber function and at 2000 Hz as a surrogate for Aβ-fiber function. The Neurometer® was used for the electrical stimulation. Additionally the above-mentioned parameters were reassessed in patients after a two-week antipruritic treatment with an emollient containing a TRPM8 agonist. Pruritus induced by electrical stimulation was more intense in patients than in HC following stimulation at 5 Hz and 2000 Hz. No differences were observed between patient groups, arguing for central sensitization in CP patients to be primarily independent of the underlying etiology. At stimulation at 5 Hz, patients reported more frequently the sensation “burning”, but not “itch”, two C-fiber associated sensory symptoms, while stimulation at 2000 Hz evoked more tingling and prickling but less throbbing in patients compared to controls. Treatment with the TRPM8 agonist led to an improvement of the pruritus without modifying the distribution of the sensory symptoms. This study revealed that patients with CP show hyperknesis upon electrical stimulation, regardless of the etiology of the pruritus, suggesting that common central chronicity mechanisms develop in CP. A further characterization of these central mechanisms is of the utmost importance to better understand the pathophysiology of CP and develop novel targeted therapies.
OP3: MRGPRX4 is a novel bile acid receptor in cholestatic itch
Huasheng Yu1–3, Tianjun Zhao1–3, Simin Liu1, Qinxue Wu4, Omar Johnson4, Zhaofa Wu1,2, Zihao Zhuang1, Yaocheng Shi5, Renxi He1,2, Yong Yang6, Jianjun Sun7, Xiaoqun Wang8, Haifeng Xu9, Zheng Zeng10, Xiaoguang Lei3,5, Wenqin Luo4*, Yulong Li1–3*
1State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing, China, 2PKU-IDG/McGovern Institute for Brain Research, Beijing, China, 3Peking-Tsinghua Center for Life Sciences, Beijing, China, 4Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA, 5Department of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing, China, 6Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China, 7Department of Neurosurgery, Peking University Third Hospital, Peking University, Beijing, China, 8State Key Laboratory of Brain and Cognitive Science, CAS Center for Excellence in Brain Science and Intelligence Technology (Shanghai), Institute of Biophysics, Chinese Academy of Sciences, Beijing, China, 9Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, 10Department of Infectious Diseases, Peking University First Hospital, Beijing, China
Patients with liver diseases often suffer from chronic itch or pruritus, yet the itch-causing pruritogen(s) and their cognate receptor(s) remain largely elusive. Using transcriptomics and GPCR activation assays, we found that an orphan, primate specific MRGPRX4 is expressed in human dorsal root ganglia (hDRG) and selectively activated by bile acids. In situ hybridization and immunohistochemistry revealed that MRGPRX4 is expressed in ~7% of hDRG neurons and co-localizes with HRH1, a known itch-inducing GPCR. Bile acids elicited a robust Ca2+ response in a subset of cultured hDRG neurons, and intradermal injection of bile acids and an MRGPRX4 specific agonist induced significant itch in healthy human subjects. Surprisingly, application of agonist for TGR5, a known sequence conserved bile acid receptor previously implicated in cholestatic itch, failed to elicit Ca2+ response in cultured hDRG neurons, nor did it induce pruritus in human subjects. In situ hybridization and immunostaining results revealed that hTGR5 is selectively expressed in satellite glial cells, unlike mTGR5 (in mouse DRG neurons), likely accounting for the inter-species difference functionally. Finally, we found that patients with cholestatic itch have significantly higher plasma bile acid levels compared to non-itchy patients and the bile acid levels significantly decreased after itch relief. This elevated bile acid level in itchy patients is sufficient to activate MRGPRX4. Taken together, our data strongly suggest that MRGPRX4 is a novel bile acid receptor that likely underlies cholestatic itch, providing a promising new drug target for anti-itch therapies.
OP4: Endogenous opioid levels do not correlate with itch intensity in hepatic pruritus
Miriam Düll, Alina Butterhof, Markus F. Neurath, Andreas E. Kremer
Department of Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
Background & Aims: Chronic pruritus is affecting up to 70% of patients with immune-mediated hepatobiliary disorders. Antagonists of the µ-opioid receptor (MOR) and agonists of the к-opioid receptor (KOR) are used to treat hepatic itch, albeit with limited success. An imbalance between ligands of these receptors was recently suggested as potential mechanism of hepatic pruritus. In this study, we investigated levels of important endogenous opioids in plasma of patients with cholestatic disorders.
Methods: Plasma samples and clinical data were prospectively collected from well-characterized patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) suffering from pruritus and age-, gender- and disease-matched controls without pruritus (n=56) as well as healthy controls (n=20). Extensive laboratory testing for hepatobiliary and renal function were performed. Levels of β-endorphin, dynorphin A, Leu- and Met-enkephalin were quantified using ELISAs. Intensity of pruritus was evaluated by VAS, NRS and questionnaires.
Results: PBC and PSC patients with or without pruritus did neither differ in disease entity and severity, nor in the presence of cirrhosis. Cirrhotic patients had compared to non-cirrhotics higher levels of Leu-enkephalin (10.6±2.8 ng/mL vs, 5.8±0.7 ng/mL, P<0.01) and KOR agonist dynorphin A (395.3±45.7 ng/mL vs, 277.4±28.6 ng/mL, P<0.05), while no differences were observed for β-endorphin and Met-enkephalin. While dynorphin A (217.6±25.4 ng/mL vs, 402.9±35.3ng/mL, vs, 521.1±35.7 ng/mL, P<0.001) and β-endorphin (49.5±5.7 ng/mL vs, 85.7±5.9 ng/mL, vs, 90.5±5.8 ng/mL, P<0.001) were lower in patients with pruritus compared to those without pruritus and healthy volunteers, the MOR/KOR-ratio was unaltered. No differences were observed for Leu- and Met-Enkephalin. Opioid levels did not correlate with the itch intensity.
Conclusions: While dynorphin A and β-endorphin were lowered in patients with pruritus, Leu- and Met-enkephalin as well as the MOR/KOR-ratio remained unchanged. Endogenous opioid levels did not correlate with itch intensity. Endogenous opioids may therefore modulate hepatic pruritus but are unlikely the major pruritogens in liver disease.
OP5: Role of cathepsin S and protease-activated receptor-2 in ciguatoxin-induced substance p release: New promising targets to relieve ciguatera pruritus
Ophélie Pierre1, Kilian L’Herondelle1, Raphael Leschiera1, Reginald Philippe2, Paul Buscaglia2, Olivier Mignen2, Laurent Misery1,3, Raphaele le Garrec1
1Laboratoire sur les Interactions Epitheliums-Neurones, University of Western Brittany, Brest, France, 2INSERM U1227, University of Western Brittany, Brest, France, 3Department of Dermatology, University Hospital of Brest, Brest, France
Ciguatera Fish Poisoning (CFP) is a widespread tropical intoxication consecutive to ciguatoxin (CTX) ingestion, which is characterized by persistent neuro-cutaneous disturbances, including an intense pruritus (itch). Currently, there is no specific treatment. The primary target of CTXs is the voltage dependent sodium channel (Nav), which is largely expressed in sensory nerves and, to a lesser extent, in keratinocytes. By activating Nav, CTXs induce neuronal hyper-excitability but the downstream molecular mechanisms leading to neuro-cutaneous disorders are poorly understood. Recent advances in dermatology reveal protease-activated receptor-2 (PAR-2) involvement in itch pathophysiology. Interestingly, this receptor is expressed in sensory neurons and keratinocytes. To better understand the pathophysiology of CFP pruritus, the purpose of the present study was to identify cellular and molecular actors involved in the substance P (SP) release elicited by P-CTX-2 from cocultured sensory neurons and keratinocytes. P-CTX-2 is able to induce calcium signal in both sensory neurons and keratinocytes. We show that antagonism of PAR-2 significantly inhibited the P-CTX-2-evoked transient calcium increase in both cells. The P-CTX-2-induced SP release was almost completely abolished by PAR-2 or cathepsin S (Cat S) antagonists, and Cat S activity was significantly increased after P-CTX-2 treatment. Moreover, P-CTX-2 is able to internalise PAR-2 in keratinocytes. Taken together, this study reveals that keratinocytes, PAR-2 and Cat S are novel actors in the P-CTX-2-induced release of SP, suggesting these are promising pharmacological targets for specifically treating CFP neuro-cutaneous disorders.
OP6: Multiplexing representation of itch, mechanical and thermal sensation in somatosensory cortex
Xiaojun Chen1,2, Yan-He Liu1,2, Juan Deng1, Ning-Long Xu1–3*, Yan-Gang Sun1,3*
1Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS 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
Much progress has been made in the neuronal mechanisms underlying somatosensory processing in the nervous system, and electrophysiological recording and macroscopic brain imaging studies have characterized responses in the primary somatosensory cortex (S1) to different types of stimuli. Previous studies on population activity in S1 mainly focused on tactile information processing in the vibrissal system, with few studies examining other S1 sub-regions. However, it is still poorly understood how S1 processes other important categories of somatosensory information, such as pruritic or thermal information, especially at perceptual level in awake animals. Here, we report that pruritic, mechanical, and thermal stimuli activate largely overlapping neuronal populations in the same somatotopic sub-regions of S1, with the local neuronal population encoding sufficient information to discriminate stimuli of different somatosensory modalities. Using in vivo two-photon calcium imaging that simultaneously monitor hundreds of layer 2/3 pyramidal neurons in S1 of awake mice, we observed neuronal responses reliably triggered by mechanical and thermal stimuli. Delivery of pruritic stimulus by precisely optogenetic control of spinal itch-selective neurons also elicited reliable responses in S1 neurons. We found that the same S1 neuronal population showed responses to all three modalities of stimuli, with the reliability and amplitude of responses varying among neurons within the population. Further decoding analysis showed that the simultaneously imaged local populations in the S1 encode sufficient information to discriminate stimuli of different modalities. Although multimodal S1 neurons responding to all types of stimuli exhibited no spatial clustering, S1 neurons preferring mechanical and thermal stimuli tend to showed local clustering. These findings pave the way for further understanding the processing and integration of multimodal somatosensory information in the cortex.
OP7: The world of itch
Occupational Dermatology, Department of Dermatology, University of Heidelberg, Germany
Although itch has been the most frequent symptom of the skin for centuries, surprisingly little is known about its etiology. In the centuries leading up to the development of modern medicine, perusal of ancient documents reveals interesting cultural attitudes toward and traditional practices for treatment of itch. Nowadays, itch can be approached in a clinical setting, at a population-based level, to address molecular, genetic, neurophysiological, epidemiological, psychological and therapeutic aspects of itch that have ramifications for public health and global disease issues. Research on patient reported outcomes and quality of life in the field of itch has complemented this complex and varied research. Systematic approaches including classification and guidelines have been, and continue to be, developed. Recently, randomized controlled trials (RCTs) have been successfully completed, something that would have not been imaginable years ago. All this has occurred in parallel with, and stimulated by, the founding of the International Forum for the Study of Itch (IFSI) in 2005. As a professional society IFSI aims to unify all aspects and challenges of itch in a multidisciplinary and multicultural world society.
Challenges of Itch
OP8: Itch in the upper airways
Pete Smith, BMedSci, MBBS, FRACP, PhD
Griffith University, Queensland, Australia
Itch is a primitive indicator of threat. Whilst we mostly focus on itch in the skin – being the largest organ and having the most contact with external threats, the upper airwaysprovide useful insights into mechanisms that may have application beyond the nose. The nasal airways warm, filter and humidify 10-12 thousand litres a day and every breath has over 100 000 molecules that requires a complex sensory system to detect threatsand danger. Itch of the eyes are nose are cardinal signals of allergic and non-allergic rhinitis. The trigeminal system is enriched with sensory nerves and receptors. The best described is TRPV1 which is present on approximately 90% of sensory nerves in thenasal airways and has site linkage with substance P and calcitonin gene related peptide. TRPV1 genes also co-locate with TNF-alpha. TRPA1 is also heavily expressed on trigeminal nerves and in addition to being co-expressed with TRPV1, it forms function hetero-dimers.
Both TRPV1 and TRPA1 ion channels can be sensitized by up to 35 G coupled protein receptors. Many mediators in allergy cause a reduction in threshold of activation of sensory nerves – a condition called priming. This occurs with both allergic and non-specific irritant triggers. Other nasal threat detecting receptors (which may increase pruritus) include T2Rs, ASICs, Acetycholine, RAGE receptors, dual pore potassium channels and IgE receptors.
Clinically our treatment of itch in the nasal airways involve use of antihistamines and steroids – with higher efficacy of antihistamines than observed in the skin. In non-allergicrhinitis, capsaicin desensitization is very efficacious and also reduces both TRPV1 and TRPA1 signaling.
OP9: The challenge of basic itch research
Department of Neurobiology, Physiology and Behavior
University of California, Davis, CA, USA
While recent decades have seen enormous advances in our understanding of itch mechanisms, several important challenges still remain. One challenge regards the existence of itch-specific markers. Recent studies reveal three subsets of pruriceptive sensory neurons highly expressing itch-related genes including those for brain natriuretic peptide, somatostatin and others. Their fibers project into the spinal cord to activate neurons expressing gastrin releasing peptide (GRP) and its receptor (GRPR), neurons that are essential to itch transmission. These in turn connect to neurons that project to the parabrachial nucleus and thalamus. Many projection neurons express the substance P (NK-1) receptor which is also important for pain. Most or all itch-sensitive spinal neurons also respond to painful stimuli. This represents perhaps the most important challenge to the field, namely to understand how itch and pain are discriminated. Understanding the supraspinal processing of itch represents yet another challenge that is currently starting to be addressed by studies of itch-related responses of neurons in thalamus, parabrachial nucleus, amygdala and cerebral cortex. Spinal inhibitory interneurons release GABA, glycine and dynorphin to modulate segmental itch transmission. A challenge is to understand how disruption of segmental inhibitory mechanisms contributes to chronic itch, and how it can be alleviated by enhancing spinal inhibition. Another major challenge to the field is the development of animal models of itch-related diseases such as atopic dermatitis and psoriasis, that recapitulate manifestations of chronic itch including alloknesis (touch-evoked or mechanical itch). Recent studies implicate spinal neurons expressing neuropeptide Y (NPY) and its receptor, NPY-1, in regulating mechanically-evoked itch. These recent advances provide novel targets for development of therapeutic strategies to relieve chronic itch and alloknesis.
Skin inflammation and itch
OP10: Transcutaneous sinusoidal currents elicit pruritus in atopic dermatitis patients
Roman Rukwied1*, Mark Schnakenberg1, Martin Schmelz1, Elke Weisshaar2
1Department of Experimental Pain Research, Medical Faculty Mannheim, University of Heidelberg, Germany, 2Occupational Dermatology, Department of Dermatology, University of Heidelberg, Germany
Background & Aims: Slowly depolarizing transcutaneous sinusoidal stimulation has been demonstrated to preferentially activate C-nociceptors in human skin. Ongoing stimulation for a minute revealed profound accommodation of C-fibers in healthy subjects, but increasing pain in patients with neuropathy. We investigated slowly depolarizing currents in patients suffering atopic eczema and additionally monitored their responsiveness to depolarizing half-sine wave stimulation.
Methods: Twenty eight patients (age 47±20 yrs) were recruited and informed about the study objective. All subjects attended a training session to familiarize with the stimulation procedure. A single half-sine wave pulse of 500 ms duration and by 0.2 mA increasing intensity (max. 1 mA, randomized order) was administered to the patients’ affected and non-affected skin site. Patients were requested to estimate stimulus evoked itch and pain intensity on a numeric rating scale (NRS, endpoints 0 to 10). Thereafter, sensation and pain-thresholds to 4 Hz sinusoidal pulses were assessed and 10 pulses (stimulus duration 2.5 s) delivered with current intensities of 0.025-0.4 mA (randomized order) to the affected and non-affected skin sites. Finally, sinusoidal stimuli of pain-threshold intensity were administered to both skin sites for 60 seconds and itch/pain intensity recorded in 10 seconds intervals.
Results: Half-sine wave stimulation induced a current intensity dependent sensation of NRS 5±2 (both skin sites). Seven patients perceived significant itch in affected (NRS 5.5±3) and non-affected skin (NRS 6.5±2, P<0.02). Sinusoidal currents of 0.05 and 0.1 mA induced itch of about NRS 7±2 (both skin sites) in 5 AD patients. Continuous stimulation (4 Hz, 0.05 and 0.1 mA) induced an average itch of NRS 3±2 (non-affected skin) and NRS 5±3 (affected skin), which persisted throughout the stimulation period without accommodation.
Conclusions: Both half-sine wave and sinusoidal waveform stimulation can induce itch in a sub-population of atopic dermatitis patients. No significant differences were analyzed between the skin sites in these subjects. The data indicate that polymodal C-fibers (stimulated by half-sine wave) and “silent” C-nociceptors (additionally activated by sine wave) can contribute to itch in both affected and non-affected skin. The role of the “spatial contrast theory” for this electrically induced itch is discussed.
Source of Financial Support: Funded by the Deutsche Forschungsgemeinschaft, FOR 2690 (#1) and project grant 397846571.
OP11: Role of spinal cholecystokinin receptor 2 in alloknesis models
Mitsutoshi Tominaga1,2, Fumiya Kusube1, Kotaro Honda1, Eriko Komiya1, Nobuaki Takahashi1, Hisashi Naito3, Yasushi Suga4, Kenji Takamori1,2,4
1Juntendo Itch Research Center (JIRC), Institute for Environmental and Gender Specific Medicine, Juntendo University Graduate School of Medicine, Japan, 2Anti-Aging Skin Research Laboratory, Juntendo University Graduate School of Medicine, Japan, 3Institute of Health and Sports Science & Medicine, Juntendo University, Japan, 4Department of Dermatology, Juntendo University Urayasu Hospital, Japan
Cholecystokinin (CCK) functions as a neurotransmitter and/or neuromodulator in the central nervous system (CNS) during certain situations such as anxiety, feeding and allodynia. Sulfated CCK8 (CCK8S) is distributed widely in the CNS. We recently found that intrathecal (i.t.) injection of CCK8S induces alloknesis via the spinal CCK2 receptor (CCK2R) in mice; however, the detailed molecular and cellular mechanisms remain unclear. We therefore investigated the role of spinal CCK2R in alloknesis in C57BL/6J mice. Histologically, in situ hybridization revealed that CCK2R mRNA is expressed in dorsal horn neurons, whereas CCK1R mRNA expression was slightly detectable. Ablation of spinal CCK receptor-expressing cells by i.t. injection of CCK-saporin attenuated CCK8S-induced alloknesis in comparison with blank-saporin control mice. Moreover, the CCK8S-induced alloknesis was inhibited by i.t. injection of L-365,260, a CCK2R antagonist, but not by SR27897, a CCK1R antagonist. Notably, CCK8S-, AEW (acetone/ether/water) treatment- or aging-induced alloknesis was inhibited by oral administration of the CCK2R antagonist L-365,260, with no effects on locomotion. These findings suggest that the spinal CCK2R plays a role in the induction of alloknesis in mice, including dry skin and aging skin conditions. Thus, the spinal CCK2R may be a promising candidate for alloknesis treatment.
OP12: Cysteinyl leukotrienes mediate chronic itch through Cysltr2 receptor in mouse model of atopic dermatitis
Tiphaine Voisin1, Marie-Angele Messou1, Manuel Leyva-Castillo2, Hans J. Solinski3, Mark A. Hoon3, Mathias Pawlak4, Lora Bankova5, Yoshihide Kanaoka5, Frank K. Austen5, Isaac M. Chiu1
1Department of Immunology, Harvard Medical School, Boston, MA, USA, 2Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA, 3Molecular Genetics Section, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA, 4Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA, 5Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
Chronic itch is associated with allergic skin inflammation, but the underlying molecular mechanisms in different skin inflammatory conditions are not well understood. Here, we investigate the role of cysteinyl leukotrienes (CysLTs) and their signaling through the Cysltr2 receptor in pruriceptor activation and itch. CysLTs (including LTC4, LTD4 and LTE4) are eicosanoid lipid mediators that drive type 2 inflammation in asthma and atopic dermatitis. LTC4 and LTD4 signal through CysLT receptor 1 (Cysltr1) or CysLT receptor 2 (Cysltr2), which are differentially expressed in different immune cells. Whole population and single cell transcriptional analysis shows that Cysltr2 is highly enriched in Nppb+ pruriceptor neurons. This led us to hypothesize that neuronal Cysltr2 plays a role in detecting CysLTs in the skin to mediate itch. We found that LTC4 and its non-hydrolysable form, NMLTC4, induces calcium influx in a subset of sensory neurons. LTC4, NMLTC4, but not LTD4 triggered dose-dependent scratching but not wiping behavior when injected into the cheek of mice. This itch behavior was abrogated in Cysltr2-/- mice, but not Cysltr1-/- or Trpv1-/- mice. We next analyzed the role of this molecular pathway in the MC903 mouse model of chronic itch and atopic dermatitis. We have found a significant increase of CysLT levels in the skin by ELISA. Cysltr2-/- mice showed significantly decreased itch behavior in the chronic phase of the MC903 model and decreased mast cell degranulation, while tissue swelling and other immune cell influx was unaffected. Overall, our study reveals that Cysltr2 marks a major subset of pruriceptor sensory neurons, and that CysLTs contribute to itch through this receptor in a mouse model of atopic dermatitis. Targeting CysLT production or signaling may be promising approaches to treat chronic itch.
OP13: Transcriptome profiling reveals Th2 bias and identifies TSLP as a key endogenous itch mediator in a model of poison Ivy contact dermatitis
Boyi Liu1, Yan Tai2, Boyu Liu1, Ana I. Caceres3, Chengyu Yin1, Sven-Eric Jordt3
1Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China, 2Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China, 3Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, USA
Urushiol, present in poison ivy, the Japanese lacquer tree and related plants, is one of the most common environmental allergens to cause allergic contact dermatitis (ACD). The immune and pruritic mechanisms associated with poison ivy ACD remain largely unexplored. Here, we compared skin whole transcriptomes and itch mediator levels in mouse ACD models induced by the poison ivy allergen, urushiol, and the synthetic allergen, oxazolone. The urushiol model produced a Th2-biased immune response and scratching behavior, resembling findings in poison ivy patients. Urushiol-challenged skin contained elevated levels of the cytokine thymic stromal lymphopoietin (TSLP), a T-cell regulator and itch mediator, and pruritogenic serotonin (5-HT) and endothelin (ET-1), but not substance P (SP) or histamine. The oxazolone model generated a mixed Th1/Th2 response associated with increased levels of substance P, 5-HT, ET-1, but not TSLP or histamine. Injections of a TSLP monoclonal neutralizing antibody, serotonergic or endothelin inhibitors, but not SP inhibitors or antihistamines, reduced scratching behaviors in urushiol-challenged mice. Our findings suggest that the mouse urushiol model may serve as a translational model of human poison ivy ACD study. Inhibiting signaling by TSLP and other cytokines may represent alternatives to the standard steroid/antihistamine regimen for steroid-resistant or -intolerant patients and in exaggerated systemic responses to poison ivy.
Psriasis and itch
OP14: Altered cutaneous nerve fiber architecture in psoriatic skin recovers upon treatment with Secukinumab
Konstantin Agelopoulos1,2, Clara Hambüchen1,2, Ruth Becker1,2, Christian Mess3, Karin Loser1, Dieter Metze1, Daniel Bäumer4, Thomas Luger1,2, Sonja Ständer1,2
1Department of Dermatology, 2Center for Chronic Pruritus, University of Münster, Münster, Germany, 3Department of Dermatology and Venerology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, 4Novartis Pharma Ltd., Nürnberg, Germany
Psoriasis is a chronic inflammatory skin condition with involvement of cutaneous TRPV1/Nav 1.8 positive nerves in the pathogenesis. However, there are conflicting reports about the morphological cutaneous nerve fiber characteristics. We therefore investigated the cutaneous nerve fiber anatomy in detail within a multicenter, randomized, double-blind placebo-controlled trial (NCT02362789) with monthly injections of Secukinumab (SEC). Skin biopsies were collected at baseline from lesional (LS) and non-lesional (NLS) skin, at week 16 (end of run-in phase) and week 32 (end of randomized withdrawal phase; half of patients with placebo or SEC). Intraepidermal nerve fiber (IENF) density and semiquantitative branching-pattern were assessed (PGP9.5 staining); IENF length and epidermal thickening were calculated in a computer assisted approach. Clinical response was evaluated by PASI-scores and pruritus intensity-rating. Extensive skin clearance (PASI≥98) and pruritus control was achieved by SEC for 61.5% of the initially 130 included patients up to week 16. During withdrawal phase full, symptomatic control was sustained with SEC whereas partial recurrence of psoriasis was observed in the placebo group. The absolute length of IENFs (spatial determination basement to horny layer) was higher in LS at baseline as compared to NLS. As expected, epidermal thickening was much more pronounced in LS compared to NLS (P<0.01). Corrected for epidermal thickening by calculating a fiber-length/epidermal-height ratio, relative length of IENFs was lower in LS compared to NLS (0.29 vs. 0.49; P<0.01). IENF density (11.33 vs. 8.55; P<0.01) and branching (2.56 vs. 1.44; P<0.001) were reduced in LS at baseline. All nerve fiber characteristics recovered after 16 weeks of treatment and remained stable irrespective of the following treatment arm until week 32. In sum, we demonstrated significant alterations in nerve fiber anatomy with lower density and branching of epidermal nerves in lesional psoriatic skin which recovered upon treatment with SEC. Furthermore, they remained stable after therapy termination despite worsening of pruritus and psoriasis indicating that nerve fiber alterations are not only responsible for induction of itch in psoriasis.
OP15: SNA-120, a novel topical non-steroidal therapy for psoriasis and associated pruritus that targets the NGF/TrkA pathway: Results from a multicenter phase 2b study
Kristina Callis Duffin1, Sonja Ständer2, Zoe Draelos3, Gurpreet Ahluwalia4, Paul F. Lizzul4
1University of Utah, Salt Lake City, UT, USA, 2Center for Chronic Pruritus, Department of Dermatology, University Hospital, Münster, Germany, 3Dermatology Consulting Services, High Point, NC, USA, 4Sienna Biopharmaceuticals, Westlake Village, CA, USA
Background: Psoriasis is a chronic relapsing inflammatory dermatosis lacking novel topical non-steroidal chronic treatment options. The NGF/TrkA axis, important for neurogenic inflammation, keratinocyte proliferation, and pruritus in psoriasis, is targeted by SNA-120 (pegcantratinib), a topical TrkA inhibitor designed using proprietary Topical by Design™ technology to achieve high local drug concentration in the skin, but with low systemic exposure.
Objective: To evaluate SNA-120 for treatment of psoriasis and associated itch.
Methods: This multicenter, randomized, double-blind, vehicle-controlled phase 2b study enrolled 208 subjects (≥18 y) with mild-to-moderate psoriasis and at least moderate itch (worst itch ≥5 on I-NRS). Subjects were randomized to BID application of SNA-120 (0.05% or 0.5%) or vehicle for 12 weeks. The primary endpoint was change on the I-NRS from baseline to Week 8. Prespecified key secondary endpoints included the IGA ≥2-grade composite and PASI-75 at Week 12. Additional psoriasis measures and adverse events (AEs) were evaluated.
Results: Mean reduction on the I-NRS was 4.2 (57%) with SNA-120 (0.05%) vs 3.9 (55%) with vehicle (P=0.362). SNA-120 (0.5%) showed similar results. SNA-120 (0.05%) demonstrated statistically significant and clinically meaningful improvements in psoriasis at Week 12: 29% vs 13% of vehicle-treated subjects achieved the IGA ≥2-grade composite response (P=0.036) and 27% vs 13% achieved PASI-75 (P=0.045). Both the IGA and PASI-75 results remained statistically significant at Week 14. Results for SNA-120 (0.5%) on the IGA and PASI-75 were not statistically significant. SNA-120 was well tolerated. Few treatment-related AEs were reported; no serious AEs occurred.
Conclusions: Adults treated with SNA-120 (0.05%) achieved statistically significant and clinically meaningful improvements on prespecified psoriasis regulatory endpoints. Itch was substantially reduced from baseline in both groups; however, the primary endpoint was not met. Targeting the NGF/TrkA pathway with SNA-120 may represent a novel topical non-steroidal treatment option for the majority of patients with psoriasis.
OP17: Is accelerometry a useful tool for pruritus severity assessment? Analysis of the data achieved in patients suffering from psoriasis
Adam Reich1, Anna Domagała2, Jacek C. Szepietowski3
1Department of Dermatology, University of Rzeszow, Rzeszow, Poland, 2Department of Dermatology, Regional Specialist Hospital, Research and Development Centre, Wroclaw, Poland, 3Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Poland
Background: Valid assessment of pruritus severity remains a challenge and there is a need for the development of objective itch measurements.
Objectives: The aim of this study was to evaluate the usefulness of accelerometry as a tool for assessment of pruritus severity.
Material and Methods: A total of 61 adult patients with plaque type psoriasis and concomitant pruritus were enrolled into the study. Patient evaluated pruritus intensity according to the Visual Analogue Scale (VAS) and the 12-item Pruritus Severity Scale (12-PSS) and the severity of psoriasis (PASI and BSA) and quality of life (DLQI) were assessed accordingly. In addition, an accelerometer ActiSleepPlus was worn on the wrist of dominant hand of the subject for 6 consecutive nights to measure the hand movements during sleeping. The digital accelerometer output was exported to software for analysis on day 7.
Results: The mean duration of scratching episodes during sleep (Nmin) was 34.6±20.7 min (range 10-138) and significantly correlated with VAS (R=0.25; P<0.05), 12-PSS (R=0.29; P=0.02) and DLQI (R=0.29; P=0.03). Mean number of registered wrist movements (LRN) was 21817.1±24459.0 (range 3587-171712) and correlated with Nmin (R=0.87, P<0.0001), VAS (R=0.35, P<0.01), 12-PSS (R=0.33, P<0.01), and DLQI (R=0.32, P=0.01). Sleeping efficacy calculated by the software significantly correlated only with Nmin (R=−0.63, P<0.0001) and LRN (R=−0.54, P<0.0001). Interestingly, longitudinal observations (over one week) revealed no significant change of Nmin, LRN and sleeping efficacy despite significant improvement of quality of life and pruritus intensity assessed according to VAS and 12-PSS.
Conclusions: Measurement of wrist movements with accelerometers could be of some value in pruritus measurement but still need to be more precisely compiled and validated to be reliably used for itch assessment in the future.
New antipruritic treatments
OP18: Novel therapies of chronic prurigo
Department of Dermatology, Center for Chronic Pruritus, University Hospital of Münster, Münster, Germany
Chronic prurigo is an own disease entity characterized by the presence of chronic pruritus and single to multiple usually symmetrically distributed pruriginous nodules, papules and/or plaques. Chronic prurigo leads to a restricted quality of life, sleep problems, social and work-related limitations, including also negative feelings of stigmatization due to visible scratch lesions. Chronic prurigo is difficult to treat and only a few treatment options for interrupting the vicious itch-scratch cycle are currently available. Experts recommend using either topical steroids, calcineurin inhibitors or capsaicin, in addition or alternatively phototherapy as a first step. Second line therapy includes gabapentinoids, μ-opioid receptor antagonists, antidepressants or immunosuppressants. However, due to a greater understanding of the pathogenesis of chronic prurigo, novel therapies target the neuronal transmission and cutaneous molecular signaling pathways. New substances are currently investigated in phase II and phase III trials including antagonists against interleukin-31, neurokinin-1 receptor, and opioid receptors. The treatment options for chronic prurigo are still rare but there is increasing evidence for novel recommendations from ongoing trials. Innovative therapies are under clinical review which target directly involved signaling pathways.
OP19: The future of itch management
Gil Yosipovitch, MD
Dr Phillip Frost Department of dermatology and the Miami Itch Center Miller School of Medicine, Miami, USA
An explosion of data regarding mechanisms of itch in the skin, spinal cord and brain has evolved in the last decade mainly from studies of acute induced itch in animal models Our improved understanding has already led to development of new therapeutic medications in phase 2-3 trials. However we still have limited number of drugs in the market. Continued interest in academic institutes and pharma understanding pruritic mechanisms can help to identify additional therapeutic modalities and to usher in a new era of targeted anti-itch treatments. There will not be one drug for all types of itch and multiple drugs will need to be used to cover the different types of itch and the diverse pathophysiolgies. Other challenges we are facing are to develop cost effective drugs, that will provide a meaningful itch reduction with a good safety profile.
OP20: The relationship between pruritus and sleep improvement: Post Hoc analysis of a randomized, double-blind, phase 3 clinical trial of abrocitinib
Rodney Sinclair1, Samantha Eisman1, Dedee F. Murrell2,3, Gil Yosipovitch4, John Su5, Claire Feeney6, Marco DiBonaventura7, Pinaki Biswas7, Hernan Valdez7
1Sinclair Dermatology, East Melbourne, VIC, Australia, 2University of New South Wales, Kensington, Sydney, NSW, Australia, 3St George Hospital, Kogarah, Sydney, NSW, Australia, 4Miami Itch Center, Miller School of Medicine, University of Miami, Miami, FL, USA, 5Murdoch Children’s Research Institute, Royal Children’s Hospital, University of Melbourne, Parkville, VIC, Australia, 6Pfizer Ltd., Tadworth, Surrey, United Kingdom, 7Pfizer Inc., New York, NY, USA
Introduction: Pruritus is a hallmark symptom of atopic dermatitis (AD) and can affect many aspects of patient quality of life (QOL). The objective of this analysis was to evaluate the relationship between pruritus and sleep disruption using data from patients with moderate-to-severe AD treated with oral Janus kinase 1 inhibitor abrocitinib for 12 weeks in a randomized, double-blind, phase 3 clinical trial (NCT03349060).
Methods: The analysis included all data from all 387 patients randomly assigned (2:2:1) to receive once-daily oral abrocitinib (200 mg or 100 mg) or placebo; for this analysis, data were collapsed across treatment arms. Outcome measures included Peak Pruritus-Numeric Rating Scale (PP-NRS; 0-10 scale), SCORing AD Sleep Visual Analog Scale (SCORAD Sleep), the sleep item of the Patient Oriented Eczema Measure (POEM Sleep), the POEM, the sleep item of the Child Dermatology Life Quality Index (CDLQI Sleep), and the CDLQI/DLQI. Pearson correlations between PP-NRS and measures of sleep and QOL were examined at baseline. The distribution of sleep and QOL measures were examined as a function of PP-NRS scores over time.
Results: At baseline, moderately-sized correlational relationships were observed between PP-NRS and SCORAD Sleep (r=0.50), POEM Sleep (r=0.39), POEM (r=0.49), CDLQI Sleep (r=0.60), and CDLQI/DLQI (r=0.44) (P<0.0001 for all). For the 72 (19%) patients whose PP-NRS scores improved to <3 at week 4, median SCORAD Sleep and CDLQI/DLQI scores were 0 and 2, respectively. At week 12, 108 (28%) and 103 (27%) patients with PP-NRS scores <3 also had median SCORAD Sleep and CDLQI/DLQI scores of 0 and 1, respectively. Conversely, for patients whose PP-NRS scores were >7 at week 4 (9%) and week 12 (8%), the median SCORAD Sleep scores were 7 at both time points.
Discussion: Pruritus was significantly associated with sleep disruption and QOL. Patients whose PP-NRS decreased to <3 reported no/minimal sleep disruption.
OP21: Effects of serlopitant on pruritus associated with psoriasis: Worst itch numeric rating scale responder analysis of a phase 2 randomized, double-blind, placebo-controlled clinical trial
David M. Pariser, MD1, Stephen K. Tyring, MD, PhD2, Jerry Bagel, MD3, Mary Spellman, MD4
1Eastern Virginia Medical School and Virginia Clinical Research, Inc., Norfolk, Virginia, USA, 2University of Texas Health Science Center, Houston, Texas, USA, 3Psoriasis Treatment Center of Central New Jersey, East Windsor, New Jersey, USA, 4Menlo Therapeutics Inc., Redwood City, California, USA
Background: Pruritus is a significant symptom of psoriasis that negatively impacts quality of life. Treatments for psoriatic lesions do not consistently alleviate psoriatic itch. An unmet medical need remains for the effective treatment of psoriatic pruritus. This phase 2 study investigated serlopitant, an oral, once-daily neurokinin 1 receptor antagonist for the treatment of pruritus associated with psoriasis (NCT03343639).
Methods: Patients were randomized to receive serlopitant 5 mg (n=102) or placebo (n=102) daily for 8 weeks. Adult patients with plaque psoriasis ≥6 months, lesions covering ≤10% of body surface area, pruritus ≥4 weeks, and a worst itch numeric rating scale (WI-NRS) score ≥7.0 were enrolled. The primary efficacy endpoint was WI-NRS 4-point responder rate at week 8. The 4-point responder rate at week 4 and 3-point responder rates at weeks 4 and 8 were also evaluated.
Results: Mean age of patients was 47.5 years; 54.2% were female and 85.2% were white. Mean baseline WI-NRS scores were similar for serlopitant (8.3) and placebo (8.1). At week 8, WI-NRS 4-point responder rates were 33.3% for serlopitant vs 21.1% for placebo (P=0.028), and at week 4, the rates were 20.8% for serlopitant vs 11.5% for placebo (P=0.039). At weeks 4 and 8, the WI-NRS 3-point responder rates for serlopitant were 31.9% and 42.1%, respectively vs 22.1% and 31.0% for placebo. At every assessed time point, the serlopitant group demonstrated greater numeric improvement than the placebo group in the WI-NRS 4-point and 3-point responder analyses. Treatment-related adverse events were reported for 4.9% and 4.0% of patients who received serlopitant and placebo, respectively.
Conclusions: Serlopitant reduced pruritus associated with psoriasis, as demonstrated by consistent WI-NRS 4- and 3-point improvements compared with placebo. These data correspond to a clinically meaningful improvement in itch and support the ongoing development of serlopitant for this patient population.
OP22: Difelikefalin reduced itch intensity in hemodialysis patients with moderate-to-severe pruritus in an 8-week randomized, placebo-controlled study
Jacek C. Szepietowski1, Robert H. Spencer2, Catherine Munera2, Frédérique Menzaghi2
1Department of Dermatology, Venereology and Allergology, Medical University, Wroclaw, Poland, 2Cara Therapeutics, Inc. Stamford, CT, US
More than 40% of patients with chronic kidney disease (CKD) undergoing hemodialysis experience associated moderate-to-severe pruritus (CKD-aP). Difelikefalin is a selective kappa opioid receptor agonist acting peripherally with a mechanism of action that includes anti-inflammatory and anti-pruritic effects. This post hoc analysis was based on data from a phase 2 study evaluating difelikefalin in patients with CKD-aP (baseline NRS score >4) and undergoing hemodialysis. Randomized (1:1:1:1) patients received an IV injection, after each dialysis, of difelikefalin 1.5, 1.0, or 0.5 mcg/kg, or placebo over 8-weeks. Results reported focus on difelikefalin 0.5 mcg/kg results, which advanced into phase 3 studies. At week 8 percentages of patients with ≥80% of daily 24-hour Worst Itching Intensity NRS score=0/1 were 28% (11/39) vs 12% (5/42) in difelikefalin vs placebo groups. Percentages of patients with change from baseline NRS score of ≥4 points were 51% (20/39) vs 24% (10/42) and percentages were 64% (25/39) vs 29% (12/42) for patients with change from baseline NRS score of ≥3 points. Among patients with NRS score ≥7 at baseline, 71% (17/24) vs 28% (5/18) had NRS score reductions of ≥3 points, and among patients with NRS score ≥4 to <7 at baseline, 53% (8/15) vs 29% (7/24) had ≥3 points NRS score reductions. Difelikefalin was well tolerated with a favorable safety profile. 28% of patients on difelikefalin experienced complete or almost complete itch relief. Meaningful itch benefits extended to patients with severe or moderate baseline pruritus. Difelikefalin delivered robust anti-pruritic activity, highlighting its potential as a novel therapy for itch in CKD-aP.
Methods in itch research (Clinical)
OP23: Is histamine-induced itch related to personality characteristics in patients with atopic dermatitis and healthy skin controls?
Christina Schut1, Pia Schleichert1, Uwe Gieler2, Jörg Kupfer1
1Institute of Medical Psychology, Justus-Liebig-University Gießen, Germany, 2Clinics for Dermatology and Allergology, Justus-Liebig-University Gießen, Germany
Theoretical Background: Itch/ scratching induced by (audio-)visual itch stimuli (“contagious itch”) has repeatedly been shown to be associated with certain personality characteristics in patients with chronic itch. Histamine-iontophoresis is a tool to induce itch in experimental settings. This study investigated whether histamine-itch is also related to personality characteristics in patients with atopic dermatitis (AD) and healthy skin controls (HSC).
Methods: Fourty AD-patients (11 m; mean age: 24.6±4.2 y) and 40 HSC (11 m; mean age: 24.6±4.8 y) were presented two non-itch inducing videos (each 9.5 min). Immediately before video 2, itch was induced by iontophoresis with 1% histamine plus 2%-methylcellulose gel at 6000mC (200mA, 30sec) on the non-leading forearm. Maximal itch during the presentation of video 1 (control condition (CC)) and during the time between the application of the electrodes and end of video 2 (experimental condition (EC)) and current itch immediately after each video were assessed using VAS (0-10). Induced itch was determined by subtracting EC itch scores from CC itch scores. Personality traits, self-consciousness, anxiety and depression were measured using validated questionnaires.
Results: Maximal induced itch was 4.3±2.9 (AD-patients: 4.0±2.6; HSC: 4.7±3.2), induced itch measured immediately after the videos was 2.8±3.0 (AD-patients: 2.5±2.9; HSC: 3.0±3.2). Correlation/regression analyses showed that in HSC, public self-consciousness was significantly positively related to maximal induced itch (r=0.354; P=0.025; corr. R2=0.10) and induced itch measured immediately after the videos (r=0.445; P=0.004; corr. R2=0.18). In AD-patients, conscientiousness was positively related to induced itch measured immediately after the videos (r=0.362; P=0.022; corr. R2=0.11).
Discussion: The results for HSC partly match with previous found links between self-consciousness and mentally induced itch. However, as far as we know conscientiousness has not been shown to be linked to induced itch in AD-patients thus far. Before, clinical implications can be drawn from this study, the findings should be replicated.
OP24: Recent advance in the use of actigraphy for chronic pruritus
Toshiya Ebata1, Akihiko Ikoma2, Takamasa Kogure3
1Chitofuna Dermatology Clinic, Tokyo, Japan, 2Department of Future Design, Maruho Co. Ltd. Osaka, Japan, 3Paramount Bed Sleep Research Laboratory, Paramount Bed Co. Ltd. Tokyo, Japan
Wrist Actigraphy (WA) is known as a non-invasive monitoring of motion by detecting an acceleration signal generated by the movement of the hand. It has been used widely for the measurement of sleep-wake status. There have been numerous reports on the use of WA devices for the evaluation of sleep in atopic dermatitis (AD). However, they may underestimate the sleep time because they detect wrist motion due to scratching while sleeping. We tried a sheet-shaped body vibrometer termed “NEMURI SCAN” for measuring sleep in AD and found that it may be more suited for the sleep evaluation of patients with chronic pruritus than WA. WA has been used for the measurement of nocturnal scratching in AD as well. However, the device was not specifically designed for scratch measurement. We have recently developed an application software containing a unique algorithm termed “Itch Tracker” to measure nocturnal scratching. This was installed into a smartwatch (Apple Watch) and used in patients with chronic pruritus. The results of three clinical studies suggested that Itch Tracker is a reliable and useful device for the measurement of nocturnal scratching and may provide indirect, but objective information on itch severity in daily clinical settings.
OP25: Using motion, sound, and machine learning to measure scratch with a skin-mounted, soft, wireless and flexible acoustomechanic sensor: performance with confounding activities
Han Heul Jo1, Jungwoo Kim2, Jong Yoon Lee2, Brad Lee3, Morgan Nguyen3, Rachel Lee4, KunHyuck Lee2, John A. Rogers, PhD2, Amy S. Paller, MD2,4, Shuai Xu, MD2,4
1University of Illinois Champaign Urbana, USA, 2Simpson Querrey Institute, Center of Bio-Integrated Electronics, Northwestern University, USA, 3Northwestern University Feinberg School of Medicine, USA, 4Department of Dermatology, Northwestern University Feinberg School of Medicine, USA
Introduction: Quantifying itch is challenging. Actigraphy is one objective tool used to measure scratch, a natural itch response. However, actigraphy is limited to nocturnal use given an inherent limitation to differentiate scratching from other movements. We hypothesize that an advanced, skin-conformable wireless sensor with the ability to capture both the sound and movement of scratching will provide superior measurement accuracy.
Methods: The flexible sensor (4.5 cm/2.1 cm/0.3 cm/7 g) includes a 3-axis high-frequency accelerometer (0-2000 Hz), and Bluetooth module encapsulated in silicone. The accelerometer captures both low frequency (movement) and high-frequency (sounds) signals. To develop the algorithm, we recruited n=8 healthy subjects to perform scratching activities on 12 locations and 8 confounding events (waving, texting, typing, tossing and turning, rubbing, idling, tapping, and random hand motions). A total of 9,600 data points were collected. The algorithm uses two convolutional neural network (CNN) long short-term memory models. The CNNs are used to extract features from the full-spectrum of the accelerometer data (sound and motion) from the sensor, and down-sampled outputs (motion only) to recapitulate expected actigraphy’s outputs. 80% of the dataset was used for training while 20% was used for validation.
Results: At full sampling of motion and acoustic signals, the scratching algorithm demonstrated 93% accuracy (98% sensitivity, 82% specificity). When the data set was down-sampled to reflect traditional actigraphy, the model performs with only 87% sensitivity and 79% specificity. In a sub-analysis, the system was challenged most by differentiating rubbing (55% accurate), waving (70%), and tapping (79%). It performed well differentiating in tossing and turning (100% accurate), idling (99%) and texting (96%).
Conclusion: A novel wearable sensor that captures both sound and motion, and a CNN-derived algorithm shows high accuracy, sensitivity, and specificity for determining scratching across multiple body locations against 8 confounding events. Further validation in affected patients (e.g. atopic dermatitis) is ongoing.
OP26: Somatoform itch and “itch-like” skin sensations: what do we know about these psychosomatic phenomena?
Andrey Lvov1, Svetlana Bobko1, Dmitry Romanov2
1Moscow scientific and practical center of dermatovenereology and cosmetology, Moscow, Russia, 2Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
Background: Somatoform itch (SI) is a distressing physical symptom, causing desire to scratch, accompanied with excessive attention (abnormal thoughts, feelings, and behaviors in response to it), repeatedly presented by a patient in spite of negative medical investigations failing to facilitate diagnosis of any known dermatosis or systemic/neurologic disease. However, along with SI there is a set of “itch-like” skin sensations (SS) with phenomenological characteristics other than itch. Here we provide a description of such SS in common psychodermatological syndromes: skin picking disorder (SPD), dermatitis artefacta (DA) and delusional infestation (DI).
Discussion: Typically, SI is not accompanied with self-inflicted lesions and migrates from one skin region to another. It could be associated with transient symptoms of neurovegetative skin dysfunction. Also there is a health anxiety secondary to SI, fear of skin related disease associated with behavior pattern to spare skin in order to avoid exposures triggering SI. SS in SPD (dysesthesias) are scattered but generally related to self-inflicted lesions. Dysesthesias could be as superficial (extrusive), as subsurface (intrusive). Respectively, there are tactile illusions either on the skin surface, or in the skin depth. Also there are anxiety and/or dysphoria secondary to dysaesthesia and associated with compulsive and/or impulsive skin picking behavior. SS in DA are quiet focal (“circumscribed”), persistent, tormenting, predominantly painful, felt deeply in/under the skin. There are multimodal illusions/hallucinations of objects, causing SS. The respective self-injuring behavior is focused on elimination of those inanimate “objects” in order to reduce SS, including as scratching, as instrumental autoagression. SS in DI (tactile hallucinations) are associated with delusions of infestation with animate objects able to transmission/contamination. The behavior pattern secondary to SS and delusions includes as scratching, as other methods to exterminate those living creatures from the skin.
Conclusion: SI should be distinguished from other “itch-like” SS observed in most psychodermatological disorders.
OP27: Measurement of nocturnal scratching with itch tracker in patients with chronic pruritus; a multi-regional study using a medical research framework for mobile APP users
Kazuaki Okamoto1, Akihiko Ikoma1,2, Toshiya Ebata3, Laurent Chantalat2, Kimitoshi Takemura2, Fabienne Mizzi4, Michel Poncet4, Didier LeClercq2
1Department of Future Design, Maruho Co. Ltd., Osaka, Japan, 2SHIELD, Nestlé Skin Health SA, USA, 3Chitofuna Dermatology Clinic, Setagaya, Tokyo, Japan, 4Research and Development, Galderma SA, France
Background and Objectives: Itch Tracker is a smartwatch application software containing unique algorithm to analyze acceleration data from Apple Watch that enables measurement of nocturnal scratching. In this study, we investigated the relationship between nocturnal scratching measured by Itch Tracker and various factors such as medical background, self-evaluated severity of itch and daytime-life/sleep disturbance due to itch.
Methods: The study participants were recruited using ResearchKit, an open-source framework offered by Apple Inc. for medical research targeting mobile device users. A total of 262 subjects anonymously participated, out of which 201 subjects were considered as evaluable. The evaluable subjects included 49 patients with atopic dermatitis, 74 with dry skin, 11 with chronic urticaria, 12 with psoriasis, 41 with other skin problems, 1 with renal dysfunction, 9 with liver dysfunction, and 7 with diabetes, whereas 81 had none of these diseases, according to self-reported diagnoses.
Results: The subjects who were suffering from atopic dermatitis, dry skin, chronic urticaria or psoriasis had a significantly longer scratching duration as compared to those who had none of the diseases. The subjects who self-reported the presence of itch or daytime life/sleep disturbance had a significantly longer scratching duration than those who did not.
Conclusion: This study has demonstrated the usefulness of Itch Tracker in the measurement of nocturnal scratching as well as its potential capability to collect big data from the globe.
OP28: The relationship between pruritus, sleep disruption, and quality of life among patients with moderate-to-severe atopic dermatitis (AD)
Marco DiBonaventura1, Peter Anderson2, Joaquin De Villarreal2, David Bell2, Gary Milligan2, Joseph C. Cappelleri3, Claire Feeney4
1Pfizer Inc., New York, NY, USA, 2Adelphi Real World, Macclesfield, United Kingdom, 3Pfizer Inc., Groton, CT, USA, 4Pfizer Ltd., Tadworth, Surrey, United Kingdom
Introduction: AD is a chronic inflammatory skin disease often characterized by intense and persistent pruritus. The objective of this study was to examine the interrelationship between pruritus, sleep, depression, and quality of life (QOL) among those with moderate-to-severe AD managed in a “real-world” setting.
Methods: Data from the 2018-2019 Adelphi Real World AD Adult Disease Specific Programmes (AD-DSP) were used. The AD-DSP is a database of patient chart information abstracted by selected physicians across the United States and integrated with patient survey data. The AD-DSP includes symptom frequency and several validated measures: Patient-Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), EuroQoL-5D (EQ-5D), and Work Productivity and Activity Impairment-Atopic Dermatitis questionnaire (WPAI-AD). Adult patients (≥18 y) with moderate-to-severe AD were included in the analysis (ie, those with Investigator Global Assessment [IGA] score ≥3, Eczema Area and Severity Index [EASI] score ≥6, or history of systemic agent use). Associations among symptoms and outcomes were examined using Pearson correlations.
Results: Patients (n=333) with moderate-to-severe AD were included (mean age [SD], 40.2 ye [5.7]; 53.8% female). Of these, 22.6% reported experiencing pruritus on a day-to-day basis; 17.2% experienced pruritus either “all the time” or “regularly.” Significant associations (P<0.05) were observed between pruritus and both sleep disruption (r=0.54) and depression (r=0.34). Decreasing pruritus frequency was significantly associated (P<0.05) with better disease-related and generic QOL as assessed by DLQI (r=0.42), POEM (r=0.42) (lower scores indicate better QOL for both measures), and the EQ-5D (r= –0.27). Decreasing pruritus frequency was also associated (P<0.05) with reduced overall work impairment (r=0.28) and activity impairment (r=0.35) as assessed by WPAI-AD.
Conclusion: Pruritus is one of the most troublesome symptoms in patients with moderate-to-severe AD and is significantly associated with sleep disruption, depression, disease-related and generic QOL, and work-related impairments, which reverse with reduction in pruritus frequency.
OP29: Transcutaneous electrical nerve stimulation for chronic pruritus management: a systematic review and meta-analysis
Yuebin Zhao1Jorge Pinilla Lopez2
1ANU Medical School, Australian National University, Australia, 2College of Engineering & Computer Science, Australian National University, Australia
Background/Objective: Transcutaneous electrical nerve stimulation (TENS) is a non-invasive form of analgesia that could also serve as an antipruritic treatment. This study aimed to evaluate the efficacy and risks associated with TENS for chronic pruritus.
Methods: A systematic review and meta-analysis of clinical trials that examined the efficacy and safety of TENS in patients with pruritus was performed according to recommended PRISMA [Preferred Reporting Items for Systematic Reviews and Meta-Analyses] guidelines.
Results: Three studies involving 98 patients with chronic pruritus secondary to lichen planus, atopic dermatitis, lichen simplex and chronic liver disease met the inclusion criteria. All studies utilized high frequency TENS (30 min to 1 h per session, 3 sessions per week) for 4 weeks. The mean difference between baseline Visual Analogue Scale (VAS) and post-treatment VAS was 5.136 (95% confidence interval, 4.136 to 5.954; P<0.001). One patient reported an adverse effect of mild erythema but no patients reportedly discontinued TENS due to adverse effects.
Conclusion: TENS provides effective and safe improvement in chronic pruritus. It is recommended to be considered as an alternative or adjuvant therapy for chronic pruritus. Future studies with the controlled group should also be considered.
Methods in itch research (experimental)
OP30: Genetic and functional studies of the role of GRP in sensory neurons and spinal cord
Zhou-Feng Chen, PhD
Center for the Study of Itch, Departments of Anesthesiology, Psychiatry, Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA
Gastrin-Releasing Peptide (GRP) is a member of the mammalian bombesin peptide family highly conserved across the animal kingdom. Our studies suggest that GRP functions as an itch-specific neuropeptide in the dorsal root ganglion (DRG) neurons, while others argue that GRP in the dorsal horn neurons activates its receptor GRPR to convey itch information. Despite recent studies, a definite evidence for the role of GRP in DRGs is lacking. To address this issue, we have generated floxed Grp mice which were mated with Nav1.8Cre mice to conditionally deleted Grp only in DRGs of mice (GRP CKO). GRP CKO displayed attenuated nonhistaminergic itch without impacting histamine-induced itch, recapitulating the phenotype of global Grp KO mice. To circumvent the inherent problem associated with BAC Grp-eGFP transgenic mice (GENSAT) which fail to show eGFP in DRGs, we generated a novel Grp-iCre knock-in (GrpCre-KI) mice and found that Cre mimics endogenous Grp expression in both DRGs and spinal cord. GRP fibers innervate the skin extensively, and opto-stimulation of the skin of GrpCre-K mice/Ai32 mice elicited frequency-dependent and itch-related scratching behavior. To determine the function of spinal Grp neurons, we selectively ablated spinal Grp neurons without impairing GRP neurons in the brain or DRGs using intersectional spinal ablation strategy. Mice lacking spinal Grp neurons showed normal itch and pain behaviors. Together, these results conclusively establish the role of GRP as an itch-specific neuropeptide in DRGs and reveal that GRP fibers are dedicated to itch transmission. Moreover, our data demonstrate the spinal Grp neurons are dispensable for itch or pain behavior.
OP31: Contagious itch behaviors in mice: from model to molecules
Institute for Biomedical Sciences of Pain, Tangdu Hospital, The Fourth Military Medical University, Xi’an, China
Objective: Socially contagious itch is ubiquitous in human society, but whether it exists in rodents is unclear. In the brain, the neural circuit and molecular mechanism mediating contagious itch are not fully understood.
Methods: Contagious itch behaviors in mice were evaluated in two paradigms. In home cage test, the demonstrator was a single BRAFNav1.8 mouse which displayed excessive spontaneous scratching due to chronic itch. In video screen test, the demonstrator was a video clip on a computer screen showing mouse nape scratching at the constant speed (30 scratches/ min). Stereotaxic surgery, toxin and AAV virus injection, and optic-fiber placement were targeted to suprachiasmatic nucleus (SCN). Immunohistochemistry (IHC) and in situ hybridization (ISH) were used for molecular examinations.
Results: Behavioral paradigms showed that mice scratched after observing a conspecific scratching. Histamine model was limited by inadequate frequency and duration of scratching bouts required for contagious itch test. Molecular mapping showed increased neuronal activity in the SCN of the hypothalamus of mice with contagious scratching. Ablation of gastrin-releasing peptide receptor (GRPR) or GRPR neurons in the SCN abolished contagious scratching behavior, which was recapitulated by chemogenetic inhibition of SCN GRP neurons. Activation of SCN GRP/GRPR neurons evoked scratching behavior.
Conclusion: These data demonstrate that GRP-GRPR signaling is necessary and sufficient for transmitting contagious itch information in the SCN. The findings may have implications for our understanding of neural circuits that control socially contagious behaviors.
OP32: Effects of rostral ventromedial medullary tachykinin 1 receptor (NK-1R) expressing neurons on the descending modulation of itch
Taylor Follansbee1, Dan Domocos2, Keiko Takanami3, Mirela Iodi Carstens1, Earl Carstens1
1Neurobiology, Physiol. & Behavior, University of California, Davis, Davis, CA, USA, 2Faculty of Biology, University of Bucharest, Bucharest, Romania, 3Mouse Genomics Resource Laboratory, National Institute of Genet., Mishima, Japan
The rostral ventromedial medulla (RVM) is important in descending modulation of spinal pain transmission. However, it is unknown if these descending pathways also modulate the spinal transmission of itch. A relevant class of RVM cells – the ON cells – facilitate spinal pain transmission and increase their firing just prior to the onset of a nocifensive withdrawal reflex. Furthermore, ON cells respond to intradermal injection of pruritogens. RVM neurons with descending spinal projections express the neurokinin-1 (NK-1) receptor, and are excited by local administration of substance P (SP). We hypothesized that ON cells express the NK-1 receptor, and have an inhibitory effect ion itch. To test this, chemogenetic and pharmacological approaches were used to activate ON cells and determine effects on itch- related behavior. Using single-unit recording, the magnitude of hindpaw pinch-evoked responses of RVM ON-cells was significantly potentiated (~50%) following local injection of SP (0.5 μl, 10 nmol); saline microinjection had no effect. In behavioral experiments, intracranial microinjection of SP (0.5 μl, 10 nmol) significantly reduced the number of hindlimb scratch bouts elicited by histamine or chloroquine. We also used a chemogenetic approach, injecting AAV5: DIO-hM3Dq-mCherry into the RVM of NK-1R-cre mice. Chemogenetic activation of RVM NK-1 receptor-expressing neurons significantly reduced pruritogen-evoked scratching behavior. In each DREADDs mouse we compared the number of scratch bouts elicited by histamine or chloroquine following systemic administration of saline (control) vs. clozapine (0.01 mg/kg). Compared to controls, clozapine administration significantly reduced the mean number of scratch bouts evoked by intradermal injection of histamine (6 vs. 76, P<0.05) or chloroquine (34 vs. 139, P<0.05). We conclude that activation of NK-1 receptor-expressing ON cells in RVM significantly reduces the spinal transmission of itch.
Grant/Other Support: NIH Grant AR057194.
OP33: Nalbuphine, a kappa opioid receptor agonist and mu opioid receptor antagonist attenuates pruritus, decreases IL-31, and increases IL-10 in mice with contact dermatitis
Saadet Inan1*, Alvaro T. Huerta3, Liselotte E. Jensen3, Nae J. Dun2, Alan Cowan1,2
1Center for Substance Abuse Research, 2Department of Pharmacology, 3Department of Microbiology and Immunology, Lewis Katz Medical School at Temple University, Philadelphia, PA, USA
Chronic itch is one of the disturbing symptoms of inflammatory skin diseases. Kappa opioid receptor agonists suppress scratching in mice against different pruritogens. Nalbuphine, a nonscheduled kappa opioid receptor agonist and mu opioid receptor antagonist, has been in clinical use for post-operative pain management since the 1980s and recently has been in clinical trials for chronic itch of prurigo nodularis (https://www.trevitherapeutics.com/nalbuphine). We studied whether nalbuphine is effective against chronic scratching induced by rostral neck application of 1-fluoro-2,4-dinitrobenzene (DNFB), an accepted mouse model of atopic and contact dermatitis. Mice were treated once a week with either saline or nalbuphine 20 min before the third, fifth, seventh, and ninth sensitizations with DNFB and the number of scratching bouts was counted for 30 minutes. Neck skin samples at week 4 were used to measure protein levels and mRNA expressions of chemokines and cytokines. Different sets of mice were used to study sedation and anhedonic-like behavior of nalbuphine. We found that: nalbuphine (a) antagonized scratching in a dose- and time-dependent manner without affecting locomotion, (b) decreased IL-31, and increased anti-inflammatory IL-10, and (c) induced more elevations in the levels of CCL2, CCL3, CCL12, CXCL1, CXCL2, CXCL9, CXCL10, IL-1β, IL-16, TIMP-1, M-CSF, TREM-1 and M1-type macrophages compared to saline. Increases in chemokines and cytokines and M1 macrophages by nalbuphine suggest an inflammatory phase of healing in damaged skin due to scratching. Our data indicate that nalbuphine is an effective antipruritic against pruritus in contact dermatitis.
OP34: Scratching and sensory deficits in an Nav1.7 gain of function mouse model
Nivanthika K. Wimalasena1,2, Jaehoon Shim1, Clifford J. Woolf1,2
1F.M. Kirby Neurobiology, Boston Children’s Hospital, Boston, MA, USA, 2Department of Neurobiology, Harvard Medical School, Boston, MA, USA
Gain of function mutations in Nav1.7, the voltage gated sodium channel encoded by the gene Scn9a, have been implicated in several genetic pain conditions in humans. These include: inherited erythromelalgia (IEM), paroxysmal extreme pain disorder (PEPD), and small fiber neuropathy (SFN). In a subset of these cases, a dying-back neuropathy has been described in which peripheral nerve terminals degenerate, leading to various sensory deficits. We have used CRISPR/Cas9 to engineer such a gain of function mutation, I228M, in mice. These mice exhibit profound insensitivity to noxious heat, as well as an unforeseen scratching phenotype, leading to lesions of the skin, which increase in severity over time. It is as yet unclear how increased itch sensation and decreased pain sensation interact to result in this pathological scratching behavior. We explore that here, and aim to understand which sensory neurons are responsible for these changes. Additionally, we utilize these mice to probe, at high spatial and temporal resolution, the dynamics of scratching itself. We aim to expand beyond the standard measures of scratching bouts and time spent scratching to uncover a metric that correlates with the degree of damage to the skin. Using these two approaches, we investigate the relationship between aberrant Nav1.7 activity, itch, and pain.
OP35: Recent evidence on the mechanism of sweat-related itch in atopic dermatitis
Hiroyuki Murota1, Ichiro Katayama2
1Department of Dermatology, School of Medicine, Nagasaki University, Japan, 2Graduate School of Medicine, Osaka City University, Japan
Sweating is known to exacerbate itch for atopic dermatitis patients. In contrast, we found via the axon reflex sweat test that subjects with atopic dermatitis possess an attenuated ability to sweat. Thus, we explored the cause of sweat-induced itch by focusing on both the components and excretion of sweat. Metabolomic analysis revealed increased glucose in the sweat metabolites of subjects with atopic dermatitis, and the sweat glucose levels significantly correlated with disease severity. Further investigation using a disrupted skin barrier animal model revealed that glucose at the same concentration as atopic dermatitis sweat impaired early stage skin barrier recovery, implying that sweat glucose may exacerbate itch through interference of skin barrier recovery in subjects with server symptoms. Subsequently, immunostaining for dermcidin, a sweat-specific antimicrobial peptide, was performed to examine the mechanism of sweat excretion. Dermcidin was not only localized inside the sweat glands but also in the surrounding dermal tissues in atopic dermatitis lesional skin, suggesting sweat gland leakage. Next, we investigated claudin-3, which creates tight junctions within sweat glands, thus forming a water barrier. Marked reduction in claudin-3 expression was observed in the sweat glands of atopic dermatitis lesions, providing a potential cause for the sweat leakage and sweat-induced itch via possible induction of kinins and other pain mediators.
Hot off the bench: Latest news by young investigators
OP36: Revisiting itch in psoriasis
Radomir Reszke, Rafał Białynicki-Birula, Jacek C. Szepietowski
Department of Dermatology, Venereology and Allergology, Wrocław Medical University, Wrocław, Poland
Introduction: Psoriasis is a frequent dermatosis in the general population. The major complaint reported by those patients is chronic itch (CI).
Objective: We aimed to investigate the frequency and detailed clinical features of CI in psoriatic patients, with a special emphasis on the possible associations with different age groups, systemic comorbidities and pharmacotherapy.
Materials and Methods: The study included 143 adult patients hospitalized in the dermatologic ward due to plaque psoriasis between January 2017 and May 2018.
Results: Among 143 patients there were 83 males (58%) and 60 females (42%). The mean age was 56.7±16.0 years. Nearly 40% of subjects were aged 65 years or older. The mean Psoriasis Area Severity Score (PASI) was 14.6±9.5 points. Seventy-two percent of subjects reported CI. Senile patients presented higher 4-Item Itch Questionnaire (4IIQ) scores (8.6±3.4 vs. 7.4±2.5 points; P=0.03) and rarely experienced itching during midday (P=0.009). CI was correlated with aspirin intake (correlation coefficient (CC)=0.24; P=0.04), and xerosis intensity (cc=0.31; P=0.003). 4IIQ scores were higher in patients with asthma/chronic obstructive pulmonary disease (cc=0.29; P=0.003), peptic ulcer disease (cc=0.27; P=0.006) and insulin takers (cc=0.38; P=0.0001). Logistic regression analysis revealed positive correlation of CI with the use of antiacids (Odds Ratio (OR)=45.1), angiotensin receptor blockers (OR=20.9), angiotensin enzyme converting inhibitors (OR=2.5), beta-blockers (OR=6.1), xerosis intensity (OR=1.8) and Physician’s Global Assessment score (OR=1.7), while psychiatric drugs other than SSRI (OR=0.015), allopurinol (OR=0.06), arterial hypertension (OR=0.09) and the use of emollients application (OR=0.29) were associated with lower frequency of CI.
Conclusions: CI remains a common complaint in psoriatic patients. Clinical characteristics of CI may vary between different age groups and reveal possible associations with comorbidities and pharmacotherapy.
OP37: Improvement of pruritus with topical dapsone in children with dermatitis herpetiformis
Maria Victoria Rosso, N. Mantero, Diego Martin Loriente, S. García, Patricia Della Giovanna
Dermatology Department, Professor Alejandro Posadas
National Hospital, Buenos Aires, Argentina
Dermatitis Herpetiformis (DH) is a chronic, polymorphic, pruritic autoimmune skin blistering disease, considered as cutaneous manifestation of Celiac Disease (CD). The current standard of care consists in gluten-free diet (GFD) and oral dapsone for rapid symptoms control. We present two cases with good response to topical dapsone. Case 1: 6 year- old boy with a 3-year history of recurrent pruritic papules involving trunk and limbs with no response to topical corticosteroids and oral antihistamines. Physical examination showed disseminated red papules and excoriated lesions. Routine blood examinations were normal, IgA antitransglutaminasa (tTG), anti-endomysium (EMAs) and anti-gliadin were positive with low level of glucose-6-phosphate dehydrogenase (G6PD). The histologic examination showed nonspecific findings. Direct immunofluorescence (DIF) revealed granular deposition of IgA and C3 on dermal papillae and along dermal-epidermal junction. Small bowel biopsy demonstrates normal villi, but increased crypt hyperplasia and intra-epithelial lymphocytes, (MARSH 2). Case 2: 4 year- old girl with atopic dermatitis with a 6-month pruritic dermatosis. Physical examination showed symmetrical grouped red papules involving scalp, extensor surface of elbows, knees and lumbo-sacral region. Routine blood examinations were normal, IgA anti-tTG, anti-EMAs and anti-gliadin were positive and low level of G6PD was detected. Histopathology showed secondary changes to acute scratching. DIF revealed granular IgA and C3 deposition along the basement membrane with accentuation at the papillary tips. Duodenal biopsy confirmed mild villous atrophy (MARSH 3a). In both cases diagnosis of DH was made. They started a strict GFD and topical dapsone 5% cream twice a day with excellent response. Early recognition of DH leads to the underlying enteropathy and prevent potential complications of CD. To conclude, topical dapsone is a therapeutic option for localized diseases or for patients in whom oral dapsone is contraindicated.
OP38: Identification of novel MRGX2-agonists triggering mast cell degranulation and potentially mediating drug-induced pruritus
Helen Kühn1*, Katharina Wolf1*, Felicitas Böhm1, Markus Glaudo1, Lisa Gebhardt1, Konstantin Agelopoulos2, Philipp Ectors4, Pavel Kolkhir3, Dirk Zahn4, Jörg Scheffel3, Tomasz Hawro3, Martin Metz3, Markus F. Neurath1, Sonja Ständer2, Andreas E. Kremer1
1Department of Medicine 1 and Translational Research Center, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany, 2Center for Chronic Pruritus, Department of Dermatology, University Hospital Münster, Münster, Germany, 3Department of Dermatology and Allergy, Charité – Universitätsmedizin Berlin, Berlin, Germany, 4Lehrstuhl für Theoretische Chemie/Computer Chemie Centrum, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
Background & Aims: Pruritus is an agonizing symptom, which can occur as adverse effect of many drugs. As this represents a clinical challenge, we aimed to understand its molecular mechanisms by analysing the role of the Mas-related G protein-coupled receptors (MRG) in drug-induced pruritus.
Methods: We established a high-throughput calcium mobilization screen to analyse drugs for activation of the human MRG receptors (X1-4, D-G). Novel agonists were examined for structural similarities using in silico 3D modelling. Physiological relevance of these agonists was assessed using calcium imaging in mast cells (MC) and murine dorsal root ganglia (DRG). Furthermore, degranulation was evaluated by β-hexosaminidase assay. Scratching in mice was objectively assessed using a magnet-based recording technology.
Results: High-throughput drug screening led to the identification of 18 pharmaceutically active compounds specifically activating MRGX2. The agonists exhibited strong structural similarities all containing two ring systems and an aliphatic amino group. The three representative compounds clomipramine, paroxetine and desipramine (EC50: 16.2-83.1 μM) were chosen for further analyses. As MRGX2 is expressed on mast cells, we assessed activation of the human MC line LAD2 and primary human skin MC. The agonists induced a rise of cytosolic calcium (EC50 in LAD2: 16.0-34.4 μM) and caused degranulation of MC. To further evaluate their pruritogenic activity in the murine system in vitro and in vivo, we confirmed agonist-mediated activation of the murine MRGX2-homologues MRGA1 and MRGB2. The agonists activated murine peritoneal MC and induced degranulation. Moreover, the agonists induced a rise of cytosolic calcium in murine DRG and functioned as pruritogens caused acute pruritus in mice, possibly both via direct neuronal activation and via MC-mediated itch signalling.
Conclusions: In summary, we were able to identify a novel class of pharmaceutically active compounds inducing itch via MRGX2 activation. Our data imply MRGX2 as potential therapeutic target to tackle drug-induced pruritus.
OP39: Nocebo effects on cowhage-evoked itch: Results of an experimental model of learning processes
Joseph S. Blythe1,2, Kaya J. Peerdeman1,2, Dieuwke S. Veldhuijzen1,2, Mia A. Thomaidou1,2, Antoinette I.M. van Laarhoven1–3, Andrea W.M. Evers1–3
1Leiden University, Leiden, The Netherlands, 2Leiden Institute for Brain and Cognition, Leiden, The Netherlands, 3Leiden University Medical Center, Department of Psychiatry, Leiden, The Netherlands
The worsening of pruritic symptoms due to negative outcome expectations, nocebo effects, may lead to increased severity and detrimental treatment responses in clinical pruritic conditions. Nocebo effects on itch have been shown to form through various learning processes, such as conditioning and observational learning. In this experiment, we sought to compare whether learning through observation alone can be as effective as conditioning for inducing nocebo effects on cowhage-evoked itch. A sample of 66 healthy female participants was randomly allocated to either a classical conditioning, observational learning, or sham conditioning (control) procedure. Participants in the classical conditioning group learned to associate the administration of a topical cream with an increase in the intensity of subsequent cowhage-evoked itch first-hand, while participants in an observational learning group were taught this association through observing a video of the conditioning paradigm. The data showed that there was a high degree of variability in response to cowhage-evoked itch. Results of the learning manipulation suggest that classical conditioning induced a significant nocebo effect on itch, while observational learning with verbal suggestion yielded a marginally significant trend towards a nocebo effect when compared to the control condition. This experiment demonstrates for the first time that associative and instructional learning processes can induce nocebo effects on cowhageevoked itch, a clinically relevant model of pruritic symptoms in chronic dermatological conditions. Conditioning through first-hand experience appears to be more effective than observational learning in the formation of nocebo effects on itch. Future research should seek to further advance our understanding of the role that psychological processes play in shaping treatment responses in chronic pruritic conditions.
OP40: Tac1-Expressing neurons in the periaqueductal gray facilitate the itch-scratching cycle via descending regulation
Zheng-Run Gao1,2*, Wen-Zhen Chen1,2*, Ming-Zhe Liu1,2*, Xiaojun Chen1,2, Li Wan3, Xin-Yan Zhang1,2, Lei Yuan1,2, Jun-Kai Lin1,2, Meng Wang1,2, Li Zhou1,2, Xiao-Hong Xu1, YanGang Sun1*†
1Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science & Intelligence Technology, Chinese Academy of Sciences, Shanghai, China, 2University of Chinese Academy of Sciences, Beijing, China, 3Department of Pain Management, State Key Specialty in Pain Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
*These authors contributed equally
Uncontrollable itch-scratching cycles lead to serious skin damage in patients with chronic itch. However, the neural mechanism promoting the itch-scratching cycle remains elusive. Here, were report that tachykinin 1 (Tac1)-expressing glutamatergic neurons in the lateral and ventrolateral periaqueductal gray (l/vlPAG) facilitate the itch-scratching cycle. We found that l/vlPAG neurons exhibited scratching-behavior-related neural activity and that itch-evoked scratching behavior was impaired after suppressing the activity of l/vlPAG neurons. Furthermore, we showed that the activity of Tac1-expressing glutamatergic neurons in the l/vlPAG was elevated during itch-induced scratching behavior and that ablating or suppressing the activity of these neurons decreased itch-induced scratching behavior. Importantly, activation of Tac1-expressing neurons induced robust spontaneous scratching and grooming behaviors. The scratching behavior evoked by Tac1-expressing neuron activation was suppressed by ablation of spinal neurons expressing gastrin-releasing peptide receptor (GRPR), the key relay neurons for itch. These results suggest that Tac1-expressing neurons in the l/vlPAG promote itch-scratching cycles.
OP41: Immunohistochemical analysis of IL-31, oncostatin M, and their receptors in prurigo nodularis
Leigh Nattkemper, Takashi Hashimoto, Christina Kursewicz, Emilie Fowler, Serena Shah, Sonali Nanda, Rachel Fayne, Paolo Romanelli, Zamaneh Mikhak, Rohan Gandhi, Gil Yosipovitch
Dr. Philip Frost Department of Dermatology & Cutaneous Surgery, Miami Itch Center, University of Miami Miller School of Medicine, Miami FL, USA
Prurigo nodularis (PN) is characterized by hyperkeratotic, severely itchy nodules, which dramatically impacting patient Quality of Life. This condition can be difficult to treat, as its pathogenesis remains unclear. Interleukin-31 (IL-31) has been reported to be elevated in the skin of PN patients, even higher than levels found in pruritic atopic dermatitis skin. This study aimed to evaluate immunohistochemically the role of Oncostatin M Receptor (OSMRβ) pathway in PN by examining the presence of pruritus-associated cytokines IL-31 and OSM and receptors IL-31Rα and OSMRβ in patient skin biopsies. Epidermal expression of IL-31 was not different in PN (n=24) skin, whereas OSM was slightly decreased (P=0.04) when compared to healthy controls (n=10). However, both IL-31+ and OSM+ cells showed a trend to be increased (P=0.08 and P=0.07, respectively) in the dermis of PN patients (n=19) compared to healthy control tissue (n=10). This increase in IL-31+ (r=0.55, P=0.02) and OSM+ (r=0.51, P=0.03) cells significantly correlated with itch intensity ratings. IL-31Rα was highly expressed in the epidermis (P=0.0001), and its expression correlated with itch intensity (r=0.74, P=0.0001). Similarly, dermal IL-31Rα+ cells were increased (P=0.002) in PN biopsies and correlated to itch intensity (r=0.48, P=0.05). Interestingly, epidermal expression of OSMRβ was significantly decreased (P=0.005), although dermal OSMRβ+ cells were significantly elevated (P=0.05) in comparison to healthy controls. Dermal OSMRβ+ cells did not significantly correlate (r=0.36, P=0.15) with itch intensity ratings, but epidermal expression of OSMRβ was negatively correlated (r=−0.78, P=0.0001). Double staining techniques were used to show that a majority of the IL-31Rα+ and OSMRβ+ cells were CD68+ macrophages, whereas IL-31+ and OSM+ cells were CD3+ lymphocytes. These data suggest that the cytokines IL-31 and OSM may play a role in the pathomechanisms of PN and as such the OSMRβ pathway is a plausible target for pharmacotherapy.
OP42: Itch, pain and nociceptor plasticity in allergic contact dermatitis
Robert LaMotte, PhD
Departments of Anesthesiology and Neuroscience, Yale University School of Medicine, New Haven, CT, USA
Allergic contact dermatitis (ACD) is a clinically significant pruritic disease with high prevalence but few treatment options. We produced ACD experimentally in humans and mouse. The goal was to use the mouse as an animal model to investigate changes in excitability of mechanosensitive cutaneous nociceptors contributing to the enhanced itch and pain of ACD. Humans and mice were each sensitized by cutaneous topical application of squaric acid dibutyl ester, a hapten not encountered in the environment. This produced a mild irritant contact dermatitis but elicited itch- and pain-like behavior only in mice. Subsequent challenge at another cutaneous site produced significantly stronger inflammation, greater spontaneous itch- and pain and additionally hyperalgesia to noxious heat and mechanical stimuli in both humans and mice. In mice, cutaneous nociceptive neurons innervating the ACD site exhibited enhanced membrane excitability and density of sodium current, irregular, low-rate spontaneous discharge, and an upregulation of chemokine receptors CXCR3 and CCR2 (in addition to their normal presence on hapten specific T lymphocytes) and their ligands, CXCL10 and CCL2. These ligands elicited site-directed sensory behavior when injected into the skin of mice. Thus, these pruriceptive nociceptive neurons may contribute to ACD by eliciting itch which, in turn, evokes scratching that could release chemokines that would exacerbate the inflammation and itch by activating receptors on neurons and attracting immune cells. A therapeutic target would be to diminish the hyperexcitability of these neurons that maintain persistent itch and hypersensitive itchy skin.
Atopic dermatitis and itch
OP43: Relationship between systemic biomarkers of atopic dermatitis (AD) and pruritus from a phase 2b study of once-daily oral janus kinase 1 inhibitor abrocitinib in moderate-to-severe AD
Melinda J. Gooderham1, Hernan Valdez2, Claire Feeney3, Elena Peeva4, Jean S. Beebe4, Elizabeth Kieras4, Michael S. Vincent4, Weidong Zhang4, Ricardo Rojo5, Rodney Sinclair6
1SKiN Centre for Dermatology, Peterborough, ON, Canada, 2Pfizer Inc., New York, NY, USA, 3Pfizer Ltd., Tadworth, Surrey, United Kingdom, 4Pfizer Inc., Cambridge, MA, USA, 5Pfizer Inc., Groton, CT, USA, 6Sinclair Dermatology, East Melbourne, VIC, Australia
Introduction: In a randomized, double-blind phase 2b clinical trial (NCT02780167), abrocitinib 200 mg and 100 mg improved pruritus numeric rating scale (NRS) score as early as day 2 (200 mg) and day 5 (100 mg) compared with placebo. After 2 weeks of treatment, 53.1% and 38.5% of patients receiving abrocitinib 200 mg or 100 mg achieved ≥4-grade improvement in pruritus NRS score. Abrocitinib also reduced concentrations of systemic AD biomarkers, including thymus- and activation-regulated chemokine (TARC) and interleukin-31 (IL-31), the concentrations of which were significantly correlated with pruritus NRS score. In this analysis, the relationship between these systemic biomarkers and pruritus is further explored.
Methods: Pruritus responders were defined as ≥3-point improvement or ≥4-point improvement in pruritus NRS score (ie, NRS3 and NRS4, respectively). Blood samples were collected at baseline and weeks 4, 8, 12, and 16. Longitudinal analysis for each biomarker was performed for responder and nonresponders using data pooled between abrocitinib and placebo groups.
Results: Throughout the study, NRS3 and NRS4 responders had lower IL-31, TARC, and IgE concentrations than nonresponders. The relationship between biomarker concentration and pruritus response appeared to be strongest for TARC, followed by IL-31; a relationship between pruritus response and IgE was less apparent. Regardless of time to response, median percentage reduction in IL-31 concentration at the time of NRS3 or NRS4 response was ~50%. Likewise, median percentage decreases from baseline in TARC and IgE were ~40% and ~15% for both NRS3 and NRS4 responders, respectively, regardless of time to response.
Conclusion: This analysis provides additional support for a direct relationship between IL-31 and TARC blood concentrations and pruritus. It suggests that this relationship may be based on biomarker threshold concentrations. Early inhibition of systemic biomarkers of itch (including IL-31 and TARC) resulted in earlier resolution of itch.
OP44: A Combined responder analysis of tradipitant demonstrates significant improvements in itch and disease severity
Sarah E. Welsh, Jim Wang, Derek Xiao, Christos Polymeropoulos, Gunther Birznieks, Mihael H. Polymeropoulos
Vanda Pharmaceuticals Inc, Washington, DC, USA
Atopic dermatitis (AD) is characterized by skin lesions and pruritus not relieved by scratching. The challenge for current therapies is to treat both of these characteristic disease symptoms. Many of the currently available therapies improve AD through clearing of the skin by targeting improvement in lesion severity. Targeting AD improvement through reduction in pruritus remains a significant unmet medical need. Tradipitant, a novel neurokinin-1 receptor antagonist, is a possible therapy that could improve AD through reduction in pruritus. We examined the possibility of AD improvement through this novel mechanism in a Phase 2 study VP-VLY-686-2012. Study VP-VLY-686-2102 was a randomized, double-blind, placebo-controlled, multi-center study that randomized 168 patients with chronic pruritus associated with atopic dermatitis. Patients received 85 mg of tradipitant or placebo orally twice daily over 8 weeks. Itch was assessed by Worst Itch (WI) VAS and disease severity was assessed by the SCORing Atopic Dermatitis (SCORAD) index. To determine whether tradipitant improved both itch and disease severity together over the course of the study, a combined responder analysis was completed in the ITT population (n=147) using the Cochran-Mantel-Haenszel test. A responder was defined as both SCORAD improvement greater than 50 percent and WI-VAS improvement greater than 40mm. Significantly more patients receiving tradipitant than placebo responded to treatment on both the combined itch and disease severity measure cutoff in the ITT population (tradipitant=38.7%, placebo=18.1%, P-0.007). When itch response and disease severity response were analyzed individually, the proportion of responders in WI-VAS and SCORAD were greater in patients receiving tradipitant (WI-VAS: tradipitant=52.6%, placebo=34.7%, P-0.037 and SCORAD: tradipitant=44.0%, placebo=20.8%, P-0.004). These findings suggest that tradipitant treatment could be a potential therapy which can improve both itch and disease severity in patients with AD. Additional studies are being conducted to confirm and extend these findings.
OP45: Mrgprs in itch
Ethan A. Lerner
Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, USA
Mas-related G-protein coupled receptors, Mrgprs, sense endogenous and exogenous pruritogens as well as certain allergens or pseudoallergens. Their expression on sensory neurons and mast cells is consistent with transmission of itch signals from the periphery as well as crosstalk with the immune system. There is the intriguing possibility that members of this receptor class have roles that have not previously been described. This multitude of roles will be discussed.
Patient’s Perspectives and Patient reported outcomes
OP46: Patient-reported outcome measures for pruritus: Issues to consider when selecting measurement instruments
Institute of Social Medicine and Health Economics, Otto von Guericke University Magdeburg, Magdeburg, Germany
A patient-reported outcome measure (PROMS) captures the status of one’s health directly from a person, without interpretation of a clinician. PROMs have become an important component of the assessment of the benefit of interventions in clinical trials or healthcare research as well as the assessment of the performance of healthcare providers in routine care. Selecting PROMs is commonly perceived as challenging, particularly in areas such as pruritus in which more and more PROMs are developed and tested. In order to make an evidence-based decision in the selection of PROMs assessing particular aspects (domains) of health and disease (such as pruritus severity or pruritus-specific quality of life), it is important to compare the quality of existing instruments. This can be achieved by systematic reviews of measurement instruments which focus on two different quality aspects: (1) the methodological quality of studies on measurement properties (reliability, validity and responsiveness) of a particular instrument, and (2) the adequacy of the measurement properties themselves. (1) is achieved by a comprehensive risk of bias assessment, (2) by applying criteria for good measurement properties. The synthesis of both aspects allows to evaluate the quality of the evidence for each measurement property of any PROM considered using the GRADE approach and should be complemented by information on the interpretability and feasibility of the instrument considered. Content validity (the degree to which the content of a PROM is an adequate reflection of the construct to be measured) is considered absolutely essential in the evaluation of the quality of a PROM. A comprehensive systematic review of the quality of PROMs for pruritus is currently being updated. Based on this, ten PROMs are considered most appropriate, five in the domain pruritus intensity, one for pruritus severity, two for pruritus-specific quality of life and two other instruments.
OP47: Itch patient-reported outcomes (PROs) with abrocitinib treatment in patients with moderate-to-severe atopic dermatitis (AD): Results from a randomized, phase 3 clinical trial
Robert Bissonnette1, Jonathan I. Silverberg2, Arnon D. Cohen3, Sonja Ständer4, Claire Feeney5, Hernan Valdez6, Pinaki Biswas6, Marco DiBonaventura6, Robert Gerber7, Ricardo Rojo7
1Innovaderm Research, Montreal, QC, Canada, 2George Washington University, Washington, DC, USA, 3Siaal Research Center for Family Medicine and Primary Care, Ben-Gurion University of the Negev, Beersheba, Israel, 4Center for Chronic Pruritus, University of Münster, Münster, Germany, 5Pfizer Ltd., Tadworth, Surrey, United Kingdom, 6Pfizer Inc., New York, NY, USA, 7Pfizer Inc., Groton, CT, USA
Introduction: Moderate-to-severe AD imparts a substantial burden for patients. Here, PROs are reported from a phase 3 trial of abrocitinib (NCT03349060), an oral Janus kinase 1 inhibitor, in patients with mild-to-moderate AD.
Methods: Patients ≥12 years with clinical diagnosis of AD were randomized (2:2:1) to receive once-daily abrocitinib 200 mg, abrocitinib 100 mg, or placebo for 12 weeks. PROs included the visual analog scale (VAS) of itch (0-10 scale) of Scoring Atopic Dermatitis (SCORAD); the itch item (1-5 scale) in the Patient-Oriented Eczema Measure (POEM); and the itch item (0-10 scale) of the Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD).
Results: Overall, 154, 156, and 77 patients received abrocitinib 200 mg, abrocitinib 100 mg, and placebo, respectively. Mean baseline scores (standard deviation [SD]) for SCORAD VAS of itch were 7.1 (1.9), 7.3 (1.8), and 7.4 (1.5) for abrocitinib 200 mg, abrocitinib 100 mg, and placebo, respectively; scores (SD) at week 12 were 2.8 (2.8), 4.0 (2.8), and 5.6 (2.7). Mean baseline scores (SD) for the itch item in POEM were 3.8 (0.7) for abrocitinib 200 mg and 3.7 (0.8) for abrocitinib 100 mg and placebo; mean scores (SD) at week 12 were 2.0 (1.5), 2.6 (1.4), and 3.2 (1.1) for abrocitinib 200 mg, abrocitinib 100 mg, and placebo, respectively. Mean baseline scores (SD) for the itch item of PSAAD were 7.1 (1.8), 6.8 (2.0), and 7.1 (1.6) for abrocitinib 200 mg, abrocitinib 100 mg, and placebo, respectively; scores (SD) at week 12 were 2.8 (2.6), 4.0 (2.5), and 5.6 (2.5).
Conclusion: Patients with moderate-to-severe AD treated with abrocitinib reported meaningful improvements in multiple itch PROs compared with patients treated with placebo.
OP48: Development and validation of the Prurigo control test (PCT) – A patient reported outcome measure to assess disease control in chronic prurigo
Karsten Weller1, Claudia Zeidler2, Nis Boehnke1, Marcus Maurer1, Sonja Ständer2, Martin Metz1
1Department of Dermatology and Allergy, Charité- Universitätsmedizin Berlin, Berlin, Germany, 2Center for Chronic Pruritus, Department of Dermatology, University Hospital Münster, Münster, Germany
Background: Chronic prurigo (CPG) is a common and difficult-to-treat disease with significant impact on quality of life. Important characteristics of CPG, i.e. itch, sleep impairment, scratching behavior, and impairment in quality of life cannot be assessed objectively. Accordingly, patient reported outcome measures (PROM) are important tools to assess the status of CPG in the patients. While itch intensity is determined by standardized assessments (e.g. numeric rating scale), there is no simple and validated PROM available that has been specifically developed to determine disease control and to guide treatment decisions in CPG patients.
Objective: To develop and validate the Prurigo Control Test (PCT), a novel, easy to administer and fast to evaluate PROM for the retrospective assessment of disease control in CPG patients.
Methods: In a first item generation phase, potential items were developed by literature research, patient interviews, and expert group input. Subsequently, item selection was performed in a combined approach based on impact analysis and additional criteria for item selection, such as item-item correlations, floor and ceiling effects and face validity. The resulting PCT instrument was then tested for its validity and reliability.
Results: A 5-item PCT addressing severity of skin lesions, scratching, sleep, quality of life, and treatment efficacy with a recall period of 4 weeks was developed based on 69 potential PCT items in the item generation and selection phase. In the subsequent validation study, 95 patients from the CPG centers of Berlin (n=44) and Münster (n=51) were recruited. Finalization of analyses regarding the PCTs’ internal consistency reliability, test-retest reliability, convergent validity and known-groups validity, as well as its cut-off value to distinguish poorly and well-controlled CPG are currently ongoing.
Conclusions: The PCT is the first PROM that is developed to assess disease control in CPG. Its retrospective approach and simple scoring would make it an ideal instrument for the management of CPG patients in clinical studies as well as in routine patient care.
OP49: Open- and closed-label nocebo and placebo verbal suggestions regarding a sham transdermal caffeine patch: effects on itch
Stefanie H. Meeuwis, MSc1, Henriët van Middendorp, PhD2, Adriana P.M. Lavrijsen, MD, PhD3, Dieuwke S. Veldhuijzen, PhD4, Andrea W.M. Evers, PhD5
1Leiden University, Faculty of Social and Behavioural Sciences, Institute of Psychology, Health, Medical and Neuropsychology Unit, Leiden, The Netherlands; Leiden Institute for Brain and Cognition, Leiden University Medical Center, Leiden, The Netherlands, 2Leiden University, Faculty of Social and Behavioural Sciences, Institute of Psychology, Health, Medical and Neuropsychology Unit, Leiden, The Netherlands; Leiden Institute for Brain and Cognition, Leiden University Medical Center, Leiden, The Netherlands, 3Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands, 4Leiden University, Faculty of Social and Behavioural Sciences, Institute of Psychology, Health, Medical and Neuropsychology Unit, Leiden, The Netherlands; Leiden Institute for Brain and Cognition, Leiden University Medical Center, Leiden, The Netherlands, 5Leiden University, Faculty of Social and Behavioural Sciences, Institute of Psychology, Health, Medical and Neuropsychology Unit, Leiden, The Netherlands; Leiden Institute for Brain and Cognition, Leiden University Medical Center, Leiden, The Netherlands; Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands
Background: Negative and positive outcome expectations have been found to influence itch sensations (i.e. nocebo and placebo effects), and can be induced by providing information regarding an inert treatment method. There is accumulating evidence that these effects may also be elicited when it is known that an inert treatment method is provided (open-label).
Methods: A randomized between-subjects study design was applied. Healthy volunteers (n=112) were randomly assigned to 1) a closed-label (i.e. concealed) negative verbal suggestions group, 2) an open-label negative verbal suggestions group, 3) a closed-label positive verbal suggestions group, or 4) an open-label positive verbal suggestions group. Participants were told that a transdermal caffeine patch would be applied, which can positively influence cognition (e.g., attention span), but which would, as a side effect, negatively or positively (depending on group allocation) influence itch. Participants in the open-label groups were given an additional explanation of nocebo or placebo effects and its mechanisms. Itch was induced at baseline and post-suggestions by histamine iontophoresis.
Results: Both open-label and closed-label suggestions influenced itch expectations and experienced mean itch, as evidenced by significant between-group differences (all P<0.008). However, within-group analyses of baseline-to-post-suggestions change showed that itch reduced significantly following positive suggestions (all P<0.001), but did not change following negative suggestions (all P>0.22). No effects on skin response to histamine were found (all P>0.23).
Conclusion: These results suggest that open-label positive verbal suggestions may be a promising method for utilizing placebo effect mechanisms in clinical practice, for example, by explaining the mechanisms involved. More research is needed to examine the effects of negative suggestions for itch under open-label conditions.
Itch and Pain
OP50: Itch and pain: an update
Department Experimental Pain Research, CBTM, Medical Faculty Mannheim, University Heidelberg, Germany
Facing the enormous advancements in characterizing specific classes of afferent nerve fibers for itch, but also for pain it is tempting to regard the question on the generation of itch vs. pain as solved. However, as we have learned from decades of pain research there are numerous factors that determine the development from acute nociception to chronic pain such as sensitization, structural and maladaptive changes. Such mechanisms are expected to also apply for the development of chronic itch. Another more basic problem for our understanding of the generation of itch is linked to the traditional explanations based on theories in their “pure” form, i.e. specificity, temporal and spatial pattern or intensity. Recent results suggest that physiologic itch processing may combine elements from these different basic theories that have been regarded as mutually exclusive. Examples of such combination are activation of a specific subpopulation of C-afferents such as MrgprA3 positive fibers that might generate itch not only via the assumed specificity, but will also activate only a subset of nociceptors innervating a given skin site. Such a combination of active and non-active nociceptors from the same skin site will thereby mimic a spatial contrast pattern. Another example would be a high number of spontaneously active nociceptors that signal pain; upon reduction of this number for example by analgesic therapy the chances to create a spatial contrast pattern by the still active nociceptors is increasing. This would represent a combination of a spatial contrast theory and the old intensity theory that could contribute to neuropathic itch. Recently, a delayed signal transmission was found in the spinal processing of itch signals between gastrin-releasing peptide (GRP) positive neurons and GRP-receptor positive spinal neurons: ongoing activity of the presynaptic neuron for dozens of seconds was required to finally evoke postsynaptic discharge. This new finding is of crucial importance for our experimental approaches that involve acute stimulation of primary afferents to induce itch in healthy volunteers or chronic itch patients. Rather than assuming that in pathological conditions there is a mutually exclusive explanation for itch purely based on one theory of itch, we rather might adapt our conceptual framework and include mechanisms that combine aspects from different theories.
OP51: A single afferent subset can transmit itch or pain by differential recruitment of trp channels
Behrang Sharif1–3, Ariel R. Ase1,2, Alfredo Ribeiro-da-Silv2,4, Philippe Séguéla1,2
1Montreal Neurological Institute – Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada, 2The Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada, 3Department of Physiology, McGill University, Montreal, Quebec, Canada, 4Department of Pharmacology & Therapeutics and Anatomy & Cell Biology, McGill University, Montreal, Quebec, Canada
Despite the known anatomical and behavioral overlap of pruriception and nociception, the underlying neurophysiological basis of itch and its relation to pain is still unclear. To examine the multimodal capacity of first order afferents, we focused on a defined subpopulation of peripheral primary C-fiber pruriceptors that express MrgprA3, the receptor for the itch-inducing compound chloroquine. To be able to evaluate the effects of a wide variety of activation conditions, we took advantage of Credependent optogenetic and chemogenetic actuators for selective activation of MrgprA3+ neurons. Quantitative behavioral analysis was performed after complete anatomical and functional validation of heterologous opsins and excitatory DREADDs in primary sensory neurons. Our behavioral studies show that chemogenetic activation of MrgprA3+ neurons evokes stereotypical itch behaviors rather than pain responses. Unexpectedly, optical activation of these same neurons, through ChR2, predominantly induces pain responses and avoidance behaviors rather than itch. Pharmacological interventions confirm that the itch modality transmitted by this afferent population is sensitive to gastrin releasing peptide receptor antagonist, while the pain modality is opioid-sensitive. Furthermore, we show that several types of calcium-permeable TRP channels are engaged in the induction of itch behavior yet opticallyinduced nocifensive behavior is unaffected by blockade of these channels.
OP52: The role of the amygdala in itch and anxiety
Tasuku Akiyama, Kristen M. Sanders, Kent Sakai, Darya Pavlenko, Hideki Funahashi
Miami Itch Center and Department of Dermatology and Cutaneous Surgery, University of Miami, Miami, Florida, USA
Chronic itch is directly linked to higher rates of emotional disorders like anxiety. In turn, stress and anxiety exacerbate itch, leading to a vicious cycle that seriously dampens the patients’ quality of life. Despite the importance of this itch-anxiety cycle in chronic itch, there has been little investigation into the neuronal mechanisms that underlie affective itch. We found that intradermal injection of pruritogens induces behavioral signs for itch and itch-related anxiety in mice. Additionally, itch stimuli led to increased activity (c-Fos expression) in the amygdala. Electrophysiological characterization of histamine-responsive amygdala neurons showed that this subset was active on a behaviorally relevant timescale. While some neurons only responded to itch stimuli, others were activated by both itch and pain. Moreover, optogenetic activation of this subset of amygdala neurons was sufficient to enhance itch- and anxiety-related behavior. Finally, an anxiolytic dose of diazepam was insufficient to inhibit scratching behavior. A subset of amygdala neurons may play an essential role in itch and itch-related anxiety, but not general anxiety.
Prurigo and other pruritic skin diseases
OP53: Diagnostic and treatment algorithm for chronic nodular Prurigo
Hartmut F. Ständer1,2, Sarina Elmariah3, Claudia Zeidler4, Mary Spellman5, Sonja Ständer4
1Dermatology Bad Bentheim, Dermatological Practice, Bad Bentheim, Germany, 2Department of Dermatology, Klinikum Dortmund gGmbH, Dortmund, Germany, 3Department of Dermatology, Massachusetts General Hospital, Boston, MA, USA, 4Center for Chronic Pruritus, Department of Dermatology, University Hospital Münster, Germany, 5Menlo Therapeutics Inc., Menlo Park, CA, USA
Chronic nodular prurigo (CNPG) also known as Prurigo nodularis is a subtype of chronic prurigo. The terms CNPG and chronic prurigo were recently introduced and defined by the European Academy of Dermatology and Venereology Task Force Pruritus. CNPG is characterized by dome-shaped pruritic nodular lesions caused by repetitive scratching due to chronic pruritus. The exact cause of CPNG is still unknown, but it may be attributed to an underlying dermatologic, systemic, neurologic or psychic condition. In many patients, no etiology but a lot of comorbidities can be found. This produced in the past uncertainty about the etiology and nature of CNPG as an own entity. To enable a standardized and comprehensive approach to the diagnostics and treatment of CPNG, we propose a clinical algorithm, which includes initial assessment of core symptoms, detailed dermatological history and clinical examination, available patient-reported outcomes, diagnostic workup, and recommended therapies. This algorithm is intended to help physicians to make a clear diagnosis within a short time and develop an optimal treatment strategy for the patient.
OP54: Trends in the demographic and treatment of Prurigo nodularis in the United States
Madison Nguyen1, Adrian Pona1, Leena Ramani1, Steven Feldman1, Alan Fleischer2
1Wake Forest University, USA, 2University of Cincinnati, USA
Prurigo nodularis (PN) is an uncommon debilitating itchy disorder. The purpose of this study is to describe a nationally representative sample to understand the demographics and treatment characteristics of PN. The National Ambulatory Medical Care Survey is a nationally representative cross-sectional survey of United States outpatient care. We used the ICD-9-CM code 698.3 from 2007 to 2015 and the ICD-10-CM codes L28.0 and L28.1 for 2016. Of the estimated 1.5 million visits for PN from 2007 to 2016, 53% were female with a median age of 59. Most PN patients were white (78%), followed by African American (15%) and Asian (7%). An estimated 4.8 out of 1000 white patients visited an outpatient clinic for PN whereas 5.4 out of 1000 African American and 6.2 out of 1000 Asian patients visited an outpatient clinic for PN. Dermatologists managed most PN ambulatory visits (78%). The yearly number of PN ambulatory visits per one dermatologist was 9, whereas 0.6 PN ambulatory visits are seen per family physician. The median time healthcare providers spent with a PN patient during an ambulatory visit was 15 minutes. The three most commonly prescribed medication classes for PN were topical corticosteroids (13%), antibiotics (4%), and antihistamines (3%). Most healthcare providers managed PN with topical corticosteroids and calcineurin inhibitors; however, no healthcare provider was observed prescribed other possibly effective therapies. Furthermore, antihistamines were the second most common prescribed medication class but are ineffective in PN. Describing treatment trends for PN may establish practice gaps in PN management.
OP55: The self-assessed psychological comorbidities of prurigo in European patients: A multi-centre study in 13 countries
Emilie Brenaut1, Jon Anders Halvorsen2, Florence J. Dalgard3,4, Lars Lien4, Flora Balieva5, Francesca Sampogna6, Dennis Linder7, Andrea W.M. Evers8, Gregor B.E. Jemec9, Uwe Gieler10, Jacek C. Szepietowski11, Françoise Poot12, Ilknur K. Altunay13, Andrew Y. Finlay14, Sam S. Salek15, Csanad Szabo16, Andrey Lvov17, Servando E. Marron17, Lucia Tomas-Aragones19, Jörg Kupfer20, Laurent Misery1
1Department of Dermatology, University Hospital, Brest, France, 2Department of Dermatology, Oslo University Hospital, Oslo University, Oslo, Norway, 3Department of Dermatology and Venereology, Skåne University Hospital, Lund University, Malmö, Sweden, 4National Centre for Dual Diagnosis, Innlandet Hospital Trust, Brumundal, Norway, 5Department of Dermatology, Stavanger University Hospital, Stavanger, Norway, 6Clinical Epidemiology Unit, Istituto Dermopatico dell’Immacolata (IDI)- IRCCS FLMM, Rome, Italy, 7Section of Biostatistics, University of Oslo, Oslo, Norway, 8Department of Health, Medicine and Neuropsychology, Leiden University, The Netherlands, 9Department of Dermatology, Zealand University Hospital, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark, 10Department of Dermatology, Justus Liebig University, Giessen, Germany, 11Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Wroclaw, Poland, 12Department of Dermatology, Universite Libre de Bruxelles, Brussels, Belgium, 13University of Health Science, Şişli Hamidiye Etfal Training and Research Center, Dermatology and Veneteology Clinic, Istanbul- Turkey, 14Department of Dermatology, Cardiff University School of Medicine, Cardiff, UK, 15School of Life and Medical Sciences, University of Herdfordshire, Hatfield, UK, 16Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary, 17Moscow Scientific and Practical Centre of Dermatovenereology and Cosmetology, Moscow, Russia, 18Department of Dermatology, Royo Villanova Hospital, Zaragoza, Spain, 19Department of Psychology, University of Zaragoza, Spain, 20Institute of Medical Psychology, Justus Liebig University, Giessen, Germany
Background: Prurigo is defined by the presence of chronic pruritus and multiple localized or generalized pruriginous lesions. Objective: The aim of this study was to assess the psychological burden of prurigo in patients of European countries.
Methods: In this multicentre European study, 3635 general dermatology outpatients and 1359 controls were included. Socio-demographic data and answers to questionnaires (regarding quality of life, general health, anxiety and depression and suicidal ideation) were collected.
Results: There were 27 patients with prurigo; of these, 63% were men, and the mean age was 58.6 years. Among patients with prurigo, 10/27 (37%) suffered from anxiety and 8/27 (29%) from depression. Suicidal ideation was reported by 5/27 (19%) of patients, and for 4 out of these 5 patients, suicidal ideation was related to their skin disease. These frequencies were higher than in the 10 commonest dermatological diseases (including psoriasis, atopic dermatitis and leg ulcers for example). The impact on quality of life was severe, with a mean DLQI of 12.4, with an extreme impact on quality of life for 23% of patients and a very large impact for 27% of patients.
Conclusion: The psychological comorbidities of prurigo are common, greater than those of other skin diseases, and their impact on quality of life is significant. Thus, it is important to study this condition and to find new treatments.
OP56: Clinical and neuro-physiological study of chronic prurigo
RNT Medical College, Udaipur, India
Background: Chronic prurigo is dermatological manifestation secondary to chronic pruritus, Patients present with symmetrically distributed intensively itchy papules, nodules and/or plaque which can be localized or generalized. Chronic prurigo is an understudied subject, this prompted us to study chronic prurigo including its neurological aspects.
Aim: (A) To define clinical profile of chronic prurigo patients. (B) To assess neurological dysfunction in patient of chronic prurigo by conducting neuro-physiological study (nerve conduction velocity).
Methods: This was a cross-sectional observational study of chronic prurigo patients in dermatology outpatient department of RNT Medical College Udaipur (India). Nerve conduction studies (NCV) was also carried out in the half of patients to assess neurological dysfunctions (if any).
Results: Sixtythree patients were included in this study. Male female ratio was 0.75:1 with most of patients in the 21-40 years age group. Prurigo lesions were generalized in 59% of patients while 41% patients had localized lesions 89% patients had a disease duration more than 0 years.pure itching sensation was noticed in 47% of patients, while 20% patients had burning mied with itching, had crawling sensation. Co- morbidities were present in 30 % of patients Hypothyroidism in 2 pts, Diabetis Mellitus in 4 patients, Hypertension in 6 patients, and peptic ulcer disease in 1 patient. History of atopy was present in 47% of patients. We also looked for presence or absence of any other type of skin lesions in these patients. Eczematous lesions were seen in 52% of patients. Nearly half of the patients (49%) showed high numerical rating score (NRS) of pruritus (7-10). Pruritus impact score (PIS) showed mild impairment in quality of life in 66% of patient and moderate impairment in 33% of patients. A large majority (60%) patients were dissatisfied with all form of treatment they recieved. In 30 patients nerve conduction velocity was carried out, only 2 patients showed sensory neural neuropathy. Both these patients had no symptoms of peripheral neuropathy and none was having any disease that could account for peripheral neuropathy.
OP57: Novel instruments for the assessment of chronic prurigo
Claudia Zeidler, Manuel Pereira, Sonja Ständer
Department of Dermatology, Center for Chronic Pruritus, University Hospital of Münster, Germany
Background: Chronic prurigo (CPG) is a burdenful disease and has recently been defined with the core symptoms chronic pruritus, history and/or signs of repeated scratching, and the presence of localized or generalized pruriginous lesions. In addition, clinical subtypes have been defined of which the nodular type (prurigo nodularis) is the most frequent one. Others are CPG papular type, plaque type, umbilicated type or linear prurigo. Several subtypes may coexist in one patient, usually one is predominant. Besides the clinical picture, the number and distribution of lesions may also vary widely from patient to patient. In the past, monitoring patients with CPG in clinical trials have focused on pruritus intensity and quality of life parameters, while no score has been available to objectively evaluate lesions of CPG.
Methods: Based on follow up visits of CPG patients, we were able to create new tools for objective assessment and for recording the lesions and the activity of chronic prurigo. The severity of CPG can be assessed using the “Prurigo Activity Score” (PAS) or an “Investigator Global Assessment” (IGA) scale, the presence of scratching activity by the “Scratch Sign Score” (SSS). All questionnaires were tested for validity in a large collective of patients with CPG (n=130).
Results: IGA and SSS showed very good test-retest reliability (ICC>0.8), PAS showed moderate to good test-retest reliability. All items correlated significantly with the itch intensity especially with the intensity of the worst itch in the last 24h on the numerical rating scale and other external constructs like quality of life.
Conclusion: Validation of this new instruments has made it possible for the first time to document the severity and activity of chronic prurigo and to monitor these over times.
OP58: Opioids and itch in the periphery – Roles of peripheral opioids in itch
1Juntendo Itch Research Center (JIRC), Institute for Environmental and Gender Specific Medicine, Juntendo University Graduate School of Medicine, Japan, 2Anti-Aging Skin Research Laboratory, Juntendo University Graduate School of Medicine, Japan, 3Department of Dermatology, Juntendo University Urayasu Hospital, Japan
In opioid-related itch, activation of μ-opioid receptors (MOR) induces itch, whereas activation of κ-opioid receptors (KOR) suppresses itch. We found the plasma level of β-endorphin (an endogenous MOR ligand) was increased, while that of dynorphin A (an endogenous KOR ligand) was decreased in systemic diseases including chronic liver disease, and in skin diseases such as atopic dermatitis (AD) and psoriasis. The ratio of β-endorphin/dynorphin A was correlated with severity of itch. Recent molecular and pharmacological findings have demonstrated that MOR1D and gastrin-releasing peptide receptor (GRPR) expressing spinal dorsal horn neurons are involved in the induction of itch by MOR ligands, and that itch is at least partly suppressed by KOR agonists at the spinal level. We reported that peripheral and central MOR and central KOR are involved pharmacologically in the modulation of scratching behavior in imiquimod-treated mice, a psoriasis-like model. Notably, we recently found that intradermal injection (i.d.) of endogenous MOR agonists such as β-endorphin and endomorphin induced scratching behavior and alloknesis in mice. The scratching behavior was suppressed by i.d. of naloxone methiodide, a peripheral MOR antagonist which does not cross the blood-brain barrier. Given that MOR and KOR or their ligands express in cutaneous cells such as keratinocytes and sensory nerves, peripheral opioids may be involved in the induction of itch and/or its hypersensitivity.
New receptors, channels and pathways for itch
OP59: Synaptic control of spinal GRPR+ neurons by local and long-range inhibitory inputs
Institute of Neuroscience, CAS Center for Excellence in Brain Science & Intelligence Technology, Chinese Academy of Sciences, Shanghai, China
Spinal gastrin-releasing peptide receptor-positive (GRPR+) neurons play an essential role in itch signal processing. However, the circuit mechanisms underlying the modulation of spinal GRPR+ neurons by direct local and long-range inhibitory inputs remain elusive. Using viral tracing and electrophysiological approaches, we dissected the neural circuits underlying the inhibitory control of spinal GRPR+ neurons. We found that spinal galanin+ GABAergic neurons form inhibitory synapses with GRPR+ neurons in the spinal cord and play an important role in gating the GRPR+ neuron-dependent itch signaling pathway. Spinal GRPR+ neurons also receive inhibitory inputs from local neurons expressing neuronal nitric oxide synthase (nNOS). Moreover, spinal GRPR+ neurons are gated by strong inhibitory inputs from the rostral ventromedial medulla. Thus, both local and long-range inhibitory inputs play important roles in gating itch processing in the spinal cord by directly modulating the activity of spinal GRPR+ neurons.
OP60: Itch-neurons and their receptors
Molecular Genetics Section, National Institute of Dental and Craniofacial Research, Bethesda, MD, USA
To determine the properties of DRG neurons which express the neuropeptide, Nppb, we investigated the sufficiency of these cells to produce itch behavior and examined their receptor repertoire. Using optogenetic stimulation, we found that Nppb-neurons are sufficient for scratching responses. Next, we determined, by differential analysis of gene expression between different population of sensory neurons, the receptors enriched in Nppb-neurons. Examination of the localization of Nppb-enriched receptors for sphingosine-1-phoshate (S1pr1), leukotriene (cystltr2), and serotonin (htr1f) showed they are expressed only by Nppb-neurons. These receptors all detect chemical mediator released by degranulating mast cells. Activation of these receptors, by cutaneous injection of cognate ligands, evoked itch and the same ligands selectively evoked increased intracellular Calcium in Nppb-neurons. Finally, selective ablation of S1pr1 from sensory neurons eliminated scratch responses to activation of this receptor. These results suggest that Nppb-neurons can couple activation of mast cells to itch responses.
OP61: α-Melanocyte-stimulating hormone and itching in atopic dermatitis
Tsugunobu Andoh1, Chihiro Akasaka1, Kyoko Shimizu2, Jung-Bum Lee3, Yoko Yoshihisa2, Tadamichi Shimizu2
1Department of Applied Pharmacology, University of Toyama, Toyama, Japan, 2Department of Dermatology, University of Toyama, Toyama, Japan, 3Laboratory of Medicinal Bio-resources, University of Toyama, Toyama, Japan
Atopic dermatitis (AD) is a chronic inflammatory skin disease with severe itching. However, the mechanisms of itching are not fully understood. α-Melanocyte-stimulating hormone (α-MSH) is an endogenous peptide hormone involved in cutaneous pigmentation. It is also suggested that α-MSH is involved in pigmentation of AD. Recently, we have demonstrated that α-MSH is an itch mediator. However, the involvement of α-MSH in itching of AD remains unclear. We therefore investigated on α-MSH and itching of AD. In the skin of AD patients and the mouse model of AD (dermatitis mice), α-MSH and prohormone convertase 2, which is the key processing enzyme for the production of α-MSH, were distributed mainly in epidermis, and these cutaneous expression levels were significantly increased, compared with healthy control. In the skin and the dorsal root ganglion (DRG) of dermatitis mice, the expression of α-MSH receptors (MC1R and MC5R) mRNA was apparently increased, compared with that of healthy mice. And these receptors were distributed in the epidermis. Spontaneous scratching in dermatitis mice was inhibited by repetitive administration of MC1R antagonist. Our previous study has shown that thromboxane (TX) A2 is involved in spontaneous scratching in dermatitis mice. TP thromboxane receptor antagonist inhibited α-MSH-induced scratching. In mouse keratinocytes, α-MSH increased the production of TXA2. In addition, α-MSH increased intracellular Ca2+ ion concentration in DRG neurons and keratinocytes. These results suggest that α-MSH is involved in itching during AD and may elicit itching through the direct action of primary afferents and TXA2 production by keratinocytes.
OP62: IL-13 as a neuronal enhancer for itch in human sensory neurons
Yannick Miron1, Paul E Miller1, Andre Ghetti1, Hans Hofland2, Ferda Cevikbas2
1AnaBios Cooperation, San Diego, CA, USA, 2Dermira Inc, Menlo Park, CA, USA
The cellular and molecular pathways in acute and chronic itch are extensively studied in rodent neurons. In our research, we aimed to translate findings from mouse studies into human with focus on crosstalk between type 2 cytokines and neurons. Among those, interleukin-13 (IL-13), IL-4, IL-5 and IL-31 are upregulated in atopic dermatitis (AD) skin lesions. IL-31 was shown to directly activate dorsal root ganglia (DRG) to elicit itch in rodents. Recently, IL-4, another well-described cytokine in the pathophysiology of AD, was reported to activate mouse and human neurons. The objective of our study series was to test the effects of IL-13 in human DRG in itch pathways. Human DRGs were treated with IL-13 alone or in combination with different pruritogens that represent histaminergic and non-histaminergic itch pathways. Live cell imaging with calcium measurement via fluorescence detection was used to measure activation of neurons. Our data showed a low direct activation of hDRGs by IL-13 stimulation and extensive sensitization of multiple itch pathways. A prolonged exposure of IL-13 on sensory neurons resulted in strongly intensified responses to pruritogens such as serotonin and BAM8-22. Lebrikizumab, a monoclonal antibody targeting IL-13, reduced the sensitization of these neuronal responses. Current studies are directed to understand the underlining mechanisms of the neuronal sensitization by IL-13. Our data suggest that IL-13 is a neuronal enhancer in different itch pathways and is potentially driving persistency of chronic itch in type 2 associated diseases.
OP63: β-alanine and bovine adrenal medullary protein 8-22 preferentially activate subtypes of polymodal C-fibers in pigtail monkeys
Amanda H. Klein, Matthew Wooten, Timothy V. Hartke, Gang Wu, Matthias Ringkamp
Department of Neurosurgery, Neurosurgery Pain Research Institute, Johns Hopkins University, Baltimore, Maryland, USA
In mouse, β-alanine (ALA) and bovine adrenal medullary protein 8-22 (BAM8-22), produce scratching behavior by activating mas-related G protein-coupled receptors (Mrgpr) D and C11, respectively, which are expressed in distinct neuronal DRG populations. What primary afferent neurons these agonists activate in primate is unclear. Previously, ALA activated “QCs”, i.e. cutaneous, polymodal C-fibers with a quick response to a stepped heat stimulus, whereas those with a slow response (“SCs”) were unresponsive. Whether these neurons differ in their responses to BAM8-22, an agonist at the human MrgprX1, and whether myelinated nociceptors respond to these agonists is unknown. Using teased-fiber techniques, neuronal activity of nociceptive afferents with receptive fields (RFs) in the hairy skin was recorded in anaesthetized nonhuman primates (Macaca nemestrina). Two blocks of intradermal injections (each 10 µl) were administered at the RF: extracellular fluid (the solvent) followed by ALA (90 µg) and BAM8-18 (the inactive truncated peptide, 1 µg) followed by BAM8-22 (1 µg). Of 24 A fibers, one responded only to BAM8-22, and 2/6 mechanoinsensitive C fibers responded to BAM8-22. Of 29 QCs, 27 responded to ALA and 19 responded to both, and ALA responses were about 1.5-fold larger than BAM 8-22 responses. Of 31 SCs, BAM8-22 activated 29 and ALA 7. BAM8-22 responses were about 10-fold higher than those to ALA. ALA responses in QCs were about 8-fold larger than in SCs, whereas BAM8-22 responses were about 2-fold larger in SCs than QCs. These results show that ALA and BAM primarily activate QCs and SCs, respectively, suggesting that their receptive terminals preferentially express MrgprD and MrgprX1.
OP64: Role of integrin in chronic allergic itch
Santosh K. Mishra1–4,7*, Joshua Wheeler1, Saumitra Pitake1, Huiping Ding5, Changyu Jiang6, Tomoki Fukuyama1, Judy S. Paps7, Patrick Ralph1, Jacob Coyne1, Jennifer DeBrecht1, Lauren C. Ehrhardt-Humbert1, Glenn P. Cruse1.2, Wolfgang Bäumer1, Ru-Rong Ji6, Mei-Chuan Ko5, Thierry Olivry2,7
1Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA, 2Comparative Medicine Institute, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA, 3The WM Keck Behavioral Center, North Carolina State University, Raleigh, NC, USA, 4Program in Genetics, North Carolina State University, Raleigh, NC, USA, 5Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC, USA, 6Pain Signaling and Sensory Plasticity, Duke University, Durham, NC, USA, 7Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA
Many painful conditions (inflammatory and neuropathic pain) are associated with integrin signaling; however, role of integrin in generation and detection of itch is unknown. Here, we employ interdisciplinary approach to demonstrate a new pathway that is possibly linked with chronic allergic itch. We have identified a novel endogenous ligand that induces itch in mice, dogs and monkeys. The receptor for this endogenous ligand is also present and functionally active in dorsal root ganglia (DRG). Additionally, the ligand activation of DRG neurons releases the neurotransmitter natriuretic polypeptide b (NPPB) to further transmit the signal to spinal cord neurons in the central nervous system (CNS). We further extend our study to demonstrate a mechanism of endogenous ligand secretion from keratinocytes in the skin. We show by binding of the cytokine thymic stromal lymphopoietin (TSLP) to TSLP receptor on keratinocytes induces endogenous ligand release. In all, this TSLP-endogenous ligand mutual activation provides a reciprocally amplifying loop that leads to itch at each round of cytokine release, thereby providing a viable hypothesis for the perpetuation of chronic itch. Finally, we establish that the JAK/STAT pathway is a key regulator of ligand secretion in keratinocytes. Overall, we demonstrate cutaneous-nerve interactions that are fundamental to neuronal responses during chronic itch associated with allergic skin diseases. These studies hold a strong potential in the future for the development of new drugs to treat allergic itch by targeting this ligand/receptor.
Epidemiology of itch and quality of life
OP65: Chronic nodular prurigo: a cross-sectional European study
Manuel P. Pereira1, Claudia Zeidler1, Elke Weisshaar2, Johanna Wallengren3, Jon Anders Halvorsen4, Simone Garcovich5, Laurent Misery6, Emilie Brenaut6, Ekin Şavk7, Svetlana Bobko8, Jacek C. Szepietowski9, Adam Reich10, Franz Josef Legat11, Martin Metz12, Markus Streit13, Sonja Ständer1; on behalf of the EADV Task Force Pruritus
1Department of Dermatology and Center for Chronic Pruritus, University Hospital Münster, Germany, 2Department of Social Medicine, Occupational and Environmental Dermatology, University of Heidelberg, Germany, 3Department of Dermatology and Venereology, Skåne University Hospital SUS Lund, Lund University, Lund, Sweden, 4Department of Dermatology, Oslo University Hospital, University of Oslo, Oslo, Norway, 5Institute of Dermatology, Catholic University of the Sacred Heart, Rome, Italy, 6Department of Dermatology, University Hospital of Brest, Brest, France, 7Department of Dermatology, Adnan Menderes University, Aydin, Turkey, 8Moscow Scientific and Practical Center of Dermatovenerology and Cosmetology, Moscow, Russia, 9Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Poland, 10Department of Dermatology, University of Rzeszów, Rzeszów, Poland, 11Department of Dermatology, Medical University of Graz, Austria, 12Department of Dermatology and Allergy, Charité – Universitätsmedizin Berlin, Germany, 13Department of Dermatology, Kantonsspital Aarau, Switzerland
Chronic prurigo has been recently considered a disease defined by chronic itch, persistent scratching behavior and by the presence of pruriginous lesions. Although highly impairing, its clinical profile remains poorly understood. In this cross-sectional pan-European study, chronic nodular prurigo patients were asked to fill out a questionnaire either electronically or on paper addressing several aspects, including demographics, itch characteristics, quality of life and therapies. Recruitment occurred at 15 centers across 12 European countries retrospectively using the center’s own databases and/or prospectively at each center. A total of 506 patients (58% female, age: 61.1±16.8 y) have completed the study. Patients reporting no current itch and/or no current pruriginous lesions (n=96) were excluded. Pruritus was severe or very severe in a substantial number of the patients as assessed by the verbal rating scale (48%, n=399), while the average itch intensity assessed by the numerical rating scale was 6.2±2.6 (n=390). Patients perceived the itch (49%), the visibility of the skin lesions (21%) and bleeding lesions (14%) as the most burdensome aspects of the disease (n=303). The quality of life in the week prior to the completion of the questionnaire was rather and severely impaired in 31% and 22%, respectively (n=402). As for therapies, 29% of patients considered no therapy to be effective, while others considered topical steroids (13%), systemic immunosuppressive drugs (12%), emollients (11%) and phototherapy (10%) to be the most effective regimens (n=350). Of the patients receiving a therapy (n=354), most reported not being satisfied with it (63%). Chronic nodular prurigo is highly burdensome due to the severe itch and the visible scratch lesions. Current therapeutic management is unsatisfactory and thus novel effective therapies are urgently needed to improve the quality of life of patients affected by this condition.
OP66: A Community epidemiological survey on the prevalence and risk factors of sensitive skin syndrome in Hong Kong using a validated sensitive scale -10 (SS-10) questionnaire
Kam Tim Michael Chan1, Amy Ho Nam Cheung, PhD2
1Specialist in Dermatology, Hong Kong Academy of Medicine, Hong Kong SAR, China, 2University of Edinburgh, United Kingdom
A community-based epidemiological study was conducted estimating the prevalence and risk factors of sensitive skin using a validated ten items Sensitive Scale – 10 (SS -10) questionnaires in different districts of Hong Kong. Methodology: In January 2018, a total of 500 subjects were recruited using quota sampling method across five districts of Hong Kong from high to lower level of pollutions: Mong Kok, Tsim Sha Tsui, Causeway Bay, Tsuen Wan and Shatin respectively. One hundred participants were recruited in each district. Face-to-face interviews were carried out by volunteers who had no prior knowledge on sensitive skin in the streets of these districts. Each participant filled out a questionnaire containing information on demography, concomitant skin diseases and SS-10. The prevalence estimation was based on the cutoff value developed on clinical data in Hong Kong (Chan, in review) Based on a cutoff value of 25.5 with a sensitivity of 91.7% and specificity of 75.5%, our study reported a prevalence of 11.4% of sensitive skin in the local community sample which is comparable to studies reported in mainland China but lower than those reported in Europe and America. The risk factors of sensitive skin were analyzed using multiple linear regression modelling with total score of SS-10 as the outcome variable. The results showed that skin conditions and districts were significant predictors. The model accounted for 67.6% variance of the total score of SS-10 and significantly differed from the null model, F (10, 489)=101.95, P<0.001 with an effect size of 2.09. Significant predictors of sensitive skin included eczema (β=17.02, P<0.001), urticaria (β=15.48, P<0.001), psoriasis (β=19.86, P<0.001), food- allergies- induced skin sensitivity (β=7.00, P<0.001) and cosmetics- induced skin sensitivity (β=14.84, P<0.001). Tsim Sha Tsui, among the five studied areas, predicted skin sensitivity significantly (β=6.46, P<0.001) with reference to Shatin.
OP67: Quality of life in patients with Uraemic pruritus
Rawalpindi Medical University, Rawalpindi, Pakistan
Background & Introduction: Chronic Kidney Disease (CKD) is a serious disease with some replacement (renal transplant or dialysis) required. End Stage Renal Disease (ESRD) is Stage 5 CKD. In Pakistan, there are more than 100 new cases of ESRD per million per year. Uraemic pruritus (UP) occurs in 20% to 70% patients. Despite this, few studies observe its impact. This study aims to quantify the impact of UP on Quality of Life (QoL) in ESRD patients undergoing Hemodialysis (HD) in Pakistan.
Materials & Methods: It was an observational study conducted in the Department of Nephrology and Dermatology, KEMU/ Mayo Hospital, Lahore from January to June, 2017. After informed consent, one hundred patients of all ages and both sexes, having ESRD undergoing HD were enrolled. Patients with pre-existing skin disease or systemic disorders were excluded. Data was collected on DLQI Urdu version. The higher the DLQI, poorer the QOL. Demographic and clinical data, including age, gender, underlying renal disease, duration of HD and presence of pruritus were noted. Pruritus features like site, severity, frequency and sleep disturbance were noted. Data were entered into SPSS. For Quantitative variables, mean and standard deviation were calculated.
Results: There were 58 males & 42 females. Mean age was 50±4 years. ESRD duration varied from 3 months to 5 years with a dialysis frequency of for 2-3 times/week. DLQI score ranged from 1-17. Mean score was 5.3±2.2. Women had a higher score. Sixty seven percent patients were suffering from urticarial pruritis. Out of these 22 patients had slight impairment of DLQI, 18 had severe impairment and 9 very severely impaired QoL; Eighteen patients did not suffer from significant impairement of quality of life.
Conclusion: Presence and intensity of Uraemic Pruritus has a significant impact on QoL. Early diagnosis and effective treatment can improve QoL in these patients.
OP68: Pruritus in bullous pemphigoid: correlation with disease activity (ABSIS and BPDAI) and quality of life (ABQOL)
Yicong Liang1,2, Tabrez Sheriff1, Dedee F. Murrell1,2
1Department of Dermatology, St George Hospital, Sydney, NSW, Australia, 2Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
Background & Objective: Pruritus is a major symptom of bullous pemphigoid (BP), having a significant impact on the quality of life. Therefore, understanding the pattern of pruritus among BP patients is crucial for successful management of BP. This research aims to evaluate the correlation between the severity of pruritus, BP disease activity and the patients’ quality of life.
Methods: A retrospective review of the medical records of thirty-three patients at the St George Campus in Sydney, Australia, was performed. The review included patients with a confirmed diagnosis of BP based on serology and/or histopathology evidence. During each visit, the BP disease activity was assessed using validated BP disease severity indices including Bullous Pemphigoid Disease Area Index (BPDAI) and Autoimmune Bullous Skin Disorder Intensity Score (ABSIS). The patient’s quality of life was assessed with an Autoimmune Bullous Disease Quality of Life (ABQOL) questionnaire. The intensity of pruritus was assessed with Bullous Pemphigoid Disease Area Index – pruritus component (BPDAI-Pruritus) questionnaire. The scores obtained during clinical visits were then collected from their medical records and the correlation between the scores was analysed statistically.
Results: The BPDAI-pruritus score was linearly correlated with ABSIS and BPDAI (P<0.001). BPDAI has a more significant correlation with BPDAI-pruritus score (r=0.828, P<0.001) compared to ABSIS (r=0.594, P<0.001). ABQOL was linearly correlated with BPDAI-pruritus score (r=0.621, P<0.001).
Conclusion: The results showed that increasing BP disease activity is associated with increasing pruritus among patients. Compared to ABSIS, BPDAI is a better indicator of pruritus severity in patients. Increased pruritus severity is associated with lower quality of life among BP patients.
OP69: Validation of TweenItchyQoL and ItchyQuant for older children
Sandy François, Shelby Smith, Grace Lee, Kuang-Ho Chen, James Roberts, Suephy C. Chen
Emory University, Georgia Institute of Technology, USA
Validated pediatric pruritus measurement tools are lacking. Measuring quality of life (QoL) in children is not merely an adaptation of adult instruments; specific aspects of QoL can be quite different. We report the validation results from our 8-17 year-old children version of the ItchyQoL (called TweenItchyQoL) and ItchyQuant (cartoon annotated NRS). Items were developed from in-depth, open-ended interviews of itchy children. For validation, 175 itchy children were recruited from clinics and administered the ItchyQuant and the 35-item TweenItchyQoL® at three different times. The mean age was 11.9 years, 62.3% were female, and 44% Caucasian, 44% Black, 12% another or more than one race. Only 4.6% were unclear as to their itch etiology. The average itch duration was 5.9 years. The average duration to complete the TweenItchyQoL was 4.7 minutes while the ItchyQuant was 33 seconds. Cronbach’s alpha for TweenItchyQoL total and all subscales ranged from 0.84 to 0.95. Test-retest reliability coefficients were 0.7 or above. The ItchyQuant test-retest reliability was 0.4. A comparison of six confirmatory factor analyses models suggested that a 3-dimensional bifactor model was most appropriate (RMSEA=0.048). When each measure was analyzed as a function of reported worsening, improvement, or no change at their final visit, the mean total and subscale TweenItchyQoL scores always decreased most for the improvement cohort, and noticeably less mean change for those reporting worsening or no change. There was a significant decrease in ItchyQuant scores in the improvement cohort (P<0.0001), increase in the worsening (P=0.0247) group, and no statistical difference in the no change group. These results suggest a new set of validated and feasible instruments to quantify itch severity and the QoL impact in older children.
New imaging techniques and other aspects of itch
OP70: Closure of Kir2 Potassium Channels and Subsequent Inactivation of A-Type Potassium Channels Underlie the Critical Role of Gastrin-Releasing Peptide in Spinal Itch Relay
Martina Pagani, Helge C. Johannssen, Hanns Ulrich Zeilhofer
Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland
Spinal transmission of pruritoceptive signals requires gastrin-releasing peptide (GRP) to prime the GRP receptor (GRPR) neurons, for suprathreshold excitation by GRP neuron input. In the present study, we combined targeted patch-clamp recordings from GRPR neurons with optogenetic stimulation of GRP neurons to undertake an in-depth analysis of the mechanisms of this priming effect. When applied to GRPR neurons in mouse spinal cord slices, GRP (300 nM) depolarized GRPR neurons by 10.0±1.5 mV. This depolarization was accompanied by an increase in membrane resistance (from 1.0±0.1 to 1.5±0.1 GΩ) and hence, most likely, due to the closure of a potassium conductance active at the resting membrane potential. We used the potassium channel blockers XE-991 (10 µM), ML365 (10 µM) and Ba2+ (200 µM) to test for an involvement of Kv7, TASK-1/3, and Kir2 channels, respectively. Only Ba2+ mimicked and occluded the GRP-induced depolarization, suggesting that GRP acted by closing Kir2 channels. GRP did not only depolarize GRPR neurons but also changed their firing from a delayed to a tonic pattern. The depolarization evoked by GRP-mediated closure of Kir2 channels partially inactivated A-type potassium channels, which in many neurons underlie the delayed firing type. In the absence of GRP, depolarization of GRPR neurons by 7-10 mV was alone sufficient to induce this change in firing patterns, and to render GRPR neurons susceptible to suprathreshold excitation by GRP neuron input. These findings establish the molecular signaling mechanisms that underlie the critical role of GRP in spinal itch relay.
OP71: 3D Neuroanatomy of the Cutaneous Itch Nervous System
Hong Liang Tey1–3, Yingrou Tan1,4, Lai Guan Ng4
1National Skin Centre, Singapore, 2Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 3Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 4Singapore Immunology Network, Agency for Science, Technology and Research, Singapore
The conventional method of identifying intra-epidermal nerve fibres (IENFs), which represents the itch nerve fibres, uses 2-dimensional (2D) microscopy of histological slides. The number of single nerve fibres crossing the dermoepidermal junction (DEJ) to enter the epidermis has been used to quantify the density of itch nerve fibres and has been used as a criterion for the diagnosis of small fibre neuropathy in neurological practice. We use a novel method to study the IENFs, through immunostaining and optical-clearing of 100 um thick sections of normal human skin, and performing 3-dimensional (3D) imaging and analysis. This 3D technique allowed us to characterise the intra-epidermal nervous architecture, which was technically not feasible using the conventional 2D technique. We found a median of 71.7% (30.8-80.0%) of the IENFs that transverse the DEJ branch out as dendrites in the epidermis, while the rest exist as single nerve endings in the epidermis. We also analysed the number of times each nerve fibre from the DEJ branches, the mean cutaneous area each of them innervate, and the degree of overlap in innervation with the adjacent nerve fibres. These data allow us to understand why itch sensation cannot be localised pin-point (unlike pain), and can possibly allow for more sensitive detection of changes in IENF density and diagnosis of small-fibre neuropathy in future studies.
OP72: Importance of BAM8-22 and its receptor MRGPRX1 in cholestatic pruritus
Babina Sanjel, Han-Joo Maeng, Won-Sik Shim
College of Pharmacy, Gachon University, Incheon, Republic of Korea
Cholestasis, which is characterized by decreased bile flow due to obstruction of bile ducts, often accompanies unexpected pruritus. Although there are multiple reports have identified possible mechanisms for the pruritus, it is still not sufficient to fully understand the symptom. Here, we show that bovine adrenal medulla (BAM) 8-22, an endogenous itch-inducing peptide, could be involved in cholestatic pruritus. By using an obstructive cholestasis model named bile duct ligation (BDL) mice, it was found that spontaneous scratching behaviors in these mice were increased. Importantly, the mRNA level of proenkephalin, a precursor polypeptide of BAM8-22, was significantly increased in the skin of BDL mice. Furthermore, the transcriptional level of Mrgprx1, which encodes a receptor for BAM8-22, was significantly increased in the dorsal root ganglia (DRG) of BDL mice. This was further corroborated by elevation of intracellular calcium levels upon BAM8-22 treatment in primarily-cultured DRG neurons. In addition, BDL mice showed augmented scratching behavior by BAM8-22 treatment, implying enhanced activity of MRGPRX1. More importantly, the skin homogenate of BDL mice induced elevation of intracellular calcium levels through MRGPRX1. Ultimately, we found that chenodeoxycholic acid specifically increased proenkephalin transcription in a human keratinocyte cell line (HaCaT). Overall, we conclude that the cholestatic pruritus could be attributed in part to enhanced action of both BAM8-22 in the skin and its receptor MRGPRX1 in sensory neurons.
OP73: Chronic stress affects itch sensitivity and male sexual function in rats
Keiko Takanami1,2, Makoto Morishita2, Tatsuya Sakamoto2, Hirotaka Sakamoto2
1Mouse Genomics Resource Laboratory, National Institute of Genetics, Mishima, Shizuoka, Japan, 2Ushimado Marine Institute, Graduate School of Natural Science and Technology, Okayama University, Setouchi, Okayama, Japan
Chronic psychological stress causes various physiological dysfunctions such as depression, chronic itch symptom (atopic dermatitis), and erectile dysfunction, but little is known about the mechanisms. In our study, chronic-stress rat model produced by the repeated administration of exogenous corticosterone for 3 weeks were used to analyze the effects of chronic psychological stress on these dysfunctions. The chronic administration of corticosterone decreased the body weight, increased plasma corticosterone level, and anxiety-like behavior as reported for depression in human. Furthermore, the chronic corticosterone treatment increased the scratching behavior elicited by serotonin, but did not change the tactile sensitivity and noxious heat sensitivity. Chronic corticosterone treatment also decreased plasma testosterone level, genital weights, semen volume, and erectile ability in male rats. We further focused on two different gastrin-releasing peptide (GRP) systems in the spinal cord. GRP system related to itch transmission is located in the spinal somatosensory system, and the other GRP system involved in the male sexual function is located in the lumbar spinal autonomic and motor systems. The chronic corticosterone administration increased GRP mRNA expression in the spinal cord involved in the itch transmission but not in the male sexual function. Finally, the itch sensitivity elevated by corticosterone was suppressed by the intrathecally administration of GRP receptor blocker. Taken together, these results showed that the itch hypersensitivity and male sexual dysfunction due to the chronic psychological stress were observed in this rat model as well as humans, and suggest that two different GRP systems in the spinal cord which control the itch transmission or the male sexual function respond independently to chronic stress.
OP74: Study of phoenixin-induced scratching in mice
Alan Cowan1,2, R.-M. Lyu3, J.-K. Chang3, Nae J. Dun1, Saadet Inan2
1Pharmacology, 2Center for Substance Abuse Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA, 3Phoenix Pharmaceuticals, Inc. CA, USA
Background: Phoenixin amide (PNX-20) is a gut-brain-skin peptide comprised of 20 amino acids that is biologically active. In rats, PNX-14 stimulates food intake in a specific manner and improves memory, and also causes anxiety-like behavior in mice. Of particular interest to us is its ability to precipitate dose-related, repetitive body scratching bouts after s.c. injection to the nape of the necks of mice.
Objective: By studying fragments of PNX-20, establish the fewest number of amino acids in the peptide that still provoke the excessive scratching.
Method: Male Swiss Webster mice (25-30 g, Taconic Biosciences) were used in the Kuraishi mouse model of pruritus. Each peptide, saline or individual amino acid was administered s.c. behind the neck of mice and the number of scratching bouts counted for 30 min. Results: PNX-14 (2-16 mg/kg, s.c.) PNX-3, ASP-PRO-PHE amide (8 mg/kg, s.c.) and PNX- 2, PRO-PHE amide (8 mg/kg, s.c.) caused statistically significant increase of scratching relative to saline-controls. A submaximal dose of PNX-2 or PNX-3 (both 8 mg/kg) which provoked scratching was attenuated by s.c. pretreatment (at-20 min) with nalbuphine (10 mg/kg). At doses of 3, 10, 20 and 40 mg/kg, D- and L-PRO and D-PHE (but not L-PHE) significantly enhanced scratching.
Conclusion: We have singled out proline as a contributory pruritogen to the overall scratch-provoking action of phoenixin in mice, probably through a kappa opioid receptor mediated link.
OP75: New perspectives for the treatment of chronic itch: From learning to itch sensitization
Andrea W.M. Evers
Department of Health, Medical and Neuropsychology, Institute of Psychology, Leiden University, Leiden, The Netherlands
There is increasing attention to study the possible role of learning mechanisms, such as expectancies, attention and affect, in the sensitization of somatic symptoms, such as itch. These learning mechanisms are theorized to play an important role in the processing of itch, due to the vicious cycles in which they shape the experience of itch by altered perceptions and interpretations in the experience and chronification of symptoms. Increasing evidence demonstrates the neurobiological underpinnings and relevance of these learning mechanisms in itch for many conditions. For example, physical complaints, such as itch, can be effectively altered by learning processes, particularly conditioning based on previous experience (“Itch already reduces when seeing the itch medication”). The same is true for negative treatments effects which are induced by expectations of a possible unfavorable treatment outcome or side effects (also called nocebo effects). Learning mechanisms also play a role for immune functioning through pharmacological conditioning. The results have direct implications for the treatment of patients with chronic itch. Treatment outcomes might be optimized, for example, by applying learning principles for therapy adherence or reducing regular pharmacological treatments by altered medication dosages that make use of learning principles. Findings also open up new horizons for prevention and treatment, by identifying patients at risk for symptom sensitization and generating targeted treatments for symptom desensitization and recovery.
OP76: Future aspects of basic pruritus research
1Department of Dermatology, Hamad Medical Corporation, Doha, Qatar, 2HMC Translational Research Institute, Hamad Medical Corporation, Doha, Qatar, 3Qatar University, Medical School Doha, Qatar, 4Weill-Cornell Medical College, Doha, Qatar, 5Weill-Cornell University New York, USA
Cellular cross-talk between the immune and nervous system elicit evolutionary responses such as itch (pruritus) or pain to protect the host from “danger signals”. Recent molecular Itch research along with genetically modified models and translational human studies have markedly improved our understanding of histamine-dependent and -independent itch. Itch is controlled at different anatomical levels. In the skin, novel studies revealed an armada of molecules capable of inducing pruritus by activating high affinity receptors such as proteases, peptides, neurotrophins, amines and cytokines, respectively. Several ion channels and G protein-coupled receptors activate signaling cascades in primary afferent sensory neurons controlling transduction of signaling as well as exocytosis of itch mediators to the dorsal horn of spinal cord under control of SNARE proteins, for example. In the spinal cord, several new mediators and circuits have been identified that regulate communication between projection and interneurons as well as astrocytes and microglia, thereby controlling central pathways of pruritus. Various new clinical trials and translational studies on the effects of central mediator-receptor interactions like neurokinins, for example, have emerged from this basic research accomplishments that will change our treatment options for chronic and neuropathic itch. Accordingly, pruritus is transmitted to the brain via ascending trails that activate various poorly defined brain regions involving motor and affective responses including scratch response and emotional responses to the pruritic trigger. Future molecular itch research in the central nervous system using modern technologies will significantly improve our therapeutic repertoire to combat chronic itch. Finally, more innovative translational human studies combined with analytic genetic and molecular approaches including omics technologies and single cell studies depicting selective cellular machineries and pathways as well as neuro-immune networks will open new avenues for treating this frequent debilitating symptom with novel systemic and topical modalities significantly impacting patient’s quality of life.
PP1: Psychophysics of histaminergic itch – Itch coding properties and impact of selective nerve conduction blockade
Florian Klemm, Hermann Handwerker, Walter Magerl
Center of Biomedicine and Medical Technology Mannheim (CBTM), University Heidelberg, Mannheim, Germany
In 22 subjects histamine was iontophoresed into the ventral forearm skin by anodal currents (10 s stimulation; total charge: 0.156, 0.625, 2.5 or 10 mC). Mean itch responses exhibited peak ratings at approximately 1 min after the current application and declined exponentially with time constants of approximately 3 min. Wheal and flare responses were highly correlated with logarithms of stimulus charges (both r=0.88, P<0.001) as was microcirculatory flux assessed by laser Doppler flowmetry (r=0.72). Wheal size was the best predictor of itch magnitude (r=0.66 vs. normalized VAS itch rating).
In 16 subjects nerve conduction blockade of the superficial radial nerve was induced by a weight-loaded band pressing the nerve against the underlying radial bone). Subjects experienced gradual sensory decay in the autonomous nerve territory until tactile and cold perception were completely lost, while warmth detection remained unchanged (i.e. total and selective A-fiber conduction blockade). In most subjects (11 of 16), full sensory recovery occurred within <5 minutes after block release. Their itch response was significantly decreased (P<0.05). Notably, in some subjects (5/16) experiencing sensory after-effects, like numbness, tingling etc. the magnitude of itch remained undiminished, and the perceived quality changed from predominantly itching to burning. Repeated painting of the skin for 2 days with capsaicin solution (1% in ethanol) until capsaicin-induced burning and heat sensitivity up to 50°C was completely lost subjects also experienced a complete loss of histamine-induced itch. We conclude that itch can be scaled with a similar precision as other nociceptive modalities. It depends primarily on the integrity of capsaicin-sensitive nociceptors. A-fiber nociceptors contribute significantly to itch perception, but only to a small extent.
PP2: Bile salt subspecies activate the G protein-coupled receptor MRGX4 expressed on sensory neurons and cause itching in humans
Katharina Wolf1, Helen Kühn1, Victoria Leibl1,2, Lisa Gebhardt1,2, Markus Glaudo1, Peter W. Reeh2, Michael J.M. Fischer3, Markus F. Neurath1, Barbara Namer2, Andreas E. Kremer1
1Department of Medicine 1 and Translational Research Center, Friedrich-Alexander-University Erlangen-Nürnberg, Germany, 2Institute of Physiology and Pathophysiology, Friedrich-Alexander-University Erlangen-Nürnberg, Germany, 3Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
Background & Aims: Pruritus is a frequent symptom in various hepatobiliary disorders. The recent beneficial effects of ileal bile acid transport inhibitors in patients suffering from cholestatic pruritus have raised interest in bile salts as pruritogens. We hypothesized that cholephilic substances in serum of cholestatic patients may activate MRG receptors thereby causing pruritus.
Methods: Human and murine MRG receptors were cloned and stably expressed in HEK293 cells. Activation of MRG receptors in HEK293 or DRGs by cholephilic substances were measured by changes in cytosolic free calcium (Ca2+)i using ratiometric fluorimetry. In mice scratch activity after intradermal pruritogen injection was quantified observer-independently measuring electric fields induced by implanted magnets. In 15 healthy volunteers itch intensity was quantified on a numeric rating scale after intradermal injection or focal application.
Results: We investigated the potential of human cholestatic serum and bile for activation of human and murine MRG receptors. Fractions containing bile salts resulted in rise of (Ca2+)i in hMRGX4 expressing HEK cells but neither of other human or murine MRG isoforms nor cultures of freshly dissociated murine DRGs. Analyzing human bile salts revealed that certain bile salt species (referred to as hMRGX4-activating bile salt species) were capable of activating hMRGX4 while others did not. The EC50 values ranged within the pathophysiological range of low micromolar concentrations. Intradermally injected bile salts did not cause significant scratching behavior in mice. In contrast, in humans focally applied or intradermally injected hMRGX4-activating bile salts caused significant itch intensity compared to non-hMRGX4 activating bile salts. Laser-doppler imaging indicated no widespread axonreflex erythema excluding relevant mast cells activation.
Conclusions: These data unravel a novel signaling pathway for bile salt subspecies that may contribute to cholestatic pruritus and may explain the differences between murine and human cholestasis. The hMRGX4 receptor represents a promising drug target to alleviate cholestatic pruritus.
PP3: Facial Atopic Dermatitis With Scratching (FADS) mouse: A novel animal model exhibiting severe itching
Satoshi Nunomura1, Isao Kitajima2, Naoko Ejiri2, Midori Kitajima2, Yasuhiro Nanri1, Kenji Izuhara1
1Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Nabeshima, Saga-shi, Japan, 2Department of Clinical Laboratory and Molecular Pathology, Graduate School of Medical and Pharmaceutical Science, University of Toyama, Toyama, Japan
Background: Persistent pruritus is a typical characteristic of atopic dermatitis (AD), although its etiology has not been fully elucidated. IKK2, a component of the IκB kinase complex, exerts pro-inflammatory responses, whereas its deficiency in keratinocytes paradoxically causes skin inflammation. In this study, we generated mice in which IKK2 is lacked in dermal fibroblasts. Unexpectedly, these mice exhibit inflammatory phenotypes similar to AD patients together with severe itching.
Methods: To generate Ikk2-deficient mice (Nestincre;Ikk2FL/FL) in which IKK2 is deleted in dermal fibroblasts, we crossed female Ikk2FL/FL mice to male Nestincre;Ikk2FL/+mice. Itch behaviors were evaluated as scratching or biting. Nestincre;Ikk2FL/FL mice were epicutaneously treated with or without drugs every day (tacrolimus ointment) or every other day (tofacitinib) from postnatal day 9 to day 27.
Results: Nestincre;Ikk2FL/FL mice spontaneously developed facial skin inflammation similar to those of AD patients and exhibited extensive itch behaviors as they grew up. The itch behaviors continued for at least five to six months. Thus, we named as Facial Atopic Dermatitis with Scratching (FADS) mice. FADS mice showed epidermal hyperplasia, eosinophil/mast cell infiltration, and periostin deposition. IKK2 deletion in tissue-resident cells was required for the development of skin inflammation. Itching was significantly reduced by topical treatment with tofacitinib (Jak inhibitor) but not tacrolimus (immunosuppressive agent), whereas epidermal hyperplasia and eosinophil infiltration in the inflamed skin was partially attenuated by tacrolimus or tofacitinib.
Conclusion: FADS mouse is a novel animal model exhibiting severe itching. FADS will be useful in clarifying the etiology of itching accompanied with AD.
PP4: Mechanisms of sensory hypersensitivity in surfactant-induced irritant contact dermatitis mouse model
Yoshihiro Inami1,2, Daisuke Uta1, Tsugunobu Andoh1
1Department of Applied Pharmacology, University of Toyama, Toyama, Japan, 2Advanced Research Laboratory, Hoyu Co., Ltd., Aichi, Japan
The repeated use of cleaning products is possible to cause dermatitis and cutaneous sensory hypersensitivity reactions characterized by itching on the skin and scalp in humans. However, the mechanisms underlying cutaneous sensory hypersensitivity induced by detergents remain unclear. In the present study, we investigated the mechanisms of cutaneous sensory hypersensitivity in mice treated with detergent (sodium dodecyl sulfate (SDS)). Repeated SDS application to the skin induced the inflammation, xeroderma and spontaneous scratching. In addition, the application also increased the elongation of peripheral nerves into the epidermis. c-Fos is well known as a functional marker of activity in neurons. When compared with vehicle-treated mice, the number of c-Fos-immunoreactive neurons was increased in lamina I-II, but not lamina III-VI, in the spinal dorsal horn (SDH) of SDS-treated mice. The neuron activities in the superficial SDH were recorded using in vivo extracellular recording technique. Spontaneous and mechanical stimulation (innocuous low force under healthy skin conditions)-evoked neuronal firing were increased in the superficial SDH neurons in lamina I-II corresponded to the skin treated with SDS but not treated with vehicle. The evoked neuronal firing in SDS-treated mice was maintained even after the end of the stimulation. In the SDH of SDS-treated mice, the number of GFAP-positive astrocytes, but not Iba1-positive microglia, was increased, compared with vehicle-treated mice. Until now, it is reported that spinal astrocytes is involved in chronic itch. Therefore, it is suggested that the epidermal elongation, and the hypersensitivity responses of SDH neurons, to which the activation of spinal astrocytes may relate, are involved in cutaneous hypersensitivity in SDS-treated mice.
PP5: Enhanced light mechanical and chemical stimuli-evoked itch in a mice model of menopause
Nao Ichimasu, Chen Yue, Sakiko Shimura, Kazumoto Katagiri
Department of Dermatology, Dokkyo Medical University Saitama Medical Center, Saitama, Japan
Introduction: Pruritus, formication, and irritability, which might be related to dysfunction of stratum corneum, are one of major symptom of menopause. However, there is no report about the mechanism of itching in menopause. Recently we found dysfunction of stratum corneum in a mice model of menopause. This study was designated to determine whether the pruritus in menopause is reproduced in the mice model of menopause and to elucidate the mechanism of the itching.
Materials and Methods: Touch-alloknesis was evaluated by number of scratch responses induced by repeated stimulation with von Frey filaments of various weight at the nape of C57BL/6 mice, who four weeks earlier received ovariectomy (OVX), ovariectomy with estrogen replacement (E2), or sham operation (control). Pruritogen-evoked alloknesis was evaluated by number of scratch bouts during 30 minutes after injection of pruritogens. Real-time RT-PCR was used for evaluation of NGF and semaphorin 3A mRNA expression in the skin.
Results: Number of scratch responses induced by von Frey filaments was increased at wide range of the weight, and significantly increased at 0.16 g and 0.4 g in OVX-mice compared with that in E2- and control-mice. The levels of pruritogen-evoked alloknesis with chloroquine, serotonin and histamine were increased in OVX-mice compared with that in E2 -mice, and were unstably increased compared with that in control-mice. The levels of mRNA of semaphorin 3A in the skin were significantly decreased in OVX-mice compared with those in E2- and control-mice.
Conclusion: This is the first report to show alloknesis in a model of menopause, which might be related to epidermal innervation due to decreased expression of semaphorin 3A.
PP6: Possible regulation of mechanical itch by CD26/DPPIV
Eriko Komiya1, Ryo Hatano2, Takumi Itoh2, Haruna Otsuka2, Yayoi Kamata1, Kotaro Honda1, Sumika Toyama1, Catharina Sagita Moniaga1, Kei Ohnuma2, Mitsutoshi Tominaga1, Chikao Morimoto2, Kenji Takamori1
1Juntendo Itch Research Center (JIRC), Institute for Environmental and Gender Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan, 2Department of Therapy Development and Innovation for Immune Disorders and Cancers, Juntendo University Graduate School of Medicine, Tokyo, Japan
In some skin diseases, innocuous physical stimuli elicit itch sensations. This phenomenon is called alloknesis (mechanical itch), but its molecular mechanism is unknown. 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. In this study, we investigated the regulatory mechanism of CD26/DPPIV in alloknesis. We applied innocuous mechanical stimuli using von Frey filaments to the rostral back of CD26/DPPIV knockout (CD26KO) mice 30 times in 5-sec intervals, and the total number of scratching responses was counted as the alloknesis score (alloknesis assay). The alloknesis score in CD26KO mice was significantly higher than that in wild-type mice. If 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. Taken together, our data suggest that CD26/DPPIV negatively regulates alloknesis through DPPIV enzymatic degradation of cutaneous EMs.
PP7: VGLUT3+ primary afferents mediate inhibition of pruritogen-responsive spinal neurons by scratching
Kent Sakai, Kristen M. Sanders, Darya Pavlenko, Hideki Funahashi, Taisa Lozada, Tasuku Akiyama
Miami Itch Center and Department of Dermatology and Cutaneous Surgery, University of Miami, Miami, Florida, USA
Amelioration of itch by scratching involves inhibition of pruritogen-responsive neurons in the spinal cord. Which subtypes of primary afferents mediate this scratch-evoked inhibition is still unknown. In this study, we examine the role of vesicular glutamate transporter type 3+ (VGLUT3+) primary afferents in scratch-evoked inhibition of pruritogen-responsive spinal neurons. To directly activate or silence peripheral VGLUT3+ nerves, mice that express Cre recombinase under the VGLUT3 promoter were crossed with mice expressing Cre-dependent excitatory opsin channelrhodopsin-2 (ChR2) or inhibitory opsin halorhodopsin (NpHR). Under pentobarbital anesthesia, a laminectomy exposed the lumbar spinal cord for single-unit recording. A small volume of chloroquine was injected into the ventral paw to isolate chloroquine-responsive units. Recordings were made from a total of 17 units in VGLUT3-ChR2 mice. Of them, 10 (59%) responded to histamine and 12 (71%) to serotonin. All units responded to blue light to the ventral paw. Neuronal responses to pruritogen were enhanced during blue light exposure, and this was followed by suppression of firing below baseline levels after termination of blue light. This suppression was not observed in capsaicin-evoked firing. Green light did not affect any neuronal responses. In VGLUT3-NpHR mice, a total of 7 chloroquine-responsive units were recorded from the superficial dorsal horn. Similar to activation of peripheral VGLUT3+ nerves by blue light, scratching within the receptive field suppressed chloroquine-evoked firing below baseline levels after termination of scratching without affecting capsaicin-evoked firing. This suppression was recovered by green light exposure during scratching. Activation of VGLUT3+ primary afferents by scratching might inhibit pruritogen-responsive neurons in a manner that depends on the input modality.
PP8: Electrophysiological and behavioral analysis of NC/Nga mice with atopic dermatitis-like symptoms
Daisuke Uta1, Norikazu Kiguchi2, Toshiaki Kume1, Tsugunobu Andoh1
1Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan, 2Department of Pharmacology, Wakayama Medical University, Wakayama, Japan
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by severe difficult‐to‐treat pruritus. Clinically, itch in AD patients is resistant to conventional treatments, and such itch is called intractable itch. The itch induces scratching behavior, resulting in greater damage to the skin barrier. This disruption of skin barrier leads to further itch, causing a vicious cycle called the itch-scratch cycle. During this cycle, even painful stimuli evoke itch in AD patients. This intractable itch lowers the quality of life in AD patients. Determining the fundamental mechanisms underlying intractable itch is therefore important in developing antipruritic treatments. Nevertheless, its underlying mechanisms are poorly understood. The present study was designed to analyze pruritic synaptic responses in spinal dorsal horn neurons of a mouse model of AD (NC/Nga mice) by using an in vivo extracellular recording. Spontaneous scratching behavior was AD-like NC/Nga mice significantly higher than that of healthy NC/Nga mice. Next, we investigated spontaneous neuronal activity of spinal dorsal horn (SDH) was recorded using in vivo electrophysiological techniques. In AD mice, the frequency of spontaneous firing in SDH neurons significantly increased compared with healthy mice. Spontaneous firing was blocked by either AMPA/kainate antagonist CNQX (10 μM) or voltage-gated Na+ channel blocker TTX (1 μM) applied to the surface of the spinal cord. Spontaneous firing neurons in AD mice were located in the superficial layer in SDH. This result consisted with Fos-like immunoreactivity analysis. These observations suggest that a subpopulation of superficial SDH neurons convey pruritic excitatory information to provoke scratching behaviors.
PP9: Cinnamaldehyde-evoked scratching in mice involves activation of TRPV4- and TRPV1- but not TRPA1-expressing sensory neurons
Amanda Nguyen1, Taylor Follansbee1, Dan T. Domocos2, Mirela Iodi Carstens1, *Earl Carstens1
1Neurobiology, Physiol. & Behavior, University of California, Davis, Davis, CA, USA, 2Faculty of Biology, University of Bucharest, Bucharest, Romania
Topical application of cinnamaldehyde (CA) elicits itch in humans and dose-related scratching in mice. CA-evoked scratching behavior was reduced ~50% in knockout (KO) mice of both sexes lacking TRPV1 or TRPV4, but not TRPA1. We presently used calcium imaging to investigate responses of dorsal root ganglion (DRG) cells to CA and other mediators. Cultured DRG cells from wildtype (WT) and various KO mice were ratiometrically imaged using Fura-2. TRPA1 agonists CA and allyl isothiocyanate (AITC) activated calcium influx in 24% and 22% of WT DRG cells, respectively. As expected, CA did not activate any DRG cells from TRPA1KO mice and AITC only activated 1.5%. CA activated significantly fewer DRG cells from TRPV4KOs (11.5%) vs. WTs, consistent with reduced CA-evoked scratching behavior in TRPV4KOs. CA and AITC activated significantly more DRG cells from TRPV1KOs (39.9 and 37.2%, respectively) even though it evoked less scratching behavior. This might reflect a compensatory increase in TRPA1 expression in TRPV1KO mice. Because CA elicited normal scratching in TRPA1KOs, it must act independently of TRPA1-expressing sensory/epithelial cells. CA is a contact sensitizer that activates CD-1-restricted T cells. We therefore tested the type-2 cytokine IL-4 (300 nM), which activated 15.8% of DRG cells from WTs, 40.3% from TRPV1KOs, and 13.5% from TRPV4KOs. IL-4 acts via TRPA1, since it did not activate any neurons from TRPA1KOs. DRG cells exhibited significant sensitization to repeated application of CA, an effect that was significantly enhanced by IL-4. In conclusion, TRPA1 is not required for CA-evoked itch. CA acts partly via TRPV4 and TRPV1 in sensory neurons to elicit itch. CA may also have a TRPA1-independent immune effect leading to production of type 2 cytokines, although activation of DRG cells by IL-4 is TRPA1-dependent and thus does not appear to mediate CA-evoked itch.
PP10: Targeting TRPV1 to alleviate UVB-induced itching
Liang Cao*, Xueping Yue*, Jing Feng, Hongzhen Hu
Department of Anesthesiology, The Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO, USA
Extreme itching sensation, which is called hell’s itch, could be a debilitating condition of exposing unprotected skin in the sun. On the other hand, narrow band ultraviolet (UV) B phototherapy has been widely used in the clinical treatment for atopic dermatitis and psoriasis, side effects such as dry and itchy skin are frequently complained by patients. However, it remains unclear whether and how UVB treatment contributes to the development of itch. To investigate the underlying mechanism, we first established a UVB-induced itch model in mice. Acute expose the nape of the neck to UVB produced a dose-dependent scratching behavior in mouse which lasted for several days. To further validate the specificity of this itch model, we delivered the UVB to the check of the mouse and observed predominantly scratching but not wiping behavior. Interestingly, chemical ablation of TRPV1-expressing sensory fibers with resiniferatoxin (RTX) markedly reduced UVB-induced scratching responses. Moreover, genetic ablation of TRPV1 but not TRPA1 or TRPV4 channel significantly improved scratching behavior in mice. These findings not only provide a novel mouse model of UVB-induced itch but also highlight the pivotal role of TRPV1 channel in UVB-induced itching and may provide new therapeutic target for UVB phototherapy-associated side effects.
PP11: TRPA1 channel is involved in non-histaminergic itch-related thermal and mechanical hyperalgesia in mice
Merab G. Tsagareli1, Ivliane Nozadze1, Nana Tsiklauri1, Mirela Iodi Carstens2, Gulnazi Gurtskaia1, Earl Carstens2
1Beritashvili Center for Exp. Biomedicine, Tbilisi, Georgia, 2University of California at Davis, Davis, CA, USA
Itch (pruritus) is an unpleasant skin sensation that evokes the desire to scratch. Among different pain reactions that lead to avoidance of noxious stimuli, itch is primarily thought to be a means for eliminating exogenous compounds such as parasites and plant spicules. Chronic itch or pruritus is a frequent symptom in the general population and in many skin and systemic diseases, such as atopic dermatitis, psoriasis, primary biliary cirrhosis and others, significantly impairing the quality of life. Antihistamines do not alleviate most types of chronic itch, treatment of which is largely unmet. Therefore, there is a need to better understand mechanisms of itch, and interactions with pain in order to develop novel evidence-based treatments for these chronic conditions. The possibility that itch mediators also influence pain is supported by recent findings that most non-histaminergic itch mediators require the transient receptor potential ankyrin 1 (TRPA1) channel. Here, we report that MrgprA3-mediated itch by its agonist chloroquine, and MrgprC11-mediated itch by their peptide agonists BAM8–22 and SLIGRL are accompanied by hyperalgesia via the TRPA1 channel. We measured nociceptive thermal paw withdrawal latencies and mechanical thresholds bilaterally in mice at various time points following intra-plantar injection of chloroquine, BAM8-22 and SLIGRL. Injection of these agonists into the mouse hindpaw resulted in heat and mechanical hyperalgesia for the first 30-45 min. Pretreatment with the TRPA1 channel antagonist HC-030031 significantly reduced the magnitude of this hyperalgesia, and significantly shortened the time-course of hyperalgesia. We revealed, thus, that non-histaminergic pruritogens chloroquine, BAM8-22 and SLIGRL elicit thermal and mechanical hyperalgesia via the activation of TRPA1 channel. This hyperalgesia was attenuated by the TRPA1 channel antagonist HC-030031. Further studies are needed to get more evidence for the potential role of TRPA1 channel inhibitors as modulators of preclinical and/or clinical itch and pain conditions.
PP12: Complementary roles of NaV1.7, NaV1.8 and NaV1.9 in acute itch signalling
Helen Kühn1, Leonie Kappes1, Lisa Gebhardt1, Katharina Wolf1, Peter Reeh2, Markus F. Neurath1, Michael Fischer3*, Andreas E. Kremer1*
1Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany, 2Institute of Physiology and Pathophysiology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany, 3Center for Physiology and Pharmacology, Medical University of Vienna, Austria
Background & Aims: Pruritus occurs in local and systemic disorders and alongside pharmacological treatment. Pruritogens induce itching through G protein-coupled receptors located on primary sensory neurons which depolarize and trigger action potentials by activation of voltage-gated sodium channels (Nav). Nav1.7, 1.8 and 1.9 have been suggested to modulate sensory capacities and were therefore analysed for their role in acute itch signalling.
Methods: The acute scratching behaviour of Nav1.7, 1.8 and 1.9 knockout mice in response to a comprehensive panel of pruritogens (histamine, chloroquine, endothelin, C48/80, 5-HT, lysophosphatidic acid, trypsin, SLIGRL, β-alanine and BAM8-22) was assessed using a magnetic field-based recording technology. Neurophysiological properties of dorsal root ganglia neurons were measured using calcium measurement. Gene expression was analysed by qrtPCR and immunofluorescence staining.
Results: Our data show an unexpected diversity of Nav-mediated itch signalling depending on the stimulus applied. Nav1.7 expression was essential for signalling of C48/80, endothelin, 5-HT, chloroquine and histamine while Nav1.8 influenced scratching only towards endothelin and 5-HT. Furthermore, Nav1.9 had overall a substantial contribution. Notably the calcium transients of sensory neurons of all genotypes in response to the pruritogens were similar, suggesting no change in sensory transduction but in action potential transformation and conduction. Nav1.7 and 1.9 deletion impaired scratching from its onset, suggesting an elevation of the action potential and, thus, itch threshold. In contrast, Nav1.8 knockout mice showed a similar onset of scratching compared to wild types but a more rapid decline for certain stimuli.
Conclusions: Our data suggests that an interplay of NaV channels is required for itch signaling. Nav1.7 acts as key mediator potentially modulating - together with Nav1.9 - the threshold of itch induction while Nav1.8 may extend the duration of strong responses. Due to the major role of Nav1.7, Nav1.7-blockers represent a promising option for treating pruritus.
PP13: House Dust Mite-Treated PAR2 Over-Expressor Mouse: Novel Model for Atopic Dermatitis and Pruritus
Leila Smith1, Solene Getault1, Laura Casals-Diaz1, Charles Métais1, Pamela Kelly2, Ulla Knaus3, Günther Eissner3, Eric Camerer4, Shaun Coughlin4, Martin Steinhoff1,5–7
1Charles Institute of Dermatology, Dublin, Ireland, 2Department of Veterinary Pathology, Dublin, Ireland, 3Conway Institute of Biomolecular and Biomedical Sciences, University College Dublin, Dublin, Ireland, 4Cardiovascular Research Institute, University of California, San Francisco, USA, 5Department of Dermatology and HMC Translational Research Institute, Hamad Medical Corporation, Doha, Qatar, 6Qatar University, Qatar, 7Weill Cornell University Doha, Qatar and New York, USA
Atopic Dermatitis (AD) is a complex pruritic skin disease involving causative effects from exogenous and endogenous sources. Murine models of the disease often fall short in one of these components and, as a result, do not fully encapsulate the disease mechanisms. After showing that protease-activated receptor-2 (PAR-2) is an important receptor in neurogenic inflammation and pruritus, we aimed to determine whether PAR-2 over-expressor mice treated with the AD trigger house-dust mite (PAR2OE + HDM) is a comprehensive representation of clinical AD in a murine model. HDM was applied topically to PAR2OE mice and AD clinical scoring, itch, skin morphology, barrier function and inflammation were assessed. Skin morphology was analysed using haematoxylin and eosin staining, barrier function was assessed by transepidermal water loss measurements. Immune infiltrate was characterised by histological and immunofluorescence staining. Comparison of the PAR2OE + HDM model with other murine AD models and human AD transcriptome in terms of key differentially expressed genes (DEGs) was performed. The PAR2OE + HDM model accurately displays the characteristic clinical symptoms including erythema, dryness and oedema, skin morphology, itch and inflammation seen in human AD. There is a significant influx of mast cells (P<0.01) and eosinophils (P<0.0001) into the dermis of PAR2OE mice. The PAR2OE + HDM model shows similar expression pattern of key DEGs as both human AD and other murine models. Thus, the PAR2OE + HDM model presents a clear and robust representation of human clinical AD encapsulating many of the critical features of the disease. It is therefore an excellent model for use in both basic research and pre-clinical trials.
PP14: IL-4 and IL-13 Evoke Scratching Behaviour in Mice
Michelle Campion1, Leila Smith1, Solene Gatault1, Charles Métais1, Joerg Buddenkotte2,3, Martin Steinhoff, MD, PhD2-5
1Charles Institute of Dermatology, University College Dublin, Ireland, 2Department of Dermatology, Hamad Medical Corporation, Doha, Qatar, 3Qatar University, Medical School Doha, Qatar, 4Department of Dermatology, Weill Cornell University New York, USA, 5Weill Cornell Medicine-Qatar, Doha, Qatar
Atopic dermatitis (AD) is a common skin disease in which IL-4 and IL-13 are key players in inflammation and neuroimmune dysfunction. Little is known about whether IL-4 or IL-13 directly and in which way contribute to pruritus. Recently, Oetjen et al found that both IL-4 and IL-13 are capable of directly activating itch-sensory neurons in vitro. Surprisingly, in contrast to IL-31, high doses of either IL-4 or IL-13 did not elicit acute itch in vivo. Similar experiments in our lab, however, suggested that these cytokines do contribute to acute itch in vivo. Study. Recombinant mouse (rm) IL-4 (1 μg), IL-13 (1 μg) alone or in combination, or histamine (50 µg) or vehicle (0.1% BSA in PBS) were intradermally injected into the right cheek of wild-type C57/Bl6 mice (9/group). After injection of rmIL-4 there was a significant increase of scratching bouts compared to vehicle and an overall significant effect of treatment (P<0.0001). rmIL-13 also induced a significant increase of scratching compared to vehicle (P<0.001). rmIL-4 and rmIL-13 together induced a significant increase of scratching compared to vehicle (P<0.0001). The combination treatment of rmIL-4 and rmIL-13 produced acute pruritus at an earlier time point than the two treatments administered alone. rmIL-4 showed a similar scratching behaviour profile to the positive control group, histamine. Together, our results suggest that IL-4 and IL-13 produce a clear, acute pruritic effect immediately after intradermal injection and are involved in acute pruritus in vivo. Possible explanation for disparity could be treatment concentrations, involvement of SOCS proteins as dose-dependent negative regulators of JAK-STAT pathway, or dose-dependent IL-13Rα2 activation. Thus, IL-4 and IL-13 directly and independently induce scratching behaviour in mice in vivo, exert an additional effect when applied simultaneously thereby being direct targets for itch therapy.
PP15: Keratinocyte-derived TRPA1 regulates itch-related cytokine release in cutaneous mastocytosis
Benjamin Meyknecht1, Carina Hillgruber1, Diana Below1, Angeliki Datsi2, Dieter Metze1, Martin Steinhoff3-7, Joerg Buddenkotte1,3,4
1Department of Dermatology, University Hospital Münster, Germany, 2Institute of Transplantation Diagnostics and Cell Therapeutics, University of Düsseldorf, Düsseldorf, Germany, 3Department of Dermatology, 4Translational Research Institute, Hamad Medical Corporation, Doha, Qatar, 5Qatar University, Doha, Qatar, 6Weill Cornell Medicine, Doha, Qatar, 7Department of Dermatology, Weill Cornell University New York, USA
Mastocytosis is a rare pruritic disease of children and adults where mast cells are abnormally increased in skin (cutaneous) or in multiple organs (systemic). A central pathophysiological mechanism of this disorder engages in the release of pro-inflammatory, pruritic and vasoactive mediators from mast cells (MC). The role of resident skin cells and the function of inflammatory and pruritic receptors in the pathomechanism of mastocytosis are poorly understood as of yet. TRP channel inducers like cold temperature, temperature changes, spicy food, alcohol, anaesthetics, mechanical forces and skin damage trigger mastocytosis. The transient receptor potential (TRP) ion channels ankyrin type 1 (TRPA1) has been described as a sensor for mechanosensation, temperature and irritants; thus, may be a candidate involved in the pathophysiology of mastocytosis. We analyzed the expression, distribution and regulation of TRPA1 channel in cutaneous mastocytosis and various more inflammatory skin diseases using immunohistochemistry and morphometry. Further, we studied the role of TRPA1 in keratinocyte function and its ability to induce mastocytosis- and itch-related cytokines. Our results show that dysregulation of epidermally expressed TRPA1 channel/ IL-6 pathway may be critically involved in the initiation and/or development of mastocytosis and itch.
PP16: Protease-activated receptor-2 in keratinocytes can drive atopic dermatitis, itch and neuroepidermal communication
Timo Buhl1,2, Akihiko Ikoma1, Joerg Buddenkotte3, Martin Steinhoff1,3-6
1Department of Dermatology, University of California, San Francisco (UCSF), CA, USA, 2Clinic of Dermatology, University of Göttingen, Germany, 3Department of Dermatology and Venereology and Translational Research Institute (TRI), Hamad Medical Corporation, Doha, Qatar, 4Department of Dermatology and Charles Institute for Translational Dermatology, University of Dublin, Ireland, 5UCD Center for Neuroscience, Davis, CA, USA, 6Weill Cornell Medicine-Qatar (WCMQ) and Qatar University (QU), Doha, Qatar
Activation of protease-activated receptor-2 (PAR2) has been implicated in inflammation, pruritus, and skin barrier regulation, all characteristics of atopic dermatitis (AD), as well as Netherton syndrome which has similar characteristics. However, understanding the precise role of PAR2 on neuro-immune communication in AD has been hampered by the lack of appropriate animal models. Par2OE newborns displayed no overt abnormalities, but spontaneously developed dry skin, severe pruritus, and eczema. Dermatological, neurophysiological, and immunological analyses revealed the hallmarks of AD-like skin disease. Skin barrier defects were observed before onset of skin lesions. Application of HDM onto Par2OE mice triggered pruritus and the skin phenotype. Par2OE mice displayed an increased density of nerve fibers, increased nerve growth factor and endothelin-1 expression levels, alloknesis, enhanced scratching (hyperknesis) and responses of DRG cells to non-histaminergic pruritogens. Our results suggest that certain proteases and KC-PAR2 are critically involved in the pathophysiology of pruritus and atopic dermatitis. KC-derived PAR2 seems to be an important link in neuro-epidermal communication with the keratinocyte-protease-PAR2 system as a forefront of sensory signaling and neuro-immune communication in inflammatory skin diseases.
PP17: Calcium/MEK1/2/AP-1 signaling axis induces semaphorin 3A expression in normal human epidermal keratinocytes
Yayoi Kamata1,2, Mitsutoshi Tominaga1,2, Yoshie Umehara1, Kotaro Honda1, Atsuko Kamo3, Catharina Sagita Moniaga1, Eriko Komiya1, Sumika Toyama1, Yasushi Suga4, Kenji Takamori1,2,4
1Juntendo Itch Research Center (JIRC), Institute for Environmental and Gender Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan, 2Anti-Aging Skin Research Laboratory, Juntendo University Graduate School of Medicine, Chiba, Japan, 3Faculty of Healthcare and Nursing, Juntendo University, Chiba, Japan, 4Department of Dermatology, Juntendo Urayasu Hospital, Chiba, Japan
Epidermal hyperinnervation plays a role in itch sensitivity at the periphery. It is mainly caused by an imbalance between nerve elongation factor (e.g. nerve growth factor) and nerve repulsion factor (e.g. semaphorin 3A [Sema3A]) produced by keratinocytes. Our previous study revealed that epidermal Sema3A levels are lower in barrier-disrupted skin, such as atopic dermatitis, than in healthy skin. However, the regulatory mechanism of Sema3A expression is currently unknown. In this study, we investigated the regulatory mechanisms of the Sema3A gene in normal human epidermal keratinocytes (NHEKs). Interestingly, Sema3A expression transiently increased in calcium-stimulated NHEKs, but markedly decreased in terminally differentiated NHEKs. In situ hybridization demonstrated that Sema3A mRNA is mainly localized in the stratum basale and stratum suprabasale of the epidermis. The 5′-flanking region of the Sema3A gene was cloned, and the proximal promoter region was identified. Activator protein (AP)-1 strongly bound the proximal promoter of Sema3A. Based on these findings, we next examined upstream signaling pathways involved in the regulation of Sema3A gene expression. Calcium-mediated transient Sema3A upregulation was suppressed by MEK1/2 (PD98059) and an AP-1 (T-5224) inhibitor. Therefore, Sema3A mRNA may be expressed in the lower epidermis under controlled conditions by calcium via the MEK1/2-AP1 axis.
PP18: Overexpression of dermal IL-31 generated by M2 macrophages and itch in murine models of atopic dermatitis
Takashi Hashimoto, MD, PhD1,2, Takahiro Satoh, MD, PhD2, Hiroo Yokozeki, MD, PhD2
1Department of Dermatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan, 2Department of Dermatology, National Defense Medical College, Saitama, Japan
Atopic dermatitis (AD) is a common skin disease with severe pruritus. Various itch mediators are involved in itch in AD, and IL-31 has recently gained attention as a potential therapeutic target for AD itch. It is generally established that IL-31 is generated by activated Th2 cells. Other cellular types are also capable of generating IL-31 including macrophages, eosinophils, mast cells, and basophils. Some reports have indicated that macrophages are the main cellular sources of IL-31 in AD lesions. Therefore, we sought to elucidate the cellular sources of IL-31 in an MC903-induced murine model of AD and a house dust mite feces (Dpf)-induced murine AD model. Both AD models showed significant scratching behavior. In lesions of both AD models, massive dermal infiltrates of IL-31(+) cells were detected, and more than 80% of IL-31(+) cells were MOMA-2(+) macrophages. MOMA-2(+)/IL-31(+) cells also expressed an M2 macrophage marker, arginase-1, indicating that IL-31(+) macrophages were M2 macrophages. These lesions featured overexpression of epidermal TSLP and dermal periostin. We also confirmed that TSLP and periostin were capable of promoting M2-skewing and IL-31 generation from M2 macrophages through ex vivo stimulation studies using murine peritoneal macrophages. In conclusion, macrophages were main cellular sources of IL-31 in murine AD models. This IL-31 generation was mediated by TSLP and periostin.
PP19: Brain allopregnanolone causes marked scratching in atopic dermatitis mice
Department of Pharmacology, Kyoto Pharmaceutical University, Japan
Atopic dermatitis (AD) is a common pruritic skin disease. It is known that clinically, emotional stress, sleep, and alcohol intake often trigger or enhance pruritus in AD, and these factors seem to primarily affect brain function. Therefore, unique brain mechanisms of itch may be involved in AD; however, its molecular basis remains unclear. We previously reported a unique, diet-induced mouse model for AD in which administration of ethanol or barbiturates markedly enhances itch-related scratching. Allopregnanolone (ALLO) is one of the neurosteroids that are synthesized in the brain and other steroidogenic organs. Since ALLO has similar pharmacological profiles to ethanol and barbiturates, we hypothesized that ALLO is involved in itch in AD mice. Intraperitoneal administration of ALLO dose-dependently and significantly increased scratching in AD mice, but not in normal ones. ALLO increased scratching when administered intracisternally, but neither intrathecally nor intradermally, suggesting that ALLO-induced scratching was mediated mainly through a supraspinal mechanism. ALLO-induced scratching was significantly inhibited by the GABAA receptor antagonist picrotoxin and the serotonin 5-HT3 receptor agonist 2-methyl-5-HT, but neither the L-type voltage dependent calcium channel agonist Bay K 8644 nor the glutamate receptor agonist N-methyl-D-aspartate. Next, we examined whether endogenously produced ALLO is involved in ethanol-induced scratching in AD mice, because ethanol administration is shown to increase ALLO in the brain. Oral administration of ethanol increased brain ALLO levels, which coincided with the increase in scratching. Pretreatment with finasteride, a synthetic inhibitor of ALLO, significantly suppressed ethanol-induced scratching and ALLO production in the brain. Collectively, our results demonstrated for the first time that ALLO administration caused marked scratching in AD mice, and ethanol-induced scratching may be mediated through endogenously produced brain ALLO.
PP20: Mechanisms of itch in stasis dermatitis: Significant role of IL-31 from macrophages
Takashi Hashimoto, MD, PhD1,2, Christina Dorothy Kursewicz, BS1, Rachel Alison Fayne, BA1, Sonali Nanda, MS1, Serena Maya Shah, BS candidate1, Leigh Nattkemper, PhD1, Hiroo Yokozeki, MD, PhD2, Gil Yosipovitch, MD1
1Miami Itch Center, Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA, 2Department of Dermatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
Stasis dermatitis (SD) is a common disease in the elderly, with pruritus as a common, bothersome symptom. However, there are few therapeutic modalities available for SD-associated itch because little is known about its pathophysiological mechanisms. Therefore, we sought to investigate the mediators of itch in SD using an immunofluorescence study on human lesions focusing on IL-31. We also used ex vivo stimulation studies using murine peritoneal macrophages to elucidate the pathological mechanisms of IL-31 generation. In SD lesions, dermal infiltrating IL-31(+) cells were increased (t-test, P=0.16) compared to healthy controls and the majority of IL-31(+) cells were CD68(+) macrophages. The presence of itch in SD was significantly associated with the presence of CD68(+)/IL-31(+) macrophages (P=0.0096) and CD68(+)/CD163(+) M2 macrophages (P=0.0004). The number of CD68(+)/IL-31(+) macrophages was correlated with the number of dermal CCR4(+) Th2 cells, IL-17(+) cells, basophils, substance P(+) cells, and the amount of dermal periostin and hemosiderin. Furthermore, murine peritoneal macrophages expressed an M2 marker arginase-1 and generated IL-31 when stimulated with a combination of substance P, periostin, and red blood cell lysate (representing hemosiderin). IL-31 from macrophages appears to play a significant role in itch in SD. This IL-31 induction is mediated by substance P, periostin, and hemosiderin.
PP21: Regulation of eotaxin, macrophage migration inhibitory factor and IL-4 expression by berberine is involved in the anti-atopic action by Kampo medicine Orengedokuto
Yoko Yoshihisa1, Tsugunobu Andoh2, Mati Ur Rehman3, Yoshiaki Tabuchi4, Tadamichi Shimizu1
1Department of Dermatology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan, 2Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan, 3Department of Radiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan, 4Division of Molecular Genetics Research, Life Science Research Center, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
Atopic dermatitis (AD) is a chronic inflammatory skin disease with severe pruritus. In Japan, Orengedokuto (OGT), as a Kampo medicine, is utilized to improve AD symptoms. However, the anti-AD mechanisms of OGT remain unclear. In this study, we demonstrated the anti-AD mechanisms of OGT using AD mouse model (NC/Nga mice) and the related cells (fibroblasts and mast cells). Repetitive oral administration of OGT in AD mice improved spontaneous scratching (an itch-related responses) and skin manifestation, and also reduced the cutaneous recruitment of inflammatory cells (eosinophils and mast cells) and serum IgE levels. In addition, the treatments inhibited the cutaneous expression of eotaxin, macrophage migration inhibitory factor (MIF) and IL-4 in AD mice. It is well known that berberine is a major active component of OGT. In fibroblasts, berberine inhibited the eotaxin expression induced by a combination of MIF and IL-4. In mast cells sensitized with IgE for 2,4-dinitrophenol (DNP), DNP induced the expression of MIF and IL-4 but not eotaxin, all of which are inhibited by berberine. Moreover, in the sensitized mast cells, a GeneChip assay identified two genes (EIF3F and MALT1) increased by DNP and these genes were downregulated by berberine. The treatment with siRNA for EIF3F or MALT1 in mast cells attenuated DNP-induced MIF and IL-4 expression. In addition to the inhibition of the inflammatory cell recruitment, these results suggest that OGT (especially, berberine as the major component) improves AD symptoms through the inhibition of not only eotaxin expression in fibroblasts, but also MIF and IL-4 expressions in mast cells. Furthermore, it is also suggested that the downregulation of EIF3F and MALT1 by berberine is involved in the regulation of MIF and IL-4 expressions in allergen-stimulated mast cells.
PP22: Peripheral interleukin-6 signaling is a leading cause of the depressive behavior induced by atopic dermatitis in NC/Tnd mice
Kenshiro Matsuda, Akane Tanaka, Hiroshi Matsuda
Laboratory of Comparative Animal Medicine, Division of Animal Life Science, Institute of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan
Background: Depression is the psychological disorder complicated in patients suffering from atopic dermatitis (AD). We previously reported that NC/Tnd mice, a murine model of AD, showed severe depressive phenotypes following the development of AD. In addition, AD-related peripheral candidate(s) suppressed hippocampal neurogenesis. Therefore, we tried to identify the targeting molecule(s) which increased in peripheral tissues by AD symptoms.
Methods: Sera collected from severe AD mice were injected to SPF NC/Tnd (without AD) mice intravenously. To reveal the effect of shared blood circulation, parabiotic pairs were designed between severe AD and non-AD mice. Hippocampal neurogenesis was analyzed immunohistochemically by the staining of double cortin-X (immature neurons) and brain lipid binding protein (progenitor cells). Serum candidate levels were measured by an ELISA. A gp130 inhibitor or anti-interleukin-6 (IL-6) antibody was injected intravenously for 2 weeks and for 4 weeks, respectively.
Results: Sera obtained from mice with severe AD induced depressive phenotypes in SPF mice. Moreover, number of immature neurons in the dentate gyrus of the hippocampus was decreased in SPF mice after parabiosis, whereas no change in number of neural progenitor cells was detected. Serum levels of IL-6 and soluble IL-6 receptor α was significantly increased in AD mice, and a gp130 inhibitor or anti-IL-6 antibody injection clearly improved hippocampal neurogenesis.
Discussion: Thus, the present results suggest that peripheral IL-6 signaling is a key regulator of developing depressive phenotypes in AD, and the signal impaired differentiation from progenitor cells to immature neurons in hippocampal niche.
PP23: Eosinophil infiltration and kallikrein 5 participate in the itching of mycosis fungoides
Tadamichi Shimizu1, Kyoko Shimizu1, Teruhiko Makino1, Yoko Yoshihisa1, Megumi Mizawa1, Tsugunobu Andoh2
1Department of Dermatology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan, 2Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
Mycosis fungoides (MF) is a form of cutaneous T-cell lymphoma (CTCL) composed of CD4-positive epidermotropic T lymphocytes. Itching can be a major symptom for patients with CTCL and becomes more severe according to the stage of disease. However, itching associated with MF is not relieved by conventional therapy using anti-histamines, suggesting that histamine is not the main pruritogen. Therefore, the underlying mechanisms of itching in MF patients remain unclear. In this study, we investigated the clinical and histopathological features in MF patients. Skin sections from MF patients and healthy subjects were used for pathophysiological analysis and evaluation of protease activity. These results were compared with the degree of itching. The MF patients without and with itching were 40% and 60% (moderate itching: 40%, strong itching: 20%), respectively. The number of eosinophils, but not mast cells, that infiltrated into the skin was increased in the group with strong itching. In the skin of the patients, both kallikrein 5 (KLK5)-immunoreactivity and the serine protease activity were increased depending on the degree of itching. By contrast, KLK7-immunoreactivity was not altered by the severity of itching. KLK5 elicits itching through proteinase-activated receptor-2 (PAR2). Although the cutaneous PAR2-immunoreactivity was increased in MF patients in comparison to healthy subjects, the expression was not altered between MF patients, in whom the grade of itching was different. Taken together, these results suggest that KLK5 and eosinophil infiltration may be involved in itching in patients with MF.
PP24: Anti-inflammatory effects of a woad extract in human skin cells and its use in treatment of dry, irritated and pruritic skin
Konstantin Agelopoulos¹, Tobias Lotts¹, Caroline-Donata Forner¹, Claudia Zeidler¹, Kathrin Kabrodt2, Johanna Hummel2, Dorit Binder2, Ingo Schellenberg2, Detlef Isermann3, Sonja Ständer¹
¹Department of Dermatology and Center for Chronic Pruritus, University Hospital Münster, Germany, 2Center of Life Sciences, Institute of Bioanalytical Sciences (IBAS), Anhalt University of Applied Sciences, Bernburg, Germany, 3P & M Cosmetics GmbH & Co, Münster, Germany
The medicinal herb Isatis tinctoria L. (woad) has a long history of being used for inflammation and infections. Woad extracts have been used in research and as ingredient of emollients for anti-irritative purposes. But, no well-defined extracts with analysis of active substances and mode of action exist, so far. Therefore the aim of our study was the exact characterization of standardized produced woad plant extracts and their anti-inflammatory properties which are both crucial for a potential dermatological use. Various extracts from properly cultured and dried leaves were examined for their active ingredients, and screened for anti-inflammatory effects using cyclooxygenase (COX)-2 activity assays. A petroleum ether (PE) extract with the main compounds p-coumaric acid methyl ester, 3-indole acetonitrile and tryptanthrin obtained the best effects. Mast cell (LAD2) degranulation experiments were performed (induction with calcium ionophore or substance P) to identify the anti-allergic potential of the extract. Anti-inflammatory activity was investigated by measuring of inflammatory cytokine expression after poly I:C or IFNg induction in human keratinocytes. Finally effects of the extract on dry and pruritic skin were analyzed in an open-label dermatocosmetic study using a cream containing the PE-extract. Mast cell (LAD2) degranulation was inhibited significantly and concentration dependent for calcium ionophore (0.005% and 0.0075%, P<0.001) and substance P (0.005% P<0.01, 0.0075% P<0.001) by the PE extract. The three main compounds did not show an effect when used alone but led to reduced degranulation in their combination. The combination also reduced the expression of the pro-inflammatory cytokines IL-6 and Il-33 significantly but the PE-extract was more effective. In the dermatocosmetic study the dry skin and symptoms improved significantly (P<0.001) for all variables like NRS, ItchCD, ODS, hydration, and quality of life. No side effects were reported. In sum, we successfully created a well-defined novel woad extract which shows anti-inflammatory properties in human skin cells and proofed effectiveness for treatment of dry and pruritic skin.
PP25: Cutaneous nerve fibers in chronic pruritus
Konstantin Agelopoulos, Manuel P. Pereira, A. Zastera, Claudia Zeidler, Sonja Ständer
Department of Dermatology and Center for Chronic Pruritus, University Hospital Münster, Münster, Germany
Chronic pruritus (CP) is a symptom of many different diseases and the neuroimmunological cutaneous mechanisms underlying CP remain unclear. It is assumed that cutaneous nerve fibers undergo peripheral neuronal sensitization due to neuroinflammation. We investigated the cutaneous neuroanatomy and sensitization of different C-fiber classes in patients (each n=40) with atopic dermatitis (AD), radiculopathy-induced brachioradial pruritus (BRP) and prurigo nodularis (PN). All patients and 40 sex- and age-matched healthy controls (HC) were stimulated with cowhage (CMH fibers), histamine (CMIA), capsaicin (TRPV1+ C-/Ad-fibers) or NaCl. Psychophysics (pruritus onset intensity and duration) was assessed and used to calculate areas under the curve (AUC). Biopsies of lesional/pruritic skin were obtained for assessment of cutaneous neuroanatomy by PGP9.5 staining. In PN patients, stimulation with cowhage led to a significantly higher pruritus intensity as measured by the AUC when compared to HC (P=0.02). Furthermore, cowhage induced a higher AUC pruritus intensity compared to histamine (AD: P=0.02; BRP: P=0.003; PN: P=0.002) and capsaicin (AD: P=0.002; BRP: P<0.001; PN: P=0.005) in all patient groups, but not in HC (vs. histamine: P>0.1; vs. capsaicin: P>0.05). AUC pruritus intensities induced by histamine and capsaicin did not differ (P>0.1) in any group. The density of intraepidermal sensory PGP 9.5-positive nerve fibers (IENF) was significantly reduced in all three CP groups as compared to HC. Assessment of intraepidermal nerve fiber branching revealed increased branching in PN and BRP but not in AD. Of interest, gene expression of the neuronal growth factor (NGF) was increased in all three CP groups whereas expression of the repulsive semaphorine-3A (SEMA3A) was increased in AD only. In sum, we found evidence for hyperknesis as a sign of peripheral neuronal sensitization with an enhanced CMH fiber (but not CMIA fiber) response upon experimental cowhage stimulation independent of the CP origin. Sensitization cannot be fully explained by increased branching of nerves due to the missing in AD and due to decreased nerve density in all CP groups. Scratching as well as imbalance of NGF and SEMA3A might be factors related to the disturbed anatomy of nerves.
PP26: Generalized chronic pruritus induced by small-fiber neuropathy: A retrospective study
Manual P. Pereira1, L. Derichs1, Gerd Meyer zu Hörste2, Konstantin Agelopoulos1, Sonja Ständer1
1Department of Dermatology and Center for Chronic Pruritus, University Hospital Münster, Münster, Germany, 2Department of Neurology, University Hospital Münster, Münster, Germany
Small-fiber neuropathy (SFN) results from damage of C and Aδ-fibers and is associated with pain and pruritus. A diagnosis of SFN can be established by detecting a diminished intraepidermal nerve fiber density (IENFD) in a skin biopsy. The clinical profile of chronic generalized pruritus (CP) arising from SFN is still poorly understood. We performed a retrospective analysis of data from patients with generalized CP and a reduced IENFD presenting at our center from January 2012 to May 2018. Patients with other causes for the pruritus (e.g. dermatosis) were excluded. We included 142 patients (60 females, 82 males, age±SD: 61.4±14.3 y). Chronic Pruritus was on average of moderate intensity (mean±SD: 5.3±2.6 NRS 24h) and occurred mostly daily (78%) and in attacks (63%). Eleven patients (8%) reported experiencing exclusively itch, while the majority (92%) also described painful sensations. The most frequently reported painful sensations were burning (50%), a sensation like needle pricks (46%) and tingling (45%). The application of cold water or cool packs alleviated the symptoms in the majority of the cases. The quality of life assessed by the ItchyQol was moderately impaired, while depression and anxiety scores assessed by the HADS were low. Based on the data retrieved from this study, we provide the first clinical characterization of chronic generalized pruritus in SFN. There is no unique pattern, but characteristics such as onset of the symptoms on normal appearing skin, association with other sensory symptoms (e.g. burning, tingling, stinging), pruritus occurring in attacks and its alleviation with cold or ice application are indications of a neuropathic origin. A reduced IENFD may confirm the diagnosis of SFN and should be performed upon clinical suspicion of SFN associated pruritus.
PP27: Comparison of characteristics of neuropathic and non-neuropathic pruritus to develop a tool for the diagnosis of neuropathic pruritus: the NP5
Johanna Huguen, MD,1,2 Caroline-Jade Clerc, MD,1 Florence Poizeau, MD,3,4 Pascale Marcorelles, MD, PhD,5,6 Gaëlle Quereux, MD, PhD,7 Alain Dupuy, MD, PhD,3,4 Emilie Brenaut, MD,1,6 Laurent Misery, MD, PhD1,6
1Department of Dermatology, University Hospital, Brest, France, 2Department of Dermatology, Quimper Hospital, France, 3Department of Dermatology, University Hospital, Rennes, France, 4Rennes University, UPRES EA 7449 REPERES Pharmacoepidemiology and Health Services Research Rennes, France, 5Department of Pathology, University Hospital, Brest, France, 6University Brest, LIEN, F-29200 Brest, France, 7Department of Dermatology, University Hospital, Nantes, France
Background: The diagnosis of neuropathic pruritus (NP), based on clinical examination, may be difficult. The treatment of NP is specific, so patient can be undertreated or treated inappropriately if the diagnosis is not done. We were inspired by the methodogy of Bouhassira et al when they developed the Douleur Neuropathique 4 (DN4) questionnaire for the diagnosis of neuropathic pain.
Objective: The aim of this study was to compare the characteristics of both NP and non-neuropathic pruritus (NNP) in order to elaborate a tool to help the diagnosis of NP.
Methods: A questionnaire was given to patients of 2 groups: with NP and with NNP.
Results: One hundred seven patients were included: 53 in the NP group and 54 in the NNP group. In multiple regression, presence of twinges, absence of burning, worsening with activity, no worsening with stress, and relief with cold ambient temperature were independent factors that were associated with NP. A score of two criteria out of five was optimal to discriminate NP from NNP with a sensitivity of 76% and a specificity of 77%. We suggest a list of 5 questions (the Neuropathic Pruritus 5, NP5) to help the diagnosis of NP: “Is your pruritus: associated with twinges? (1 point if positive response), associated with burning? (1 point if negative response), worse with activity? (1 point if positive response), worse with stress? (1 point if negative response), relieved by cold ambient temperature? (1 point if positive response).”
Conclusions: The 5 questions mentioned above can be retained to provide guidance for the diagnosis of NP.
PP28: Sensitive skin can be small fiber neuropathy: Results from a case-control quantitative sensory testing study
Flavien Huet,1,2, A. Dion3, Alexandre Batardière4, A.S. Nedelec4, F. Le Caër4, P. Bourgeois4, Emilie Brenaut1,2, Laurent Misery1,2
1Department of Dermatology, University Hospital, Brest, France, 2Laboratory on Interactions Neurons-Keratinocytes (LINK), University of Western Brittany, Brest, France, 3INSERM CIC 1412, University Hospital of Brest, Brest, France, 4Complife, Brest, France
Introduction: Sensitive skin syndrome (SSS) is defined as the occurrence of unpleasant sensations (itch, pain, burnings, prickling…) in response to stimuli that should not normally cause such sensations. Previous studies show that SSS could be a small-fiber neuropathy but quantitative sensory testing (QST) is lacking.
Objective: Using QST, the aim of the study was to determine the presence or absence of tactile sensitivity disorder, mainly heat-pain threshold (HPT 0.5), in subjects with SSS. Neuropathic pain was assessed by two questionnaires: the DN4 and the Neuropathic Pain Symptom Inventory (NPSI).
Materials and Methods: This monocentric case-control study included 21 subjects with SSS and 21 controls. The subjects underwent quantitative sensory testing. Neuropathic pain was assessed by two questionnaires: the DN4 and the Neuropathic Pain Symptom Inventory (NPSI).
Results: Forty-two subjects were included in the study. The HPT 0.5 was significantly lower in the cases (14.5+/−2.8) than in the controls (17.8+/−2.5) (P<0.001). Intermediate pain (HPT 5.0) was also significantly decreased in SSS. The DN4 and NPSI scores were significantly higher in the cases compared to the controls.
Conclusion: The decrease in HPT in subjects with SSS compared to controls suggests the presence of hyperalgesia, probably due to the damage of C-fibers. These findings, as well as the increased DN4 and NPSI scores, strengthen the neuronal hypothesis of SSS and are new arguments for consideration of SSS as small fiber neuropathy.
PP29: A systematic review of sensitive skin syndrome with its proposed pathogenetic mechanism of small fiber neuropathy
Kam Tim Michael Chan
Specialist in Dermatology, Hong Kong Academy of Medicine, Hong Kong, SAR, China; Adjunct Professor of Master Course on Common Goods and Public Health in the Baptist University of Hong Kong
Sensitive skin syndrome is a complex skin condition with an unclear pathogenesis. Management in primary health care setting is difficult. Proposed pathogenesis includes the controversial pathogenetic association of small fiber neuropathy with sensitive skin. A Pubmed systematic literature search was performed on sensitive skin pathogenesis and its relation to small fiber neuropathy. The aim is to reveal evidence based scientific knowledge in counselling, explanation, prevention and management of the condition in clinical setting. Methodology: as no previous studies reporting the direct relationship between peripheral neuropathy and sensitive skin; the link between sensitive skin and disrupted skin barrier is well reported; it is highly possible that increased TEWL and decreased epidermal barrier integrity may facilitate the penetration of irritant or allergen into the skin; eventually induce more stress in the skin which lead to alternation in epidermal nerve innervation and affect the perceived dysfunctional sensation. Hence, the following keywords are used for this literature search: “sensitive skin”, “intraepidermal nerve fiber”, “epidermal nerve innervation”, “trans epidermal water loss (TEWL)”, “tight junction” and “focal adhesion”. The online published articles are searched on the PubMed data base based on above keywords. A unique identifier is assigned to an online journal article. Results: a total of eleven Pubmed indexed articles with their PMID were retrieved, their PMID and author summary and the reasons why they are related to the topic of neuropathy and sensitive skin will be presented. No PMID result was found on direct key word search on peripheral neuropathy and sensitive skin. Focal adhesion of keratinocytes in stratum corneum of skin epidermis, patient’s genotypes, intraepidermal nerve fiber, nerve growth factors, matrix metalloproteinases involved inflammation and TEWL were the key underlying features revealed. As a distressing condition with significant health burden, more scientific studies are mandated to unveil its exact pathogenetic mechanism.
PP30: Increased Nerve fibers and transient receptor potential vanilloid 1 in aged human skin
Sangbum Han1,2*, So Min Kang1,2*, Jang-Hee Oh1,2, Dong Hun Lee1,2, Jin Ho Chung1–3†
1Department of Dermatology, Seoul National University College of Medicine, 2Institute of Human-Environment Interface Biology, Medical Research Center, Seoul National University College of Medicine, 3Institute on Aging, Seoul National University, Seoul, Republic of Korea
*These two authors contributed equally to this work
The skin is a sensory organ that is innervated by various types of nerve fibers which enable the sense of touch, pressure, temperature, and pain/itch. The sensory nerve in the skin is responsible for processing and transmitting pain and other noxious sensations to the spinal cord. When these nerves in the skin are dysfunctional, neurogenic inflammation as well as aberrant sensory responses such as hyperesthesia or dysesthesia ensue. Previously, we showed that expression of transient receptor potential vanilloid 1 (TRPV1) is increased in the dermis of the aged skin. To address whether nerve fibers may be elevated in the aged skin as TRPV1 is highly expressed in the nerve fibers, we investigated the expression patterns of genes by immunofluorescence staining, western blot analysis, microarray analysis, and quantitative RT-PCR from young and aged skin samples. Indeed, TRPV1 and nerve fibers were elevated in the aged skin, and several genes related to the nervous system were identified by microarray analysis. Next, we discovered that substance P (SP), one of the neuropeptides provoking itching, and other genes related to SP signaling including neurokinin 1 receptor (NK1R), nerve growth factor (NGF), and cannabinoid receptor type 1 (CB1R) were elevated together in the aged skin. Collectively, increased nerve fibers and related factors in the aged skin could lead to certain skin conditions such as hyperesthesia and itch.
PP31: Exploring the pathological factor of keloidal itch via microarray analysis
Misachi Asai1, Yuta Koike1, Kazuya Kashiyama2, Yosuke Yagi3, Yutaka Kuwatsuka1, Atsushi Utani1, Hiroyuki Murota1
1Department of Dermatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan, 2Department of Plastic and Reconstructive Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan, 3Department of Dermatology, Osaka Red Cross Hospital, Osaka, Japan
Keloid is a hypertrophic scar condition characterized by mesenchymal cell proliferation and excessive extracellular matrix deposition. In addition to their appearance problems, patients with keloids are often suffering from their intractable itch. To examine the mechanism of keloidal itch, we performed identification of genes associated with keloidal itch by microarray comparison between keloids and normal tissues (n=5). Network analysis from microarray data revealed that FN1, ITGA4 and MDFI were located center of the network in keloid tissues. Furthermore, we focused on 300 genes, which were upregulated in all five keloid samples with more than 2-fold compared to normal tissues. Major function of these upregulated gene products were the “extracellular matrix-related molecules (85 genes)” and followed by “nerve group (17 genes)”. Interestingly, genes related to itch, such as HRH1, 5-HTR2A and EDNRA, strongly expressed in keloid tissues. Pathway analysis and heatmap analysis implied that serotonin related molecules strongly participated in the pathology of keloid. These results suggested that keloidal itch might mainly be regulated by locally impaired serotonergic synapse signaling.
PP32: Density and morphology of corneal epithelial dendritic cells are different in allergy
Zahra Tajbakhsh, Isabelle Jalbert, Sailesh Kolanu, Fiona Stapleton, Blanka Golebiowski
School of Optometry and Vision Science, University of New South Wales, Australia
Purpose: The role of corneal epithelial dendritic cells (CEDC), a subtype of antigen presenting cells, in ocular allergy remains largely unknown. This cross-sectional study evaluated the density and morphology of CEDC in participants diagnosed with systemic allergy, to increase our understanding of the role of CEDC in ocular inflammation associated with systemic allergy.
Materials and Methods: A convenience sample of 50 participants was categorised into allergic and non-allergic groups (31 allergic and 19 non-allergic) based on the results of skin prick test (SPT). Ocular allergy symptoms, clinical ocular surface signs and serum IgE were assessed. In vivo confocal microscopy was performed on the right eye only. The number of CEDC in a 1mm2 region at both the central and mid-peripheral cornea was manually counted. CEDC morphology was graded on a 1 to 3 scale.
Results: Ocular surface symptoms, signs (other than eyelid oedema), and serum IgE were significantly higher in the allergic (SPT+) group. CEDC density at the mid-peripheral cornea was significantly lower in the allergic group (P=0.003). CEDC morphology grades were significantly higher in allergic participants in the central cornea (P=0.02), with the highest-grade morphology observed only in allergic participants. No associations were evident between CEDC density or morphology and ocular signs, symptoms or serum IgE.
Conclusions: The study showed reduced CEDC density and cells with longer dendrites in allergic participants. The more mature CEDC morphology in the allergic group is suggestive of an inflammatory or immune response.
PP33: Cannabinoids and itch
Tabrez Sheriff1, Matthew J. Lin2, Hooman Khorasani2
1St George Hospital, Department of Dermatology, Sydney, New South Wales, Australia, 2Icahn School of Medicine at Mount Sinai, New York, USA
Introduction: Topical cannabinoids are emerging as potential agents for the treatment of pruritus. The manipulation of the newly identified endocannabinoid system in the skin with topical cannabinoid receptor agonists has demonstrated a promising role in reducing itch particularly in conditions such as atopic dermatitis and uraemic pruritus.
Methods: A literature search was performed using PUBMED and clinical trial registries using search terms: cannabinoids in pruritus, cannabinoids in eczema, cannabidiol, atopic dermatitis, chronic pruritus. Case reports, case series, cohort studies and clinical trials were included in the initial screening. Selection was based on relevance, sample size, and adequate follow up periods.
Results: There are many studies that suggest a potential therapeutic potential of cannabinoids in treating pruritus. Activation of cannabinoid receptors 1 and 2 by endocannabinoids on epidermal cells has a number of downstream effects including inhibition or activation of keratinocyte proliferation, sebum production, hair production and inflammation. Topical cannabinoids can potentially reduce pruritus via inhibition of the fatty acid amide hydrolase enzyme (FAAH) or inhibition of an ion channel TRPV1 on nociceptive neurons. TRPV1 is an ion channel expressed mainly in nociceptive neurons of the peripheral nervous system and is responsible for cutaneous induction (burning pruritus). More recently, TRPV1 has also been found on numerous non-neuronal cell types including epidermal keratinocytes, dermal mast cells, Langerhans cells, sebocytes and various keratinocyte populations of the hair follicle. Topical cannabinoids such as Anandamide (AEA), a ligand at CB1, CB2 and TRPV1, and Palmitoylethanolamide (PEA) have demonstrated a significant reduction in pruritus in patients with atopic dermatitis and uraemic pruritus.
Conclusions: There is a promising role of topical cannabinoids in treating pruritus via various mechanisms including TRPV1 and FAAH inhibition, particularly in conditions such as atopic dermatitis. Clinical trials investigating cannabinoids, such as cannabidiol, are emerging however further human randomized trials are needed prior to recommending them as alternative treatments.
PP34: Chronic itch-scratch behaviour is a cognitive movement phenomenon mediated through neuroendocrine receptors in the central nervous system in our mind
Kam Tim Michael Chan
Specialist in Dermatology, Hong Kong Academy of Medicine, Hong Kong, SAR, China; Adjunct Professor of Master Course on Common Goods and Public Health in the Baptist University of Hong Kong
Mas-related G protein-coupled receptor C11, MrgprD, Transient Receptor Potential (TRP) vanilloid 1, TRP ankyrin 1, histamine receptors, thymic stromal lymphopoietin receptors (TSLP) expressed afferent neurons in skin mediated histaminergic and non-histaminergic pruritogenic signals through agonists especially TSLP, interleukin- 31 and Gastrin Releasing Peptide (GRP) interact with IL-31 and GRP Receptors in spinal cord resulting pruritus. Hedonic grooming activated primary somatosensory cortex gave the perception of mindful pleasantness in the cingulate cortex. The striatum, ventral tegmental area, nucleus accumbens, caudate nucleus and ventromedial prefrontal cortex were shown by MRI studies to be activated in this rewarding circuitry. Pathological scratching surmounted when pruritic sensitization became unrestrained. The stressful Cognitive-Emotional (CogEm) aspect of itch especially anxiety was centered in hippocampus, amygdala, subcallosal gray matter, nucleus accumbens and insula of the primitive brain. Mis-wiring, imbalance of neurotransmitters and opioids are involved. The pruritic-scratch-cognitive-emotion anatomical pathways and cybernetic neural network of CogEm macrocircuit will be discussed. Identification of a specific pruritic pathway involving cognition, emotion and motor brain function provide basis to develop psycho cognitive man-machine interaction to rehabilitate chronic pruritic patients. The authors utilized non-invasive finger sensors to volunteers suffered from severe chronic atopic dermatitis; resistant to conventional therapy; to detect scratching movements through electromyography. With the help of frequency analysis from Google deep Learning framework Tensorflow and wavelet transformations, relationships between received signals from the electrodes setup on hand muscle movements can be visualized and analyzed in different circumstances. Non-invasive signals like melody through the free download Apps of Void (https://void.com.hk/) will be timely feedback to the patients enabling relaxation through breathing techniques and finger exercises. Existence of a pruritogenic circuitry inherently bind with amygdala, neocortex, motor areas of brain and skin allow the restructuring of a new cognitive approach on integrated pharmacological and non-pharmacological management of chronic resistant pruritic dermatosis.
PP35: Effectiveness of musical intervention on pruritus: an open randomized prospective study
Sirin Demirtas1, Camille Houssais1, Julien Tanniou2, Laurent Misery1,3, Emilie Brenaut1,3
1Service de Dermatologie, CHRU de Brest, Brest, 2Délégation à la recherche clinique et à l’innovation, CHRU de Brest, Brest, 3Université de Brest, LIEN, Brest, France
Pruritus is a common symptom in skin diseases and can significantly alters the quality of life. Available treatments do not always relieve patients. Music therapy has shown interest in the management of many diseases such as pain, depression or anxiety. This prospective randomized controlled trial included inpatients with pruritus intensity ≥3/10 in chronic pruritic skin diseases. Patients were randomized to receive the application of an emollient or listen to a music session in a U-shaped sequence of Music Care® for 20 minutes on the headphones with a ocular mask. The primary endpoint was evolution of the pruritus EN before and one hour after the procedure. Fifty patients were included (25 per group), 62% of whom were men, with an average age of 60.7 years. The most common skin diseases were psoriasis (n=10), atopic dermatitis (n=8), and contact dermatitis (n=6). The average ItchyQol score was 64.8. The musical intervention allowed a significant decrease in the score of pruritus of 2.28±2.05 compared to the application of emollient: 1.20±1.68 (P<0.05). There was a decrease in anxiety (measured with STAI Y-A scale) in both groups with no significant difference between the groups. Among patients who received the musical intervention, 64% reported feeling an improvement, 86% would recommend music intervention and 70% would like to continue the practice. The management of pruritus is complex, our actual treatments do not always allow its relief. It is useful to find other ways to support them and the musical intervention has shown interest in our study. As in the management of pain, music therapy probably works by the activation of inhibitory neural circuits. The use of music is a simple non-pharmacological method that can be a tool in the management of chronic pruritus.
PP36: Differences in the perception & impact of itch in patients with chronic pruritus
Jordan D. Rosen, Christina Kursewicz, Emilie Fowler, David Castillo, Leigh Nattkemper, Gil Yosipovitch
Department of Dermatology & Cutaneous Surgery, Miami Itch Center, University of Miami, FL, Miami, USA
Epidemiological studies have shown that chronic pain and its characteristics distribute differently between females and males. We believe it is also important to report the distinctions between females and males suffering from chronic itch. We administered a cross-sectional survey to obtain information on patients with chronic pruritus seen at the Department of Dermatology at the University of Miami and at Temple University from 2015 to 2018. The study included data collected from 254 patients, including 168 female and 86 male subjects. The most common category of chronic itch was inflammatory itch (58.7%, n=149), followed by neuropathic itch (18.5%, n=47). Both inflammatory and neuropathic itch were more common in females. Chronic pruritus average intensity was significantly higher in females than in males (8 vs 7.7; P< 0.05). This difference between females and males was also significant for current pruritus (7.7 vs. 7.6; P<0.05). Females experienced more severe pruritus – more often described as dreadful, unbearable, hurting, oppressive –than males (P<0.05). Meanwhile, sleep disturbances were significantly worse in males than in females (2.9 vs 2.8; P <0.05). The overall quality of life mean score was significantly higher in females than in males (3.6 vs 3.3; P<0.05). Although there was a difference in the “symptoms” and “functioning” subcategories of the quality of life survey between males and females, only the “emotional” subcategory significantly affected females (3.9) more than males (3.4), P<0.001. Significant differences exist between females and males with chronic pruritus in terms of itch intensity, quality of life, and itch characteristics. Our results indicate that females have higher overall itch intensity than males, which is consistent with results from other recent studies from Germany. Understanding the differences between females and males with chronic pruritus can help health care providers to better manage patients and personalize treatment plans.
PP37: Worst itch numerical rating scale for prurigo nodularis: A psychometric evaluation
Sonja Ständer1, Claudia Zeidler1, Manuel Pereira1, Jacek C. Szepietowski2, Lori McLeod3, Shanshan Qin3, Nicole Williams3, Thomas Sciascia4, Matthias Augustin5
1University Hospital Münster, Germany, 2Wroclaw Medical University, Wroclaw, Poland, 3RTI Health Solutions, USA, 4Trevi Therapeutics, USA, 5University Medical Center Hamburg-Eppendorf, Germany
Objective: Prurigo nodularis (PN) is characterized by persistent itch with papules and nodules that are often excoriated or ulcerated. Study TR03 evaluated the safety and antipruritic efficacy of nalbuphine HCl extended-release tablets for PN (NCT02174419). These post hoc analyses aimed to assess the psychometric properties of the Worst Itch Numerical Rating Scale (WI-NRS), the TR03 primary endpoint.
Methods: Study TR03 was a double-blind, placebo-controlled, phase 2 trial for treatment of itch in PN patients (N=62) with documented scores on the WI-NRS (0 [no itching]–10 [worst itch imaginable]) ≥5 on ≥5 of 7 days before baseline. Using TR03 data, the WI-NRS’s psychometric properties were evaluated according to US FDA guidance on use of patient-reported outcome measures. Reliability, validity, and ability to detect change were evaluated; a responder threshold was estimated to facilitate interpretation of WI-NRS score changes.
Results: Among 62 patients randomized to treatment (median age, 55 y; 54.8% female), improvements in mean [SD] (median) WI-NRS were observed between baseline (8.2 [1.21] (8.1)) and week 10 (5.8 [2.43] (6.0)). The WI-NRS had an intraclass correlation coefficient of 0.96 (95% CI, 0.93-0.98) in 42 patients with stable Itchy Verbal Rating Scale (VRS) scores from week 9-10, supporting strong test-retest reliability. Construct validity of the WI-NRS was supported, with strong correlations at week 10 with Average Itch NRS (r=0.87) and Itchy VRS single-day/weekly mean scores (r=0.81/0.89) and moderate correlations with Itchy QoL total/domain scores (r=0.41-0.43). The WI-NRS discriminated between predefined severity subgroups based on Itchy VRS and detected changes in itching severity (effect-size estimate: 2.05; standardized response mean: 1.21). An anchor-based threshold for change of a two-category improvement in the single-day Itchy VRS suggests a responder threshold of ≥3.8 points (~40% improvement on a 0-10 WI-NRS).
Conclusions: The WI-NRS shows good measurement properties, supporting its use in evaluating treatment change in PN.
PP38: Validity assessment of the 10-item pruritus severity scale
Adam Reich, Agnieszka Bożek
Department of Dermatology, University of Rzeszow, Rzeszow, Poland
A validated assessment of pruritus intensity is an important but still difficult clinical problem due to subjective nature of pruritus. The aim of this study was the assessment of the reliability of the 10-item Pruritus Severity Scale (10-PSS) developed based on the 12-Item Pruritus Severity Scale (12-PSS).
Material and Methods: A total of 148 patients with pruritic dermatoses were asked to assess pruritus intensity using the 10-PSS and Visual Analogue Scale (VAS). In addition, 109 patients were also asked to complete the Dermatology Life Quality Index (DLQI). Test-retest comparison was conducted in 33 subjects who completed the 10-PSS twice with the 3- to 5-day interval. All results were analyzed statistically.
Results: We have created the new itch questionnaire (10-PSS) assessing pruritus intensity (two questions), pruritus extent (one question) and duration (one question), influence of pruritus on concentration and patient psyche (four questions), and scratching as a response to pruritus stimuli (two questions). The results showed strong internal consistency of 10-PSS (Cronbach α coefficient 0.81). A significant correlation was observed with VAS (r=0.61, P<0.001) and quality of life level according to DLQI (r=0.46, P<0.001). The test-retest comparison in 33 subjects revealed a good reproducibility of achieved results (ICC=0.81).
Conclusions: The 12-PSS and its shorter 10-item version are reliable methods of severity pruritus assessment and both may be used in daily practice and clinical studies.
PP39: Validation of ItchyQoL-Mini: A pilot study
Laura Ragmanauskaite, BS1, Devon Barrett, BS1, Kevin Luk, MD, MPH1, Chao Zhang, PhD1, Robert A. Swerlick, MD1, Suephy C. Chen, MD, MS1,2
1Department of Dermatology, Emory University, Atlanta, GA, USA, 2Regional TeleHealth Service, VISN 7, Atlanta, GA, USA
ItchyQoL is a validated 22-item patient reported outcomes (PRO) tool used to assess the impact of chronic itch on patients’ quality of life. It includes questions pertaining to patients’ itch symptoms, resulting functional limitations, and emotional impact. While relatively brief, the increasing utilization of PRO tools during patient visits has led to the desire to abbreviate the tool in order to increase visit efficiency. The current retrospective study examines how well the ItchyQoL-mini, a three-item questionnaire that globally assesses each of the domains (symptoms, function, and emotion) in ItchyQoL, captures itch burden compared to the full-length tool. Twenty-five patients seen at the Emory Dermatology Clinics between January 1st, 2019 and January 31st, 2019 completed both the full 22-item the 3-item scales in a random sequence during their visit. Spearman correlation was performed to measure the association between the three individual questions from ItchyQoL-mini and the composite scores for questions pertaining to each domain of ItchyQoL. Statistical analyses found correlations of 0.568 (P=0.003) in the symptom domain, 0.534 (P=0.006) in the functional domain, and 0.768 (P<0.001) in the emotional domain. While the results are modest, given the current study’s small sample size, they are promising, suggesting that the ItchyQoL-mini could be utilized to efficiently measure patient related outcomes in clinic. Larger prospective studies should examine the ItchyQoL-mini validity and clinical utility. Additionally, careful review and revision of the questions may help more accurately capture the itch impact in each quality of life domain.
PP40: Measurement properties of patient-reported outcome measures in pruritus: An updated systematic review
Janine Topp1, Christian Apfelbacher2, Sonja Ständer3, Matthias Augustin1, Dominic Schoch1, Christine Blome1
1Institute for Health Services Research in Dermatology and Nursing (IVDP), University Medical Center Hamburg, Hamburg, Germany, 2Institute of Social Medicine and Health Economics, Otto von Guericke University Magdeburg, Magdeburg, Germany, 3Department of Dermatology, Center for Chronic Pruritus, University Hospital of Münster, Münster, Germany
Various patient-reported outcome measures for pruritus have been developed and tested, capturing for instance intensity of pruritus or pruritus-specific quality of life. To inform choice of instrument, an overview of the quality of the available instruments is desirable. This systematic review aims to provide an update on measurement properties of patient-reported outcome measures for pruritus. A PubMed literature search was conducted to identify new validation studies published between October 2015 and July 2019. The methodological quality of validation studies and the measurement properties of patient-reported outcome measures were evaluated based on the COSMIN checklist. Sixteen new studies were included and added to the 23 studies identified in a previously published systematic review. Evidence of all 39 studies evaluating 35 different measures was summarized.
Of the newly identified studies, seven included patients with chronic pruritus, eight patients with a particular diagnosis associated with pruritus, and one study included healthy individuals. A novelty of this update was that outcome measures were partly assessed in an online format. Overall, seven new instruments could be identified. In total, 22 outcome measures were unidimensional composed of one to six single items. While all measures on pruritus intensity were unidimensional, severity and health-related quality of life measures were primarily multi-dimensional and differentiate between up to seven single dimensions. Ten outcome measures are currently considered most appropriate: three versions of the Numerical Rating Scale (NRS-11 average itch past 24h, NRS-11 worst itch past 24h, NRS-6 momentary itch), Visual Analogue Scale (VAS) average itch past 24 hours, Verbal Numerical Rating Scale (VNRS-4) momentary itch, Itch Severity Scale (ISS), Itchy Quality of Life, Uremic Pruritus in Dialysis Scale (UP-Dial), Patient Benefit Index Pruritus (PBI-P) and Dynamic Pruritus Score (DPS). For those measures, methodological quality of reliability and validity evidence was moderate and measurement properties were adequate.
PP41: Correlation of age-of-onset of Atopic dermatitis with Filaggrin loss-of-function carrier status in atopic dermatitis study
Sandra Smieszek*, Derek Xiao, Sarah Welsh, Christos Polymeropoulos, Gunther Birznieks, Mihael H. Polymeropoulos
Vanda Pharmaceuticals Inc, Washington, DC, USA
The genetic background of chronic pruritus in Atopic Dermatitis (AD) is complex. Filaggrin (FLG) is the most studied gene in the context of skin barrier dysfunction. We investigated the frequency and effect of rare FLG loss-of-function (LOF) variants in association with self-reported age-of-onset of AD. Samples were obtained from clinical study VP-VLY-686-3101, a randomized, double-blind, placebo-controlled, multi-center study in patients with chronic pruritus associated with AD treated with tradipitant, novel neurokinin 1 antagonist or placebo. The dataset consisted of 356 whole genome sequencing (WGS) samples and 414 samples genotyped for 2 most prevalent FLG mutations (R501X, 2282del4). We observe a significant association between FLG LOF status and age-of-onset, with earlier age of onset of AD in FLG LOF carrier group (P-value 0.0003, Wilcoxon two-sample test). We first tested this on the 2 prevalent FLG mutations. The effect is stronger when considering all detected FLG LOF variants. Having two or more FLG LOF variants associates with onset of AD at 2 years of age. The OR of having onset before 10 years of age if the subject is a mutation carrier is 3.27 (P-value 0.0037). In a high itch cohort, we observe a stronger effect (P-value is 0.00008), and OR of onset<5 of 7.9. Previously, we have shown enrichment of WGS for rare variants in the EDC region in AD cases. Age of onset analysis recapitulates the effect of FLG and EDC variants in terms of heightened risk of AD, but foremost enables to predict early onset, lending further credence to the penetrance and causative effect of the identified variants. Understanding the genetic background and risk of early onset is suggestive of skin barrier dysfunction etiology of the itch-scratch cycle present in early onset AD.
PP42: Pruritus response and skin biomarkers of atopic dermatitis (AD) with crisaborole versus vehicle in patients with mild-to-moderate AD
Robert Bissonnette1, Emma Guttman-Yassky2, John L. Werth3, Chuanbo Zang3, Amy Cha4, Bonnie Vlahos3, Daniela E. Myers3, Karl H. Nocka5, William C. Ports6
1Innovaderm Research, Montreal, QC, Canada, 2Laboratory for Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA, 3Pfizer Inc., Collegeville, PA, USA, 4Pfizer Inc., New York, NY, USA, 5Pfizer Inc., Cambridge, MA, USA, 6Pfizer Inc., Groton, CT, USA
Introduction: Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate AD. The mechanism of action of crisaborole is not well defined. This post hoc analysis of an intrapatient phase 2a study (NCT03233529) assessed the relationship between pruritus response and changes in key skin biomarkers with crisaborole versus vehicle.
Methods: Patients ≥18 years with clinical diagnosis of mild-to-moderate AD were included. Two moderate-to-severe lesions were randomized intrapatient (1:1) to double-blind twice-daily crisaborole or vehicle for 15 days; thereafter, patients applied open-label crisaborole twice-daily to all affected areas for 28 days. Lesion pruritus severity was assessed daily for each lesion during the double-blind period using a pruritus numeric rating scale (NRS). Pruritus NRS2, NRS3, and NRS4 responses were defined as ≥2-, ≥3-, and ≥4-point improvement in pruritus NRS score, respectively. Punch-biopsy specimens were collected for biomarker analysis at baseline (pre-dose), day 8 (optional), and day 15.
Results: Forty patients were included in the study; 38 completed the study. Statistically significant differences for crisaborole versus vehicle in proportion of patients achieving lesion pruritus NRS2, NRS3, and NRS4 responses were observed starting at days 4 (after 3 days of treatment), 5, and 8, respectively. On day 15, lesion pruritus NRS2, NRS3, and NRS4 responses (95% CI) were reported for 84.6% (69.5-94.1) versus 51.3% (34.8-67.6), 77.1% (59.9-89.6) versus 48.6% (31.9-65.6), and 63.6% (45.1-79.6) versus 31.4% (16.9-49.3) of crisaborole- versus vehicle-treated lesions, respectively (P<0.01 for all). Crisaborole significantly reduced the expression of itch-related interleukin-31 versus vehicle, the correlation of which (along with other skin biomarkers) to NRS response was calculated.
Conclusion: Crisaborole significantly improved lesion pruritus NRS score responses as early as day 4 compared with vehicle in patients with mild-to-moderate AD. Correlations between lesion pruritus NRS response and skin biomarkers further define the mechanism of action of crisaborole.
PP43: Characteristics of pruritus in relation to self-assessed severity of atopic dermatitis
Flavien Huet1,2, Marie-Sarah Faffa1, Florence Poizeau3,4, Stéphanie Merhand5, Laurent Misery1,2, Emilie Brenaut1,2
1Department of Dermatology, University Hospital, Brest, France, 2Laboratory on Interactions Neurons-Keratinocytes (LINK), University of Western Brittany, Brest, France, 3Rennes University, UPRES EA 7449 REPERES Pharmacoepidemiology and Health Services Research, France, 4Department of Dermatology, University Hospital, Rennes, France, 5French Association of Eczema, Redon, France
Pruritus is a primary symptom of atopic dermatitis (AD) and constitutes one of the major diagnostic criteria. This condition has a high burden, with serious psycho-social impact and impaired quality of life. Only a few studies have explored the characteristics of pruritus in AD and none have analysed the correlation of pruritus with severity of AD. The objective of this study was to explore characteristics of pruritus in atopic dermatitis in relation to the severity of AD. A web-questionnaire was available on the website of the French Association of Eczema. It included the Patient-Oriented SCORing Atopic Dermatitis index (POSCORAD), the 5-D itch scale and the Brest questionnaire. A total of 170 participants were included (86.5% women, mean age 30.9 y). Mean POSCORAD was 50.8±17.9. Severity of AD was mild for 8.2% of patients, moderate for 38.2% and severe for 53.5%. Mean 5-D itch scale was 13.2±3.4. The mean intensity of pruritus was 5.8, and mean sleep loss was 4.7 (from 0 to 10). The participants frequently described burning (61.8%) and stinging (58.8%); these symptoms suggest a neuropathic component. Pruritus was worse in severe AD compared with moderate AD (mean 5D itch scale 14.8 vs 11.9, P<0.001), exhibiting a higher impact on sleep and more associated symptoms (stinging, tickling, stabbing, burning and stroking). The majority of participants reported sleep disturbance as a result of pruritus. In conclusion, the characteristics of pruritus varied depending on the severity of AD.
PP44: Pruritus outcomes with crisaborole by baseline atopic dermatitis (AD) severity
Gil Yosipovitch1, Mizuho Kalabis2*, Chuanbo Zang2, Bonnie Vlahos2, Paul Sanders3, Daniela E. Myers2, Andrew G. Bushmakin4, Joseph C. Cappelleri4, Linda F. Stein Gold5
1Miami Itch Center, Miller School of Medicine, University of Miami, Miami, FL, USA, 2Pfizer Inc., Collegeville, PA, USA, 3Pfizer Ltd., Tadworth, Surrey, United Kingdom, 4Pfizer Inc., Groton, CT, USA, 5Henry Ford Health System, Detroit, MI, USA
*At the time of this analysis
Introduction: Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate AD. Phase 3 trials (NCT02118766; NCT02118792) established its efficacy and safety, including improvement in AD-associated pruritus. This pooled, post hoc analysis of the 2 trials assessed pruritus outcomes stratified by baseline AD severity (mild or moderate) per Investigator’s Static Global Assessment (ISGA).
Methods: Patients ≥2 years received twice-daily crisaborole or vehicle (2:1 ratio) for 28 days. Pruritus was assessed via Severity of Pruritus Scale (SPS; range, 0 [no itching] to 3 [bothersome itching/scratching that disturbs sleep]). The proportion of patients and time to achieve improvement in SPS score (SPS ≤1 with ≥1-point improvement from baseline) were based on weekly and daily average SPS scores, respectively. Only patients with average baseline and postbaseline assessments were included. χ2 tests and Kaplan-Meier analyses were performed.
Results: All results are presented as crisaborole versus vehicle. When stratified by baseline ISGA score, mean baseline SPS was 1.60 (n=297) versus 1.57 (n=138) for mild AD and 1.96 (n=465) versus 1.89 (n=230) for moderate AD. Significant differences (P<0.05) in proportions that achieved SPS improvement were observed from week 1 (17.5% vs 8.7%; P=0.0068) through week 4 (37.4% vs 25.0%; P=0.0094) for mild AD and from week 1 (19.1% vs 10.0%; P=0.0007) through week 4 (34.8% vs 18.4%; P<0.0001) for moderate AD. Median time to SPS improvement (95% CI) was 5 days (4-6) versus 8 days (4-13) for mild AD (P=0.1093) and 4 days (3-5) versus 11 days (7-17) for moderate AD (P<0.0001). Proportions and times to achieve ≥1-point improvement from baseline in SPS and pediatric data stratified by AD severity will also be reported.
Conclusion: Significantly greater proportions of crisaborole-treated patients ≥2 years with mild-to-moderate AD achieved improvement in SPS score through week 4 than vehicle-treated patients, regardless of baseline AD severity.
PP45: Analysis of related factors of eye complications during dupilumab treatment for Japanese patients with atopic dermatitis
Michie Katsuta, Yozo Ishiuji, Kenichi Yasuda, Hiroyuki Matsuzaki, Yoshimasa Nobeyama, Takaoki Ishiji, Akihiko Asahina
Department of Dermatology, Jikei University School of Medicine, Nishishimbashi, Minato-ku, Tokyo, Japan
Dupilumab is an anti-IL-4/IL-13 monoclonal antibody that has been available for treatment for patients with atopic dermatitis in Japan. Dupilumab consistently showed robust efficacy and acceptable safety in adult patients with moderate-to-severe atopic dermatitis. Although dupilumab has relatively few side effects, the ocular issues such as conjunctivitis, keratitis, blepharitis, eye pruritus and dry eye were found to occur during dupilumab treatment. However, the precise mechanism of eye complications during dupilumab is unknown. In this study, we examined the eye complications in Japanese adult patients with atopic dermatitis during dupilumab treatment. Eczema area and severity index(EASI), serum eosinophil and basophil count, immunoglobulin E (IgE), and thymus and activation-regulated chemokine (TARC) were examined over time for 6 months after the initiation of dupilumab treatment. As a result, the eye complications were observed in 65% of patients with atopic dermatitis during dupilumab treatment. In the group of the patients with eye complications, TARC tended to be higher before the initiation of dupilumab treatment, and the most frequent eye symptoms were observed around 8 to 10 weeks after the initiation of dupilumab treatment. In addition, serum eosinophil count was elevated in line with the onset of eye symptoms, while the group without eye complications showed conversely eosinophil count declined at the same period. From our results, we can conclude that eosinophils are closely related to the onset of eye complications during dupilumab treatment.
PP46: Itching in atopic dermatitis (AD): Results from the German national registry TREATgermany
Elke Weisshaar1, Eva Haufe2, Luise Heinrich2, Susanne Abraham3, Inken Harder4, Annice Heratizadeh5, Andreas Kleinheinz6, Andreas Wollenberg7, Matthias Augustin8, Franca Wiemers9, Alexander Zink10, Ralph von Kiedrowski11, Melanie Hilgers12, Margitta Worm13, Mario Pawlak14, Michael Sticherling15, Isabel Fell16, Christiane Handrick17, Knut Schäkel18, Petra Staubach-Renz19, Andrea Asmussen20, Beate Schwarz21, Magnus Bell22, Thomas Werfel5, Stephan Weidinger4, Jochen Schmitt2and the TREATgermany study group
1Occupational Dermatology, Department of Dermatology, University of Heidelberg, Germany, 2Center of Evidence-based Healthcare, University Hospital and Medical Faculty Carl Gustav Carus, TU Dresden, Germany, 3Department of Dermatology, University Allergy Center, Medical Faculty Carl Gustav Carus, TU Dresden, Germany, 4Center for Inflammatory Skin Diseases, Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel, Germany, 5Division of Immunodermatology and Allergy Research, Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany, 6Clinics for Dermatology, Elbe Klinikum Buxtehude, Germany, 7Clinics and Outpatient Clinics for Dermatology and Allergy, LMU Munich, Germany, 8Institute for Health Services Research in Dermatology Hamburg, University Medical Center Hamburg Eppendorf, Germany, 9Practice Dr. med. Franca Wiemers, Leipzig, Germany, 10Department of Dermatology and Allergy, Technical University of Munich and Clinical Unit Allergology, Helmholtz Zentrum Munich, German Research Center for Environmental Health GmbH, Germany, 11CMSS – Company for Medical Study and Service, Selters/Westerwald, Germany, 12Clinics for Dermatology and Allergy, University Hospital Aachen, Germany, 13Clinics for Dermatology, Venerology and Allergy, Charité Berlin, Germany, 14Practice Dr. med. Anika Hünermund and Mario Pawlak, Heilbad Heiligenstadt, Germany, 15Department of Dermatology, University Hospital, Friedrich Alexander University Erlangen-Nuernberg, Germany, 16Hautmedizin Bad Soden, Germany, 17Practice Dr. med. Christiane Handrick, Berlin, Germany, 18Department of Dermatology, Ruprecht-Karls University Heidelberg, Germany, 19Department of Dermatology and Allergy, University Medical Center Mainz, Germany, 20Practice Dermatologie an der Lesum, Bremen, Germany, 21Practice Dr. med. Beate Schwarz, Langenau, Germany, 22Practice Dr. Magnus Bell, Thomas Kaiser, Andernach, Germany
Itching is described to be the most devasting and impairing symptom by patients suffering from atopic dermatitis (AD). TREATgermany is an investigator initiated prospective disease-based registry and part of the European registry family TREAT. It investigates physician and patient reported disease severity (EASI, oSCORAD, POEM, PGA), patient reported symptoms (itch, sleep disturbance) and quality of life (DLQI) as well as course of therapy. Six hundred twelve AD patients (mean age 42.6±14.2 y, 38.2% females) were enrolled by 32 German recruiting sites (dermatological clinics and practices) between 06/2016 and 01/2019. The current analysis focusses on itch ranging from 0 (no itch) to 10 (maximum imaginable itch) documented for the previous 3 days prior to baseline visit. Analysis was performed using Stata 14 to perform Spearman’s ranksum test and rank correlation incl. 95% CI for describing associations. 586 (95.6%) patients suffered from itch, 233 (38.7%) with scores 7 and higher resembling severe itch. Mean itch severity was 5.4±2.7 and was significantly higher in females compared to males (5.7 vs 5.2, P=0.0213). The itch severity moderately correlated with severity of AD objectively measured by oSCORAD (rho=0.46(0.39-0.52)) and EASI-score (rho=0.44(0.37-0.50)). Moderate and severe AD showed highest itch scores. We found strong correlation to self- reported disease severity as PGA (rho=0.67(0.62-0.71)) and POEM-sum score (rho=0.64(0.60-0.69)). There was a moderate positive correlation of itch with quality of life impairment (rho=0.56(0.50-0.61)). This is the first analysis of itch in TREATgermany and to our knowledge the first from AD routine care. The data show a high prevalence of itch in AD associated with a great individual impairment. Itch as a subjective complaint is closer associated with patient reported outcomes than with objective assessments by the physician.
PP47: Chronic prurigo: Update on the terminology and classification
Manuel P. Pereira, Claudia Zeidler, Sonja Ständer; on behalf of the EADV Task Force Pruritus
Department of Dermatology and Center for Chronic Pruritus, University Hospital Münster, Germany
Chronic prurigo (CPG) is a severe pruritic condition, in which pruriginous lesions erupt upon a prolonged scratching behavior. The clinical manifestation of the skin lesions may vary extensively from small papules to large plaques. As a result many terms have been associated with CPG conditions, leading to misunderstandings among physicians and researchers. The Task Force Pruritus of the European Academy of Dermatology and Venereology addressed this issue in two consensus conferences, in order to achieve a clear definition of CPG and to reach a clinical oriented classification. Consensus was obtained when ≥75% of the voting members agreed on a statement, as per the Delphi’s method. In the first consensus conference (February 2017; Münster, Germany), members agreed that CPG should be regarded as a distinct disease, characterized by the presence of chronic pruritus (i.e. ≥6 wk), a prolonged scratching behavior and pruriginous lesions (obligatory criteria). The subtypes of CPG were defined according to the predominating morphology of the lesions as papular, nodular, plaque or umbilicated. In the second consensus conference (April 2018; Brussels, Belgium), linear prurigo was added to the subtypes of CPG since all the obligatory criteria for CPG are met in these patients. From a pathophysiological point of view, experts considered that neuronal sensitization mechanisms as well as the itch-scratch cycle play a pivotal role for the development and perpetuation of the disease, and thus treating the original cause of the itch alone may not suffice to reach an improvement of the condition. The new terminology of CPG reflects a novel unifying understanding of the disease and its varied clinical manifestations. Considering CPG a disease in its own right allows a better definition of this patient population, facilitates enrollment in clinical trials and highlights the need of development of targeted therapies for this condition.
PP48: Epidemiology of chronic prurigo in Poland
Adam Reich, Anna Ryczek
Department of Dermatology, University of Rzeszow, Rzeszow, Poland
Introduction: Epidemiology of chronic prurigo is largely unknown.
Objective: The aim of the current study was to evaluate the prevalence of chronic prurigo in Poland. We have chosen this European country, as Poland has a unique health insurance system, in which the health care data of the entire population are collected by one institution, namely the National Health Found.
Methods: We have gained the data from the National Health Found in Poland regarding the patients treated between 216 and 2018 with the diagnosis of prurigo nodularis (L28.1 acc. to ICD-10) or other prurigo (L28.2) divided according to particular region of the country.
Results: A total of 10,369 patients were treated because of prurigo in the analyzed time period (2016 – n=3474; 2017 – n=3339; 2018 – n=3556) with the annual prevalence ranging between 0.0087% to 0.0093% of the entire population; prurigo nodularis was diagnosed in 0.0058% to 0.0065%, while other prurigo in 0.0027% to 0.0032%. The mean age of all patients was 60.2±21.6 years. Majority of patients with prurigo were treated in outpatient specialized clinics (86.8%) while the rest were hospitalized (13.2%). Prurigo was twice more often diagnosed in women (n=6933) than in men (n=3436) (ratio: 2:1).
Conclusions: Chronic prurigo mostly affects elderly people, with higher prevalence in women. The major limitation of this study is possible underdiagnosis of prurigo in routine daily practice. However, inspite of this our study gives on overview on prurigo diagnosis reported to health care systems giving the opportunity to assess the health care costs spent for this group of patients.
PP49: Refractory prurigo nodularis successfully treated with thalidomide
Gayun Baek, Min-Soo Kim, Jiho Park, Mihn-Sook Jue
Department of Dermatology, Veterans Health Service Medical Center, Seoul, Republic of Korea
Prurigo nodularis (PN) is highly pruritic chronic dermatosis which caused by repeated scratching and rubbing of the skin. The definite pathogenesis of PN is unclear, yet hypothesis concerning increased cutaneous nerve fiber are generally accepted for possible etiology. The complex and obscure etiologies of PN makes its treatment more challenging because complete cease of symptoms requires multiple complicated interferences among pathogenesis steps. A 75-year-old male presented outclinic of dermatology in 2008 with chief complain of severe pruritus and multiple keratotic nodules on both forearms. He had no medical history of atopic dermatitis or contact dermatitis. Except for diabetes mellitus, hypertension and hyperlipidemia, he had no specific general medical condition, either. The hyperkeratotic pruritic skin-colored papules and nodules were disseminated on both forearms, posterior neck and shins with excoriations secondary to the severe pruritus were accompanied. Although lab tests for identifying possible causes for pruritus were executed including complete blood count, thyroid function test, hepatitis panel, liver and kidney function tests and urinanalysis, there were no plausible abnormalities were found. Biopsy from elbow revealed hypertrophic dermatitis with perivascular mononuclear inflammatory cells which is consistent with PN. He treated with multiple topical agents including diflucortolone valerate, tacrolimus hydrate, desoxymethasone which were failed to relief the subjective symptom of the patent and oral medications such as amitriptyline, antihistamines, azathioprine, pregabalin also showed disappointing effects on pruritus. Cryotherapy and intralesional steroid injection (ILI) were performed and made mild, transient improvements of the lesions. The response to these oral medications, ILI and topical agents were unsatisfactory for the patient and he still suffered from pruritus. In 2016, thalidomide was added up to his medication to weaken the severe, refractory PN on dosage of 50 mg, daily. The patient had no side effects such as neuropathy which is known to be associated to thalidomide use and reported significantly reduced pruritus after 3 weeks of thalidomide administration. Except for the occasional ILI, other oral medications and topical agents were stopped while treating using thalidomide due to the rapid improvement of pruritus symptoms. His relieved status is sustained with initial dose, 50 mg of thalidomide, daily for 3 years. Thalidomide has antipruritic, anti-inflammatory effect which shown to have beneficial results on PN reported by Mattos, 1973. Although it has teratogenicity and neuropathic side effects, it can be used as a competent tool for chronic pruritus dermatologic conditions including PN, uremic pruritus, actinic prurigo and many other diseases which do not shows satisfactory response to the first line medications. Sedative effect of thalidomide is helpful to those with chronic pruritus and its inhibition of TNF-a production which result to IL-8 regulation may have beneficial effect for PN. Except for neuropathy and teratogenicity, thalidomide has minimal toxic side effects for liver and kidney. This is a great portion of its advantages, especially in elderly patients who have higher risk for insufficient renal or liver function, in general.
PP50: Patients with chronic prurigo suffer more than patients with chronic pruritus
Claudia Zeidler, Manuel P. Pereira, Matthias Borowski, Sonja Ständer
Department of Dermatology, Center for Chronic Pruritus, University Hospital of Münster, Germany
Background: Chronic pruritus is a high burdensome symptom. Patients show a substantial impairment of quality of life and can develop sleep disturbances and reactive psychological disorders like anxiety and depression. Chronic pruritus can lead to chronic prurigo (CPG) by developing multiple pruriginous lesions due to a neuronal sensitization and an itch-scratch cycle. Aims of this retrospective, explorative statistical analyses were to compare patients with CPG vs. patients with chronic pruritus regarding the severity of symptoms and its consequences.
Methods: Data from more than 4500 patients with CPG (IFSI III; n=1723) or chronic pruritus on non-lesional skin (IFSI II; n=2781) were analyzed. These data consisted of demographic and medical data, patient completed questionnaires for quality of life, pruritus characteristics, anxiety and depression. All statistical analyses were predetermined in a statistical analysis plan.
Results: Patients with CPG were higher burdened by longer history and had higher scores on the itch intensity scales. Their pruritus occurred more often and lasted nearly the whole day and night which led to more loss in sleeping hours. Patients with CPG had higher values for depressions in the Hospital Anxiety and Depressions Scale, higher impaired quality of life ratings measured by ItchyQoL and had more needs in predefined treatment goals in the Patient Benefit Index.
Conclusion: Patients suffering from chronic prurigo have a high burden and suffer from higher itch intensities as well as greater psychological impairment compared to patients with chronic pruritus.
PP51: Prevalence of itch in patients hospitalized with heart failure
Małgorzata Ponikowska1, Jan Biegus2,3, Robert Zymlinski2,3, Jacek C. Szepietowski1
1Department of Dermatology, Venerology and Allergology. Wrocław Medical University, Wroclaw, Poland, 2Department of Heart Diseases, Medical University, Wroclaw, Poland, 3Department of Cardiology, Centre for Heart Disease, 4th Military Hospital, Wroclaw, Poland
Background: Itch is a common, distressing symptom, often complicating non-dermatological, chronic systemic diseases. Despite patients with heart failure (HF) are at high risk to develop itch, only a few studies investigated the subject.
Objectives: This study was set-up to investigate the prevalence of itch in patients hospitalized with acute HF. We aimed to provide clinical characteristics of patients reporting itch and explore potential underlying causes.
Material and Methods: We prospectively recruited 84 consecutive patients with acute HF (75% men, mean age: 67±5 y) who received standard cardio-vascular management. Itch assessment was performed before hospital discharge using the visual analogue scale (VAS), numerical rating scale (NRS), 4-Item Itch Questionnaire. Moreover, Dermatology Life Quality Index (DLQI) was used.
Results: Fourteen patients (17%) with acute HF reported history of itching. From this group 11 patients (79%) reported itch occurring during the last 3 days with the mean intensity at 4.4±2.8 on VAS and 4.2±2.9 on NRS. In the majority (71%) of patients itch was limited to a certain area of the skin, mostly limbs (50%). There were no consistent factors responsible for alleviation or aggravation of this sensation. The following factors were associated with itch: use novel oral anticoagulants, more severe symptoms on admission, complicated clinical course and elevated bilirubin level (all P<0.05 in univariate analysis).
Conclusions: Itch was moderately frequent symptom reported by patients with acute HF. There can be an association between itch reported by patients hospitalized due to acute HF and HF severity, medications and comorbidities.
PP52: Itch in the elderly: A cross-sectional study
Radomir Reszke1, Rafał Białynicki-Birula1, Karolina Lindner2, Małgorzata Sobieszczańska2, Jacek C. Szepietowski1
1Department of Dermatology, Venereology and Allergology, Wrocław Medical University, Wrocław, Poland, 2Department of Geriatrics, Wrocław Medical University, Wrocław, Poland
Introduction: Aging is associated with numerous medical afflictions, including dermatological symptoms and disorders. Chronic itch (CI) in the elderly is a frequent complaint of diverse etiology.
Objective: To assess the prevalence and detailed clinical characteristics of CI among elderly patients, including associations with comorbidities and pharmacotherapy.
Materials and Methods: This cross-sectional study included 153 consecutive subjects aged 65 years and over hospitalized in the geriatric ward between January 2018 and May 2018.
Results: CI affected 35.3% of subjects, mostly as a result of skin conditions, mixed etiology and neurological disorders (53.7%, 25.9% and 11.1% of pruritic subjects, respectively). The mean itch intensity assessed by 4-Item Itch Questionnaire (4IIQ) was 6.6±2.8 points. Higher 4IIQ scores were associated with viral hepatitis (P=0.02), higher serum creatinine concentration (P=0.02) and coexistent purpuric lesions (P=0.002). In logistic regression analysis CI positively correlated with female sex (Odds Ratio (OR)=4.4), atopic dermatitis (OR=13.9), immobility (OR=21.4), rheumatoid arthritis (OR=25.2) and ischemic neurological diseases (OR=2.5), while low molecular weight heparins (OR=0.03), antipruritic drugs (OR=0.07), allergy (OR=0.09), rosacea (OR=0.2) and higher hemoglobin concentration (OR=0.9) acted conversely.
Conclusions: CI is a frequent and interdisciplinary problem among elderly subjects. Its management requires holistic clinical approach.
PP53: Chronic pruritus: Cost-effectiveness of guideline-based specialized care
Svenia Müller1, Mandy Gutknecht3, Matthias Borowski4, Matthias Augustin3, Sonja Ständer2, Sabine Steinke2
1Department of Dermatology and Allergy, University Hospital Bonn, Germany, 2Department of Dermatology and Center for Chronic Pruritus, University Hospital Münster, Germany, 3German Center for Health Services Research in Dermatology (CVderm), University Medical Center Hamburg-Eppendorf (UKE), Germany, 4Institute of Biostatistics and Clinical Research, University of Münster, Germany
Patients suffering from chronic pruritus (CP; duration at least 6 wk) require extensive diagnostics and often long-term, specialized therapies. The study compares costs and benefits of a guideline-based care at a university specialized itch center to outpatient routine care.
Patients and Methods: Treatment data from patients attending the specialized center for the first time were collected. Six months prior to (T0) and after the first consultation (T1) direct medical (inpatient and out-patient diagnostics and treatment) and non-medical (e.g. skin care, travel expenses) costs were calculated from patients’ and medical records to analyze treatment benefit. Pruritus intensity (Numerical rating scale [NRS, 0-10]; Visual analogue scale [VAS, 0-10]), quality of life measurements (Dermatology Life Quality Index [DLQI, 0-30]; ItchyQol [0-110]) and the Patient Benefit Index (PBI, 0-4) were assessed. Statistical analyses were performed using descriptive methods and Wilcoxon sign-rank test.
Results: A total of 300 adult patients with CP attending a specialized university outpatient clinic for the first time were recruited within routine care. The patients’ pruritus intensity could be reduced from 5.3±2.5 (T0) (mean±standard deviation) to 3.7±2.8 points (T1) on the NRS [P≤0.001], from 6.1±2.3 (T0) to 3.4±2.8 (T1) points on the VAS [P≤0.001]. Quality of life was affected moderately at first consultation (T0: DLQI 8.9±6.5 points; ItchyQol: 65.8±17.0 points). Six months after the first consultation at the itch center (T1) the quality of life was less affected (DLQI 5.6±5.4 points [P≤0.001]; ItchyQol 56.1±19.4 [P≤0.001]. Furthermore, the Patient Benefit Index increased (T0: 1.2±1.3; T1: 2.1±1.3 points). Inpatient treatment costs were reduced from 316±313 € (T0) per patient (pp) to 103±528 € pp (T1) [P≤0.01], outpatient treatment costs from 320±490 € pp (T0) to 196±339 € pp (T1) [P≤0.001]. Especially costs of topical skin treatment were reduced more than 50% (84±235 € (T0) vs. 40±87 € pp (T1) [P≤0.001]. Costs of systemic therapy were marked down to one-fifth (108±347 € (T0) vs. 87±230 € pp (T1) [P≤0.05].
Conclusions: Guideline-based care of CP patients at a specialized university itch center is cost-effective and improves patients’ benefit and quality of life compared to outpatient routine care.
PP54: Topical cryosim-1 (selective TRPM8 agonist) gel on itching
Hye One Kim, Seok Young Kang, Min Je Jung, Yong Won Choi, Bo Young Chung, Chun Wook Park
Department of Dermatology, Kangnam Sacred Heart Hospital, Hallym University, Seoul, Korea
Transient receptor potential cation channel subfamily M member 8 (TRPM8) is a non-selective cation channel, first characterized as a detector of cold. Topical cryosim-1 was developed to relieve itching sensation. The 1-diisopropyl heptylphosphine oxide (Cryosim-1) is a selective TRPM8 agonist that gives a cold sensation to the skin without altering the tissue temperature and suppresses irritated, itchy, and painful sensations. Within a few minutes, one can feel “cooling” and relax other uncomfortable sensations. Therefore, the authors wanted to compare the effect of a topical cryosim-1 gel and placebo gel on itch. Patients with itching sensation were asked about their itching sensation 2 hours after application. The reduction of itching was evaluated for a week of application. Dermatologic disorder associated with itching such as atopic dermatitis, seborrheic dermatitis, urticarial dermatitis, postherpetic neuralgia and prurigo were included in this study. Itching sensation of various dermatologic disorders was markedly decreased for two hours after application of the gel and symptom have been reduced for one week. In conclusion, topical cryosim-1 gel can be a treatment option for reducing itching sensation in various dermatologic disorders.
PP55: Topical acetaminophen for itch relief
Leigh Nattkemper1, David Lebo2, Gil Yosipovitch1
1Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, Miami Itch Center, University of Miami, Miami FL, USA, 2Department of Pharmaceutical Sciences, Temple University, Philadelphia PA, USA
There is an unmet need to develop effective topical anti-pruritic medications for acute and chronic itch, as currently there are few topical formulations that have a direct effect on itch. We have developed a formulation of topical acetaminophen (APAP) for itch relief that would inhibit both histamergic and non-histaminergic itch. Drug skin permeations within human cadaver skin showed that 5% APAP in ointment formulation had low permeation under non-occluded conditions; however, under occlusion it provided 2-20 μg/cm2 of APAP into the skin in the first hour. The 5% APAP in gel formulation in non-occluded conditions provided about 10-40 μg/cm2 of APAP within the first hour, while the 2.5% APAP gel in the same condition and time frame provided 2-20 μg/cm2. Occlusion of the gel formulations did not change permeability. The efficacy of the topical 5% APAP cream was tested in a pilot study in 6 healthy subjects. Teat areas on the volar forearm were pretreated with 5% APAP cream and vehicle control for 30 minutes. Cowhage was used to induce itch in a non-histaminergic manner, and subjects rated their itch intensity every 30 seconds on a visual analog scale. The 5% APAP cream significantly reduced cowhage-induced itch over the placebo throughout the time course of the itch (P=0.05). The duration of itch was significantly reduced by 2 minutes, and the peak intensity was reduced by 50% (P=0.03). Erythema caused by the cowhage application was also reduced by the 5% APAP cream compared to the placebo cream. We are currently testing multiple concentrations of the APAP in a gel formulation on healthy controls using non-histaminergic and histaminergic itch induction in a single-blinded, placebo controlled trial. These new topical formulations of APAP offer anti-pruritic treatment of acute and chronic itch, along with not causing further skin irritation.
PP56: Difelikefalin significantly reduced sleep disturbance in hemodialysis patients with moderate-to-severe pruritus in an 8-week phase 2, randomized, placebo-controlled study
Sarbani Bhaduri, Robert H. Spencer, Catherine Munera, Frédérique Menzaghi
Cara Therapeutics, Inc. Stamford, CT, US
Patients with chronic kidney disease (CKD) undergoing hemodialysis often have CKD-associated pruritus (CKD-aP). More than 40% of CKD patients suffer from moderate-to-severe itch with associated poor quality of life (QoL) and sleep disturbance, which carries an increased mortality risk. Difelikefalin is a selective kappa opioid receptor agonist acting peripherally with anti-inflammatory and antipruritic effects. In a study in hemodialysis patients with moderate-to-severe pruritus, difelikefalin demonstrated significant efficacy in reducing itch intensity and improved itch-related QoL measures. Here we further characterized the impact of itch reduction with difelikefalin on sleep disturbance. Randomized (1:1:1:1) patients received an intravenous injection of difelikefalin 1.5, 1.0, or 0.5 mcg/kg, or placebo, after each dialysis, over an 8-week treatment period. The sleep disturbance subscale, part of the MOS sleep scale (MOS-S), focuses on trouble falling asleep, sleep restlessness, awakening during sleep, and time to fall asleep during the past week. The MOS-S was administered on Day 1 (predose), at Week 4, Week 8, and at the end of treatment (EOT, Day 57). This analysis focused on difelikefalin 0.5 mcg/kg dose, which was advanced into Phase 3 studies. Patients treated with difelikefalin (n=44), vs placebo (n=45), exhibited mean improvements from baseline in sleep disturbance scores of −8.6 vs 2.2 [P=0.013] at Week 4; −9.8 vs −2.2 [P=0.077] at Week 8; −13.8 vs −1.3 [P=0.006] at EOT, respectively. Difelikefalin significantly improved MOS-S sleep disturbance scores indicating a clinically sustained improvement in sleep through Week 8 that was associated with a robust and sustained reduction in itch intensity. Difelikefalin is under investigation in patients with CKD-aP in Phase 3 studies.
PP57: Difelikefalin improved quality of life (5-D Itch Scale-Domains) in hemodialysis patients with pruritus: 8-week phase 2 study results
Steven Fishbane1, Robert H. Spencer2, Catherine Munera2, Frédérique Menzaghi2
1Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY, US, 2Cara Therapeutics, Inc. Stamford, CT, US
Many patients with chronic kidney disease (CKD) undergoing hemodialysis (>40%) have moderate-to-severe pruritus, which is associated with poor quality-of-life (QoL). Difelikefalin is a selective kappa opioid receptor agonist that acts peripherally with an anti-inflammatory/antipruritic effect and negligible abuse potential to date. In a study of hemodialysis patients with CKD-associated pruritus, difelikefalin significantly reduced itch intensity (Worst Itching Intensity Numerical Rating Scale [WI-NRS]), which correlated with significant improvements in itch-related QoL. To further characterize the impact of itch reduction on patient QoL, we present 5-D Itch scale domain results. Randomized (1:1:1:1) patients received an IV injection of difelikefalin 1.5, 1.0, 0.5 mcg/kg or placebo, after dialysis, over an 8-weeks. This analysis focused on the 0.5 mcg/kg dose that was advanced into Phase 3 studies. The 5-D Itch scale domains used measured Degree, Duration, Direction, Disability, and Distribution – each on 5-point increasing severity scale.
At Week 8 difelikefalin-treated patients (n=44) exhibited clinically meaningful improvements in 5-D Itch total scores vs placebo (n=45) (−5.7 vs −2.8 LS mean [P<0.001 vs placebo]), with a significant correlation between WI-NRS and 5-D total scores (r= 0.71, P<0.0001). Improvements from baseline were reported across 4/5 subdomains in difelikefalin vs placebo groups at end of Week 8; Degree: −1.1 vs −0.5 [P<0.001 vs placebo]; Duration: −1.2 vs −0.6 [P=0.003]; Direction: −1.6 vs −0.7 [P<0.001]; Disability: −1.2 vs −0.5 [P=0.004]. Significant improvement in QoL was obtained with difelikefalin as measured by the 5-D Itch multidimensional questionnaire. Results demonstrate itch intensity reduction with difelikefalin is associated with improved QoL.
PP58: Successful treatment of dupilumab in the neurofibromatosis type 1 patient with atopic dermatitis
Kenichi Yasuda, Yozo Ishiuji, Michie Katsuta, Hiroyuki Matsuzaki, Yoshimasa Nobeyama, Takaoki Ishiji, Arihito Ota, Akihiko Asahina
Department of Dermatology, Jikei University School of Medicine, Nishishimbashi, Minato-ku, Tokyo, Japan
Background: Neurofibromatosis type 1 (NF-1) is a hereditary disorder commonly associated with cutaneous, neurologic, and orthopedic manifestations. Atopic dermatitis (AD) is a common, chronic or chronically relapsing, eczematous skin disease. Chronic, localized, or even generalized pruritus is the common manifestation of both NF-1 and AD. It was reported that NF-1 patients had a significantly higher incidence of AD compared with controls. Recently dupilumab is an anti-IL-4/IL-13 monoclonal antibody that has been available for treatment for patients with moderate-to-severe AD. It consistently showed robust efficacy and acceptable safety in adult patients with AD.
Case Presentation: A 42-year-old Japanese man had a 39-year history of AD and a 29-year history of NF-1. He had been treated with topical steroids and oral antiallergic agents, however those were ineffective. At the age of 42, dupilumab was started because he had severe pruritus, exacerbation of AD symptoms, and deterioration of quality of life (QOL). Dupilumab significantly improved pruritus, eczema area and severity index (EASI), serum eosinophil and basophil count, immunoglobulin E (IgE), and thymus and activation-regulated chemokine (TARC). In addition, dupilumab significantly improved pruritus and eczema especially around the nodules of cutaneous neurofibroma.
Conclusions: Our case report indicated that dupilumab was highly effective for NF-1 patients with AD.
PP59: A pilot observational study on application of nano size hyaluronic acids in relieving signs and symptoms on acute sensitive skin facial skin eruptions
Kam Tim Michael Chan
Specialist in Dermatology, Hong Kong Academy of Medicine, Hong Kong SAR, China
Acute sensitive facial skin eruption secondary to cosmetics and aesthetic procedures are common problems in clinic setting. Steroid phobia and anxiety of the distressed patients needed prompt effective management in gaining patient’s confidence. We reported using Nano size hyaluronic acid (N – HA) base serum rapidly relieving signs and symptoms.
Methodology: In August, 2018, five patients with diagnosis of acute sensitive facial skin eruption were recruited with consents. All reported history of sensitive skin. Patients requested treatment with steroids are excluded. The product used was called Hyalo-Oligo R; a N-HA with molecular weight of 7000 by conversion to intrinsic viscosity. Average molecular size of the hyaluronic acid is 15-25 nm. The serum contained 1% of N-HA in the form of Hyalo-Oligo R. A finger- tip size of 0.5 ml serum was gently message to the face and after 5 minutes, cotton gauze pads soaked with sterile normal saline was compressed to the treated areas for a further 10 minutes. The results measurements included patients’ subjective and physician objective assessments through a Visual Analogue Scale of signs and symptoms with documented pre and post treatment photographs.
Results: Noticeable improvement of signs and symptoms were observed with no reported adverse reactions. A significant improvement of subjective and objective mean scores of 7.5 + 1.5 and 8 + 1.0 respectively were reported (P<0.05). Post compared to pre-treatment photographs showed subsiding of erythema. Gap among cells of stratum corneum is 40-50 nm. We hypothesized N-HA was delivered through these gaps via a direct, indirect trans epidermal and trans appendageal routes through percutaneous absorption. Propose mechanisms of N-HA were blockage of barrier defects, reduction of transepidermal water loss through humectant effects, modulation of inflammation with early tissue repairs. N-HA may rapidly subside acute sensitive facial skin eruption worth further investigation.
PP60: Management of pruritus in patients with cutaneous T-cell lymphoma
Georgia Farrah, BSc, MBBS (Hons), PGDipClinDerm1, Odette Spruijt, MBChC, DipObs, FRACP, FRAChPM1, Chris McCormack, MBBS, FACD1, Odette Buelens, MN1, Miles Prince, MBBS (Hons), MD, FRACP, FRCPA, AFRCMA, MACD, FAHMS1, Smaro Lazarakis2
1Peter MacCallum Cancer Centre, Melbourne, Australia, 2Health Sciences Library RMH, RWH, PMCC and Victorian Mental Health, Parkville, Victoria, Australia
Cutaneous T cell lymphomas (CTCL) represent a rare group of primary cutaneous lymphomas. Multiple subtypes of CTCL are recognized, of which mycosis fungoides and the leukaemic variant Sézary syndrome are the most common. Pruritus is a common feature of CTCL, and is often the presenting symptom of disease. Itch is often more severe in later stages of disease, and in certain subtypes such as Sézary syndrome and folliculotropic mycosis fungoides. Itch associated with CTCL is a challenging symptom to manage, and often fails to respond to standard itch treatments such as anti-histamines. Treatments used for the management of pruritus in CTCL can be considered disease-directed, or itch-directed. Disease-directed therapies are used to control the underlying lymphoma, therefore reducing itch associated with disease. In contrast, itch-directed therapies target the symptom of pruritus. We propose a systematic review on interventions demonstrating efficacy in reducing CTCL-associated pruritus. We aim to identify all disease-directed and itch-directed therapies demonstrating clinical benefit in patients with CTCL. The lack of standardized methods used to measure and report itch in clinical studies makes comparing the efficacy of treatments across studies challenging. As a secondary aim, we will outline the various tools used in clinical studies to quantify pruritus.
PP61: Omalizumab therapy for treatment of refractory chronic spontaneous urticaria
Amruta Trivedi, Connie Katelaris
Campbelltown Hospital, Sydney, Australia
Background: Chronic spontaneous urticaria (CSU) is characterized by the sudden onset of recurrent wheals, angioedema, or both, that lasts greater than six weeks. Omalizumab is a humanized recombinant anti-IgE (immunoglobulin E) antibody with excellent safety and efficacy data demonstrated in trials involving patients with H1-antihistamine-refractory moderate-to-severe CSU.
Objectives: There is limited published data regarding omalizumab efficacy and optimal dosage in the real-life setting. The aim of this study was to observe the response patterns of patients with refractory CSU treated with omalizumab.
Methods: A retrospective analysis of 55 patients was conducted. Data included baseline characteristics, duration & severity of CSU, previous medication use, and duration & efficacy of omalizumab. Seven-day urticaria activity score (UAS7) and urticaria control test (UCT) were utilised to assess severity of CSU and clinical response to Omalizumab.
Results: The mean age of the patient population was 44.1 years, with a female majority of 87% (44/55 patients). Mean disease duration prior to omalizumab was 59.4 months. 69.1% of patients (38/55) were corticosteroid dependent prior to omalizumab, while 16.4% of patients (9/55) previously required immunosuppression. Mean UAS7 score was 30.5 prior to omalizumab commencement. At 12 weeks, 74.5% of patients (41/55) had a rapid & complete response to omalizumab, with UCT scores of 12-16. Of the remaining 14 patients, 9 patients (16.3%) had a partial response to omalizumab, with UCT scores ranging between 8-12. The remaining 5 patients (9.1%) were poor responders to omalizumab. 2 of these patients had a raised body mass index (BMI) of > 30 and have required intermittent prednisone and uptitration of omalizumab dosing.
Conclusions: Omalizumab is an effective therapy for the management of refractory CSU, with the majority of patients achieving a complete and rapid response within 12-24 weeks. Updosing may be required to achieve satisfactory outcomes in patients with an elevated BMI.
PP62: Efficacy and safety of gabapentin for uremic pruritus: A systematic review and meta-analysis of randomized controlled trials
Yuebin Zhao1, Jorge Pinilla Lopez2
1ANU Medical School, Australian National University, Australia, 2College of Engineering & Computer Science, Australian National University, Australia
Background/Objective: Uremic pruritus (UP) is a common and burdensome symptom for patients with chronic kidney disease. The aim of this study was to determine the efficacy and risks associated with gabapentin therapy for UP.
Methods: A systematic review and meta-analysis of randomized controlled trials (RCTs) that examined the efficacy and safety of gabapentin in patients with UP was performed according to recommended PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.
Results: Five RCTs involving 223 patients met the inclusion criteria. The three RCTs included 113 patients with UP who were randomized to gabapentin or placebo. The mean decrease from baseline Visual Analogue Scale (VAS) was significantly higher in the gabapentin group than in the placebo group (standard mean difference, 2.731; 95% confidence interval, 2.265 to 3.197; P<0.005). One RCT with 60 patients comparing gabapentin with pregabalin showed no statistical difference in mean VAS reduction (standard mean difference, 0.01; 95% confidence interval, −1.431 to 1.450; P>0.7). Another RCT involving 50 patients demonstrated the VAS reduction did not differ between the gabapentin group and dexchlorpheniramine group (P>0.7). A total of three patients reportedly discontinued gabapentin due to adverse effects. Common reported side effects included somnolence, dizziness, fatigue, nausea, drowsiness, diarrhoea, tremors and dry mouth.
Conclusion: Gabapentin is an effective agent with a manageable safety profile in the treatment of UP in haemodialysis patients. No difference was observed between gabapentin and dexchlorpheniramine, or between gabapentin and pregabalin.
PP63: A study of use of a sustained release preparation of pregabalin in chronic pruritus
RNT Medical College, Udaipur, India
Background: Because of known similarities between pain and itch neuromodulators such as gabapentin and pregabalin have been used occasionally in chronic pruritus, still there is need to further define their role in management of chronic pruritus.
Objective: Evaluate efficacy and safety of a sustained release preparation of Pregabalin in management of chronic pruritus.
Material and Methods: An open prospective study comprising 17 patients of chronic pruritus (pruritus of more than 6 wk duration, unresponsive to antihistamines.). Patients received 75 mg of a sustained release pregabalin daily for a 8 week period. Efficacy assessed with numerical rating scale (NRS) ranging from 0 (no pruritus) to 10 (the most intensive pruritus they can imagine) and scored at the baseline, after 1st week, 2nd week, 4th week and 8th week. Statistical analysis was carried out. The statistical significance was set at P<0.05 throughout.
Results: 14/17 patients completed the study. Mean age was (52.35±18.43) 10 /17 patients had generalized pruritus while 7 had localized pruritus of different etiologies. The improvement in mean NRS was significant at 1st week (3.42±1.55) (P value <0.0001), 2nd (4.78±1.92) (P value <0.0001) and 4th week (5.35±1.73) (P value <0.0001). No additional improvement was achieved beyond 4th week. Adverse events were minor, including drowsiness, and giddiness in 2 /14 patients. The drug was most efficacious in the uremic itch and least in cholestatic itch.
Conclusion: A single daily dose of 75 mg sustained release preparation of pregabalin may offer benefit in chronic pruritus of different causes. Although it is an open study Use of sustained release preparation of Pregabalin is a novelty here. This allows a lower dose of the drug and a more predictable clinical outcome.
PP64: Clinical characteristic of pruritus in cutaneous lupus erythematosus: Report of a multicenter, multinational cross-sectional study
Justyna Szczęch1, Dominik Samotij1, Aleksandra Dańczak-Pazdrowska2, Alice Verdelli3, Diletta Bonciani3, Emiliano Antiga3, François Chasset4, Mohammad Rafiqul Mowla5, Adriana Polańska2, Minoru Hasegawa6, Hideo Hashizume7, Laurent Misery8, Hee Joo Kim9, Aleksandra Lesiak10, Daisuke Tsuruta11, Fukumi Furukawa12, Jacek C. Szepietowski13, Marzia Caproni3, Victoria P. Werth14, Adam Reich1
1Department of Dermatology, University of Rzeszow, Rzeszow, Poland, 2Department of Dermatology, Poznan University of Medical Sciences, Poznan, Poland, 3Department of Surgery and Translational Medicine, Section of Dermatology, University of Florence, Florence, Italy, 4Sorbonne University, Department of Dermatology and Allergology, Tenon Hospital, Paris, France, 5Department of Dermatology, Chittagong Medical College, Chittagong, Bangladesh, 6Department of Dermatology, Division of Medicine, Faculty of Medical Sciences, University of Fukui, Yoshida-gun, Japan, 7Department of Dermatology, Shimada Municipal Hospital, Shimada, Japan, 8Department of Dermatology, University Hospital of Brest, Brest, France, 9Department of Dermatology, Gil Medical Center, Gachon University College of Medicine, Incheon, South Korea, 10Department of Dermatology, Pediatric Dermatology and Dermatological Oncology, Medical University of Lodz, Łódź, Poland, 11Department of Dermatology, Osaka City University Graduate School of Medicine, Osaka, Japan, 12Department of Dermatology, Wakayama Medical University, Wakayama, Japan, 13Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Wroclaw, Poland, 14Perelman School of Medicine, University of Pennsylvania and Corporal Michael J. Crescenz VAMC, Philadelphia, USA
Introduction & Objectives: Cutaneous lupus erythematosus (CLE) is an autoimmune disease encompassing a wide range of dermatologic manifestations. Pruritus is an important symptom frequently accompanying various inflammatory skin conditions and some recent data indicated, that it may be associated with autoimmune connective tissue diseases. However, studies on the prevalence and clinical characteristics of pruritus in CLE are limited.
Materials & Methods: A multinational, prospective, cross-sectional study was performed to assess the prevalence, intensity and clinical characteristic of pruritus in adult patients suffering from various subtypes of CLE. Centers from various continents with special interest and experience in CLE diagnostics and treatment were selected to cover possible racial and environmental differences: 6 centers from 3 countries in Europe (France, Italy, Poland), 6 centers from 3 countries in Asia (South Korea, Japan, Bangladesh), and 1 center from North America (USA, Pennsylvania). The study was conducted in accordance with the Data Protection Act and according to the ethical guidelines of the Declaration of Helsinki and was approved by the Ethics Committee at Wroclaw Medical University in Poland. A total of 151 patients with with active CLE lesions were included in the study. Their age ranged between 17 and 82 years (mean 49.8±15.4 y), and 115 patients (76.2%) were women. Diagnosis of CLE has been established based on clinical manifestation and skin biopsy, if necessary. Patients with other skin diseases, which might influence the achieved results, were excluded. The disease activity and damage of CLE were assessed according to the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). Pruritus severity was assessed with Numeric Rating Scale (NRS) and the 12-Item Pruritus Severity Scale. Dermatology Life Quality Index and EQ-5D questionnaire were used measure quality of life.
Results: Pruritus was present in 116 (76.8%) of patients. Most commonly itch was localized on the scalp, face (excluding ears and nose) and arms (40.5%, 36.2%, 31.9%, respectively). Pruritus was most severe at the time when the new skin lesions appeared (38.8%), while 21.6% of patients did not see any correlation between the appearance of the new skin lesions and the pruritus severity. Sensations connected with pruritis were most frequently described as burning, tingling and like ants crawling feeling (31.0%, 15.5%, 15.5% respectively), but 31.9% patients described it as “pure itch”. More than half of patients reported that pruritus was present every day and it was most frequent during the evenings (42.2%). The pruritus scoring and the CLASI activity score were correlated (P=0.047), although it did not correlate with the CLASI damage score (P=0.333). Both the maximum and average itch intensity were correlated with the activity of the systemic lupus erythematosus activity measured with the Systemic Lupus Erythematosus Disease Activity Index.
Conclusions: Pruritus is a common, but frequently overlooked symptom of CLE. Its intensity correlates with the activity of CLE, but not with the skin damage. In more than a half of patients it occurs on a daily basis. The correlation between the intensity of pruritus and the activity of the skin lesions and the systemic involvement might indicate that pruritus could be an individual indicator of both, SLE and CLE activity.
PP65: Interesting cases of pruritus from clinic
RNT Medical College, Udaipur, India
The presentation is a compendium of interesting cases of Pruritus showcasing the diverse etiology and therapeutic challenge that these cases poses to clinician
Case 1: A 62 years old diabetic female presented with intense itching of both palms. The itching was subsequently found to be of neuropathic origin secondary to carpel tunnel syndrome. The case highlights the importance of recognising localised pruritus as a sole manifestation of neuropathy. Case 2: Persistant itchy nodular lesions in cases of scabies poses some therapeutic challenge to dermatologists. The case discusses the benefit that topical calcineurin inhibitors (Tacrolimus) can provide in managing these lesions. Case 3: A 70 years old male presented with generalised itching of 3 months duration with no specific skin lesions.On DIF and Eliasa, the case was diagnosed as cutaneous pemphigoid, the itch responded to low dose methotrexate. This case highlights the importance of recognising this uncommon presentation of cutaneous pemphigoid. Case 4: A 52 year old male presented with itchy papules on exposed skin, few of the papules were having urticarial component. The skin biopsy from the lesion was consistent with papular urticaria. The patient subsequently developed follicular lymphoma. The case highlights the importance of recognising papular urticaria like lesions in an adult as a warning signal for haematological malignancies.
PP66: Study of pruritus and its impact on quality of life via a novel pruritus impact scale in chronic dermatophytosis
RNT Medical College, Udaipur, India
Background: Recalcitrant dermatophytosis is a major issue faced by dermatologist across India. Pruritus is one of the major symptoms of dermatophytosis. It adversely affect the quality of life of patients. There has been no study on different aspects of pruritus in chronic dematophytosis till date.
Objective: To characterize the burden of pruritus in patients of dermatophytosis and to evaluate its impact on quality of life using a novel Pruritus impact scale (PIS).
Materials and Methods: Non interventional, cross sectional clinico-epidemiological study comprising 100 patients of recalcitrant dermatophytosis. A self structured QOL called as Pruritic impact scale (PIS) was devised and validated using appropriate statistical tools. PIS evaluated impact of pruritus on various dimensions of q uality of life of patients. Intensity of pruritus was measured on a 10 point Numerical rating scale (NRS). The PIS and NRS scores were correlated. Global assessment of pruritus was also done in terms of frequency, distribution, diurnal and seasonal variation, sensory quality and affective dimension.
Results: Almost all patients of dermatophytosis suffered from pruritus; the frequency of pruritus was daily. Mean intensity by NRS scale was moderate (5.7±1.75). Intensity of pruritus was associated significantly with the increasing age (P value 0.026) and atopic background (P value 0.000). It also correlated well with extent of disease (% BSA involved) [r= 0.537; P value =0.00]. Mean QOL of the cohort was 1.62±2.48. Quality of life impairment measured by a novel pruritic impact scale correlated well with intensity of the pruritus as measured by NRS. [r=0.705; P value =0.00].
Conclusions: Pruritus in dermatophytosis affects the QOL of patients. Newly designed self structured pruritus impact scale (PIS) was and validated can be a versatile tool in assessment of pruritus and its impact on quality of life
PP67: Comprehensive evaluation of pruritus in patients of chronic dermatophytosis using a novel “pruritus impact scale”
RNT Medical College, Udaipur, India
Background: In recent year chronic dermatophytosis is a major issue faced by dermatologist across India. Pruritus is one of the major symptoms of dermatophytosis. It may adversely affect the quality of life of patients. There has been no study on different aspects of pruritus in chronic dematophytosis till date.
Objective: To characterize the burden of pruritus in patients of dermatophytosis and to evaluate its impact on quality of life using a self designed validated comprehensive itch questionnaire Pruritus impact scale (PIS).
Materials and Methods: Non interventional, cross sectional study comprising 100 patients of chronic dermatophytosis. A self structured QOL score was devised and validated using appropriate statistical tools. Questionnaire evaluated impact of pruritus on various dimensions of quality of life of patients. Intensity of pruritus was measured on a 10 point Numerical rating scale (NRS). The QOL and NRS scores were correlated. Global assessment of pruritus was also done in terms of frequency, distribution, diurnal and seasonal variation, sensory quality and affective dimension.
Results: Almost all patients of dermatophytosis suffered from pruritus; the frequency of pruritus was daily. Mean intensity by NRS scale was moderate (5.7±1.75). Intensity of pruritus was associated significantly with the increasing age (P value 0.026 ) and atopic background (P value 0.000). It also correlated well with extent of disease (% BSA involved) [r=0.537; P value =0.00]. Mean PIS of the cohort was 1.62±2.48. Quality of life impairment correlated well with intensity of the pruritus as measured by NRS [r=0.705; P value =0.00].
Conclusions: Pruritus in dermatophytosis affects the QOL of patients. Newly designed self structured QOL questionnaire “Pruritus impact scale” is a validated and can be a versatile tool in evaluation of different dimensions of pruritus.
PP68: The effect of itch self-treatment on quality of life for community-dwelling older adults
Julia C. Paul, PhD, RN, ACNS-BC, CCRN, CWS, NP1, Judith Fouladbakhsh, PhD, RN, PHCNS-BC, AHN-BC, CHTP1, Deirdre Wallace-Steele, MSN, RN2, Husain Yarandi, PhD3
1School of Nursing, Oakland University, Rochester, MI, USA, 2Ascension Health, Madison Heights, MI, USA, 3College of Nursing, Wayne State University, Detroit, MI, USA
Purpose/Background: Itch is a frequent complaint that significantly affects the quality of life (QOL) of older persons living in the community. Prevalence of itch among individuals age 60 and older is estimated to be as high as 41% with concurrent negative effects on QOL that include disturbed sleep, increased anxiety and depression, and altered social relationships. Self-treatment can improve QOL and generally has advantages including convenience, positive clinical and financial benefits, and resource sparing for health care agencies. As many as 80% of older persons use self-treatment, but their self-treatment of itch is not well described in the literature. The purpose of this study is to determine the relationship of itch self-treatment to quality of life in community-dwelling older adults.
Methods: This exploratory-descriptive study is in progress to examine the prevalence of itch and self-treatment approaches in a community-based convenience sample of adults aged 60 years and older (n=200) in a metropolitan geographic area. Instruments used include the Pruritus Severity Scale and the SF-36 to determine effects of itch prevalence and severity on QOL. The Self-Treatment of Symptoms Questionnaire developed by the researchers will provide information on conventional biomedical and complementary/integrative approaches used to manage the symptom of itch. Study outcomes include prevalence, intensity, QOL and self-treatment approaches.
Results: Data collection is currently in progress with one fourth of the proposed participants recruited at this point in time. Descriptive and correlational analysis will be conducted using Statistical Package for Social Sciences (SPSS) 26.0.
Conclusions: This study will identify the prevalence and severity of itch and relationship to overall QOL among older adults living in the community. Self-treatment approaches selected by this population will be identified illuminating the choices made by those burdened with this bothersome symptom. Relationship of self-selected approaches, including over-the-counter and complementary/integrative therapies, to QOL will be determined.
PP69: Teaching the body placebo effects for itch through behavioral conditioning: Can we do this when people know about it?
Stefanie H. Meeuwis, MSc1, Henriët van Middendorp, PhD2, Gustavo Pacheco-Lopez, PhD3, Maarten K. Ninaber, MD, PhD4, Adriana P.M. Lavrijsen, MD, PhD5, Nic van der Wee, MD, PhD6, Dieuwke S. Veldhuijzen, PhD7, Andrea W.M. Evers, PhD8
1Leiden University, Faculty of Social and Behavioural Sciences, Institute of Psychology, Health, Medical and Neuropsychology Unit, Leiden, The Netherlands; Leiden Institute for Brain and Cognition, Leiden University Medical Center, Leiden, The Netherlands, 2Leiden University, Faculty of Social and Behavioural Sciences, Institute of Psychology, Health, Medical and Neuropsychology Unit, Leiden, The Netherlands; Leiden Institute for Brain and Cognition, Leiden University Medical Center, Leiden, The Netherlands, 3Metropolitan Autonomous University, Campus Lerma, Health Sciences Department, Lerma, Edo Mex, Mexico; Leiden University, Faculty of Social and Behavioural Sciences, Institute of Psychology, Health, Medical and Neuropsychology Unit, Leiden, The Netherlands, 4Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands, 5Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands, 6Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands, 7Leiden University, Faculty of Social and Behavioural Sciences, Institute of Psychology, Health, Medical and Neuropsychology Unit, Leiden, The Netherlands; Leiden Institute for Brain and Cognition, Leiden University Medical Center, Leiden, The Netherlands, 8Leiden University, Faculty of Social and Behavioural Sciences, Institute of Psychology, Health, Medical and Neuropsychology Unit, Leiden, The Netherlands; Leiden Institute for Brain and Cognition, Leiden University Medical Center, Leiden, the Netherlands; Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands
Background: Studies show that it may be possible to reduce allergic symptoms by behaviorally conditioning the effects of antihistamines. These findings may extend to histamine-induced itch in general. Traditionally, these types of effects are elicited by concealed placebo administration, and the effects of open-label conditioning (i.e. being told about the involved learning mechanisms) are not yet clear. Demonstrating the efficacy of (open-label) conditioning may lead towards new treatment possibilities for allergies and skin conditions.
Methods: A two-phase randomized conditioning paradigm was used. In a learning phase, a to-be-conditioned (neutral) stimulus (CS; a distinctively-tasting beverage) was repeatedly combined with an unconditioned stimulus (UCS; the antihistamine levocetirizine). In the testing phase, the CS alone was presented. Ninety-two participants were assigned to 1) an open-label conditioned group, 2) a closed-label (i.e. concealed) conditioned group, 3) a conditioned-not-evoked control group, or 4) a placebo control group. At baseline and on the final testing day, itch was induced through histamine iontophoresis.
Findings: Participants in the combined conditioned groups reported marginal lower itch than the combined control groups (P=0.076), but no differences between separate groups were found (P-values ≥0.23). Heart rate reduced consistently during evocation for the control groups, and less consistently for the conditioned groups (P=0.031).
Discussion: Limited evidence is provided for the efficacy of behavioral conditioning of antihistamines for itch. There was no evidence that the open-label procedure resulted in less efficacious conditioning for itch in comparison to closed-label conditioning. More research is needed to examine under which circumstances placebo effects elicited by (open-label) conditioning may influence itch.
PP70: Do placebo and nocebo effects generalize from pain to itch?
LingLing Weng1,2, Kaya J. Peerdeman1,2, Antoinette I.M. van Laarhoven1–3, Andrea W.M. Evers1–3
1Health, Medical and Neuropsychology Unit, Faculty of Social and Behavioral Sciences, Leiden University, Leiden, The Netherlands, 2Leiden Institute for Brain and Cognition (LIBC), Leiden University, Leiden, The Netherlands, 3Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands
Both itch and pain are associated with reduced quality of life, particularly when chronic. Both of them can be effectively decreased by placebo effects and increased by nocebo effects via conditioning and verbal suggestion. Generalization of nocebo effects from pain to itch may play a role in comorbidity across conditions, whereas generalization of placebo effects from pain to itch can be beneficial in chronic itch treatment. Whether placebo and nocebo effects generalize from pain to itch has however never been experimentally studied. The aim of the present study is to investigate whether placebo and nocebo effects can generalize from pain to a different type of pain and to itch, in healthy participants (n=82). The data collection is ongoing currently. Participants were randomized to a placebo group or a nocebo group. First, in the learning phase, expectations were induced by verbal suggestion (“heat pain intensity will decrease/increase due to the activation of this device”) and conditioning (by decreasing/increasing heat stimulus intensity when a TENS device is supposedly switched on), and tested in heat stimuli. To test generalization of these effects to pressure pain and itch, pressure stimuli and cowhage spicules were applied subsequently, consecutively, when the TENS device was supposedly on or off. This study could provide a novel perspective on the role that generalization may play in physical symptoms (e.g., itch and pain).
PP71: Pruritus strongly reduces quality of life in PBC patients – real life data from a large national survey
Miriam Düll1, Stefanie Hönig1, Barbette Herder2, Achim Kautz2, Christian Trautwein3, Andreas E. Kremer1
1Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany, 2Leberhilfe Project gUG, Köln, Germany, 3Department of Medicine 3, RWTH-University Aachen, Aachen, Germany
Background & Aims: Pruritus is a common symptom in patients with primary biliary cholangitis (PBC). Epidemiological data is however scarce and validated questionnaires investigating quality of life (QoL) have not been performed in larger cohorts of PBC patients.
Methods: We developed and validated a detailed questionnaire with a total of 89 questions. QoL in regard to pruritus was measured by the validated ItchyQoL questionnaire. Itch intensity was rated on a numeric rating scale (NRS). Data is given as mean±SD.
Results: In total 577 PBC patients were included this large German national survey, sex ratio was 11:1 (92% women, 8% men). The mean age was 53,2(±14,6) years with PBC being diagnosed in average 6,9 (0-37) years ago. Reported symptoms included fatigue (82%), pruritus (56%), joint pain (62%) and abdominal pain (49%) while only 8% of patients stated to be asymptomatic. More than 70% of patients reported on a reduced QoL. Two third of patients with pruritus reported to suffer since many years. Mean itch intensity during the last four week was rated 4.2 (49.3% moderate, 9.1% severe intensity), while worst itch reached a level of 5.5 (51.4% moderate, 25.8% severe intensity). The QoL of affected patients quantified by ItchyQoL closely correlated with mean and worst itch intensity (Spearman correlation coefficient: r=0,46; P<0.001; r=0,42; P<0.001). Self-management of patients to improve pruritus consisted among others of topical treatment, cold water, rubbing, use of scratch tools, and cold/ice pads. Medical treatment was performed only in 19% of patients with the majority receiving antihistamines. Other treatments consisted of cholestyramine, opioid antagonists, rifampicin and fibrates.
Conclusions: The prevalence of pruritus in the real life setting is high. Pruritus significantly reduces the QoL with the majority of patients being not or only inadequately treated. Patients are forced to perform self-management. Pruritus represents a major unmet clinical need in PBC.
PP72: Psoriatic patient perspective: Extent and impact of pruritus on well-being
Karen Smith, JD1, Mary Spellman, MD1, David Luery2, Michael Rosenberg3, Mark Lebwohl, MD4
1Menlo Therapeutics Inc., San Francisco, CA, USA, 2Tucson, AZ, USA, 3Plymouth Meeting, PA, USA, 4Icahn School of Medicine at Mount Sinai, New York, NY, USA
Background: Pruritus has a negative effect on quality of life. Although pruritus is reported by 60%-90% of patients with psoriasis, the association between pruritus and psoriasis is not well characterized.
Objectives: This online market research study evaluated the impact of pruritus on patients with psoriasis.
Methods: Potential respondents were invited to complete an online screening questionnaire. Qualified respondents were adults with psoriasis who had experienced itching for ≥3 weeks and scored their worst itch in the past week as ≥4 on a 0 (none)-to-10 (worst itch imaginable) scale. The main study questionnaire explored the relationships between severity of psoriasis, degree of pruritus (including intensity, location, and duration), and current treatments.
Results: Of the patients who self-identified as having psoriasis during screening (n=781), 70.3% reported that they experienced moderate, severe, or very severe itching. 304 respondents were included in the main study (worst itch score ≥4). A majority experienced severe pruritus, regardless of psoriasis severity. Most respondents reported experiencing pruritus regularly since they were diagnosed with psoriasis. Fifty-percent experienced psoriasis for ≥5 years and 53% experienced pruritus ≥5 years. While the most common locations with lesions were also the top sites of pruritus, 46.9% of respondents reported itch at sites without plaques. Almost half of respondents experienced pruritus for ≥6 hours a day. Pruritus frequently affected activities of daily living, including sleep, in 44.6% of respondents. Seventy-three percent ranked pruritus as one of their 3 most troublesome symptoms, but less than half of respondents reported their itch was well controlled with their psoriatic treatment. When asked to choose, almost 40% would rather eliminate itch over lesions.
Conclusions: Patients with psoriasis, regardless of severity, commonly report pruritus as a bothersome symptom that is not adequately controlled. The results of this study support the need to address pruritus in patients with psoriasis.
PP73: Characteristics of pruritus in bullous pemphigoid and impact on quality of life: A multicenter prospective study
Clémence Briand1, Greta Gourier1, Florence Poizeau2, Lamia Jelti3, Marie Bachelerie4, Gaëlle Quéreux5, Geraldine Jeudy6, Marie Acquitter7, Saskia Oro8, Frederic Caux9, Anne Sophie Darriguade10, Diane Heron Mermin10, Claire Abasq1, Laurent Misery1, Emilie Brenaut1and the Bulles Group of the French Society of Dermatology
1Department of Dermatology, Brest University Hospital, Brest, France, 2Dermatology Department, Rennes University Hospital, Rennes, France, 3Dermatology Department, Rouen University Hospital, Rouen, France, 4Dermatology Department, Clermont Ferrand University Hospital, Clermont Ferrand, France, 5Dermatology Department, Nantes University Hospital, Nantes, France, 6Department of Dermatology, Dijon University Hospital, Dijon, France, 7Department of Dermatology, CHIC, Quimper, France, 8Dermatology Department, Henri Mondor Hospital, Créteil, France, 9Department of Dermatology, Avicenne Hospital, Bobigny, France, 10Department of Dermatology, Bordeaux University Hospital, Bordeaux, France
Pruritus is a main symptom in bullous pemphigoid (BP) but no data are available in the literature concerning its characteristics. This multicenter prospective observational study (15 French hospitals) included patients with newly diagnosed and pruritic BP. Patients with cognitive impairment were excluded. Different questionnaires were completed by the doctor on the activity of the disease (BPDAI questionnaire) or by the patient on the quality of life (ABQOL questionnaires, ItchyQol) and the pruritus characteristics (Brest questionnaire and 5D Itch Scale). 60 patients were included, with a mean age of 77.4 years (43-98) and a sex ratio of 1. Pruritus had been present for several months (52%) or weeks (30%), with an average pruritus intensity of 5.2/10. Tingling sensations were present in 72.4% of patients and burns in 68.9% of them. Impaired quality of life was explained by the need to scratch (85%), sleep disorders (56%), pain (42%) and shame (38%). 30% of patients reported scratching “very often” and 52% “often”. The pruritus occurred in erythematous skin (83%), on bullous lesions (65%) but also on healthy skin (65%). The average ItchyQol score was 56.2/110 and the average 5D score was 16.5/25. In univariate analysis, the severity of pruritus was not related to age, sex, BP activity score, eosinophilia, or BP230 and BP180 antibody levels. The intensity of pruritus is average in BP, comparable for example to psoriasis. The associated symptoms and aggravating factors are similar to those found for other skin diseases. Impairment of quality of life is important and is explained primarily by pruritus. The pathophysiology of pruritus is still unknown but seems to be related to cytokines such as interleukin 17. This first study of pruritus in BP shows that pruritus is poorly tolerated, although not as intense as expected, and is the leading cause of impaired quality of life.
PP74: A Systematic review of drug induced pemphigoid
Matthew J. Verheyden¹, Asli Bilgic, MD2,3, Dédée Murrell, MA, BMBCh, FACD, FAAD, FRCP, MD2,4
1School of Medicine, University of Notre Dame, Sydney, Australia, 2St George Hospital, Department of Dermatology, Sydney, Australia, 3Antalya Research and Training Hospital, Antalya, Turkey, 4Faculty of Medicine, University of New South Wales, Sydney, Australia
Pemphigoid is an autoimmune subepithelial inflammatory disease that is characterised by the generation of pruritus followed by urticarial plaques and finally bullae on the skin and mucosa. Drug-induced pemphigoid (DIP) is a term used to describe instances of pemphigoid demonstrating clinical, histological, or immunopathological features identical or similar to those of the idiopathic form of the disease, induced by the systemic ingestion, or topical application of particular drugs. In this report, we concisely describe the epidemiology, genetic implications, aetiology, pathophysiology of the drug reaction, followed by a comprehensive discussion of the drugs implicated in drug-induced pemphigoid.
Methods: We performed a comprehensive search of the literature according to the PRISMA guidelines using the PubMed, MEDLINE, EMBASE and Cochrane Library, Scopus, ProQuest, and Web of Science databases. Search criterion used to facilitate this were: [“Pemphigoid, Bullous/chemically induced*” MeSH]. The search was limited those published before the 13th January 2019. Case-control studies and case reports were identified. Further studies were identified through manual evaluation of the references included in the retrieved publications.
Results and Conclusion: At present, over ninety medications have been associated with inducing pemphigoid. An appreciation of the medications associated with pemphigoid enables clinicians to identify potential cases of DIP earlier and cease the offending medication. With contemporary studies continuing to investigate genetic susceptibility, underlying mechanisms and natural history of DIP we are likely to develop a greater understanding of those predisposed to the condition, and the medications that may place the certain groups at risk.
PP75: Pembrolizumab associated itch
Subashini Gnanendran, Andrew Miller
The Canberra Hospital Dermatology Department, Australian Capital Territory, Australia
The introduction of immune checkpoint inhibitors in the treatment of metastatic melanoma has been a new and exciting paradigm for both patients and providers. As the use of these novel agents has increased, the cutaneous toxicities associated with these medications have risen in parallel. Pembrolizumab is a humanised monoclonal anti-programmed cell death 1 (PD-1) antibody that has been shown to improve response rates in melanoma previously unresponsive to targeted therapy. Bullous pemphigoid (BP) has been reported to be a rare cutaneous side effect of anti PD-1 antibodies. The exact pathogenesis of anti PD-1 associated BP has not been demonstrated. We report the case of a 74-year-old Caucasian male who presented with a 3 month history of worsening pruritis eventuating to blistering skin lesions after the ninth cycle of Pembrolizumab. Examination and histopathological evaluation confirmed the diagnosis of bullous pemphigoid. Through this case we review the literature on cutaneous toxicities of immune checkpoint inhibitors and predicaments in diagnosis and early management.
PP76: Triggering factors in sensitive skin from the worldwide patient’s point of view: a systematic literature review and meta-analysis
Emilie Brenaut1,2, Thomas Barnetche3,4, Christelle Le-Gall Ianotto1, Alain-Claude Roudot1, Laurent Misery1,2, Anne-Sophie Ficheux1
1University Brest, LIEN, F-29200 Brest, France, 2Department of Dermatology, University Hospital, Brest, France, 3Department of Rheumatology, Bordeaux University Hospital, Bordeaux, France, 4FHU ACRONIM, Bordeaux University Hospital, Bordeaux, France
Sensitive skin (SS) is a syndrome defined by the occurrence of unpleasant sensations in response to stimuli that normally should not provoke such sensations. These unpleasant sensations cannot be explained by lesions attributable to any skin diseases. In most patients, symptoms occur within one hour following exposure to trigger factors and may persist for minutes or even hours. Numerous triggering factors (physical, chemical or psychological) are suspected and described in articles. The aim of this article was to perform a systematic literature review to collect data on the triggering factors involved in SS and to then perform a meta-analysis. Among the 490 articles identified, thirteen studies were included in the systematic literature review. Seven studies were made by phone, 4 by internet, 1 in face to face and 1 by post. Studies took place in different countries: Europe (8 studies), USA (3), Japan (1), Corea (1). Subjects were classified into groups, SS or no sensitive skin (NSS), and triggering factors were researched through responses to different questions. SS could be triggered by numerous factors. The most important triggering factor was cosmetics, with an odds ratio (OR) equal to 7.12 [3.98-12.72]. Other triggering factors were physical (variations in temperature, cold, heat, wind, sun, air conditioning, wet air, and dry air), chemical (water and pollution) or psychological (emotional) factors. After cosmetics, the most important factors were wet air, OR 3.83 [2.48-5.91]; air conditioning, OR 3.60 [2.11-6.14]; heat, OR 3.5 [2.69-4.63]; and water, OR 3.46 [2.56-4.77].
PP77: Efficacy and tolerability of phototherapy with light-emitting diodes for sensitive skin: a pilot study
Haitham Sonbol1, Emilie Brenaut1,2, Emmanuel Nowak3, Laurent Misery1,2
1Department of Dermatology, University Hospital, Brest, France, 2University Brest, LIEN, Brest, France, 3CHRU Brest, INSERM CIC 1412, Brest, France
Sensitive skin (SS) syndrome is defined by the occurrence of unpleasant sensations in response to stimuli that should normally not induce such sensations. It is generally recommended to limit the use of cosmetics or to use products with a high tolerability. Phototherapy by light-emitting diodes (LEDs) is increasingly being used in dermatology for various inflammatory skin disorders with success and good tolerability. Our objective is to obtain preliminary data on the effectiveness of phototherapy with LEDs for alleviating SS symptoms and increasing tolerance in subjects with SS that is not associated with other facial skin disorders. This monocentric pilot study included 30 subjects with SS who had a Sensitive Scale-10 score ≥40. The treatment consisted of three-minutes of red LED light exposure twice a week until success with a maximal treatment length of 8 weeks. Success was defined by a 60% decrease in the SS-10 score compared to the baseline. Thirty subjects were included; 83% were women, and the mean age was 28.9 years old. Two patients were considered lost to follow-up. Twenty-eight patients (93.3%, 95% CI 77.9 to 99.2%) achieved the primary outcome. Success was achieved in 77% of subjects in 6 sessions or fewer. The mean (SD) SS-10 scores were 54.7 (12.1) at inclusion, 14.4 (6.0) at the last session and 13.9 (7.5) 2 months after the last session, suggesting that the benefits persist for a few weeks. Two side effects were reported: both were allergic reactions to the nickel contained in the protective goggles.
PP78: A prospective study on the characteristics of sensitive skin patients attending a private clinic-based setting in Hong Kong
Kam Tim Michael Chan1, Amy Ho Nam Cheung, PhD2
1Specialist in Dermatology, Hong Kong Academy of Medicine, Hong Kong SAR, China, 2University of Edinburgh, United Kingdom
A prospective study was carried out during 1st May 2018 to 30 April 2019 in a private clinic located in the center of Kowloon district; Hong Kong. The objectives were to find out the proportion of clinically diagnosed sensitive skin in new clinic attendees by a dermatologist and to study their demographic and clinical characteristics.
Method: All new clinic patients during this period were invited to complete a Chinese version of the ten-item Sensitive Skin Scale-10 (SS-10) before the consultation, while the clinical diagnosis and past medical history were recorded during consultation. The participation was voluntary. Patients diagnosed clinically with sensitive skin were followed up with counselling and emollients and their SS-10 scores were recorded again during the second visit.
Results: Out of the 1,111 recruited patients, 84 (7.56%) were diagnosed with sensitive skin. A female to male gender ratio of 2.65 to 1 was found. Among the diagnosed individuals, 84% were within the age 19 to 49, while 24%, 13%, 10% reported to have a past history of allergic contact dermatitis, atopic dermatitis, seborrheic dermatitis respectively. Face was the commonest site (60%) especially in female (92% versus 8% in male) (P<0.05) followed by genital organs (16%), the scalp (13%) and the hands (8%). Skin irritation is the most frequent presented complaint. All sensitive skin patients scored above 20 in the SS-10 (average score=41.38). Most sensitive patients showed improvements and scorings in follow up. We concluded that sensitive skin is a common disease presented in Hong Kong private dermatology clinic and SS -10 is a vital tool in management. Comparing the SS-10 scores in individuals with and without sensitive skin provides valuable data in developing the cutoff value through plotting the Receiver Operating Characteristic (ROC) curve in future clinical studies.
PP79: Application of receiver operating characteristic (ROC) curve to determine the diagnostic ability of a validated Ten - Item Questionnaire (SS – 10) in estimating the prevalence of sensitive skin in Hong Kong population
Kam Tim Michael Chan1, Amy Ho Nam Cheung, PhD2
1Specialist in Dermatology, Hong Kong Academy of Medicine, Hong Kong SAR, China, 2University of Edinburgh, United Kingdom
Sensitive skin is a complex global skin condition. Patients mainly presented with subjective neurological symptoms made clinical diagnosis and large-scale epidemiological studies across populations difficult. Prevalence of sensitive skin across populations vary from 13% in Chinese cities to a three-fold higher in American and European countries. While a well-validated self-report instrument is lacking, self-report of sensitive skin relies on subjective estimation and perception which attributes to individual differences. Our study aims to develop a cutoff value using the Receiver Operating Characteristics curve (ROC) in clinical sample in Hong Kong and examine sensitive skin prevalence in a community sample across five districts of Hong Kong.
Method: The first group of participants consisted of a total of 1,111 new clinic attendees in a local clinic in Kowloon area of Hong Kong. The second group of data was collected from 500 community samples across 5 areas of Hong Kong, with the geographic characteristics ranging from highly to less densely populated. Participants were invited to fill in a questionnaire which contained their demographic information as well as the 10-item version of Sensitive Skin Scale (SS-10). For the clinical sample, a dermatologist diagnosed all the participants for sensitive skin and identified 84 cases (7.56%) of true sensitive skin and 1027 as true negative cases with their respective SS -10 scores.
Results and Conclusion: The Area Under the Curve (AUC) of 0.866 of the ROC curve suggested a good diagnostic ability of SS-10 in clinical population in Hong Kong. A cutoff value of 25.5 with a sensitivity of 91.7% and specificity of 75.5% gave rise to a sensitive skin prevalence of 11.4% in the community sample which is coherent with that in Mainland China. The study may have significant clinical and epidemiological implications for SS-10 to be a standardized and cost-effective screening tool in Asian populations.
PP80: Pruritus and pain with the most frequent skin diseases: Data from the french study “objectifs peau”
Flavien Huet1–3, Charles Taieb1, Florence Corgibet1,4, Emilie Brenaut1–3,5, Marie-Aleth Richard1,5,6, Laurent Misery1–3,5
1Société Française de Dermatologie (SFD), Paris, France, 2Service de dermatologie, CHRU de Brest, Brest, France, 3University Brest, LIEN, Brest, France, 4Fédération Française de Formation Continue et d’Evaluation en Dermatologie-Vénéréologie (FFFCED), Paris, France, 5Collège des Enseignants en Dermatologie de France (CEDEF), Paris, France, 6Service de dermatologie, CHU Timone, Assistance Publique Hôpitaux de Marseille, Marseille, France
Background: Few population-based studies have assessed the prevalence of pruritus and pain with the most frequent skin diseases.
Objective: To assess the frequency of pruritus and pain with the five most frequent dermatoses using epidemiological data from the Objectifs Peau survey, as well as data on their psychological impact.
Methods: A sample of 20,012 individuals was created using the usual quota method to be representative of people in the French population over 15 years of age. People answered a web questionnaire addressing various items, including demographic and socio-professional data, lifestyle, skin phototype, skin functional signs, skin type, skin history and psychological impact. The quality of life was assessed by the EQ-5D scale, in particular, by its analog scale. We only retained patients who reported only one skin disease.
Results: Pruritus was reported in 72.45% of patients with atopic dermatitis, 67.86% with contact eczema, 65.38% with urticaria, 51.34% with psoriasis, 48.55% with acne, 43.24% with mycoses, 44.35% with warts and 36.51% with rosacea. For skin pain, the results were 11.22%, 10.71%, 13.65%, 27.59%, 10.40%, 16.13% and 7.69% for atopic dermatitis, contact eczema, urticaria, psoriasis, acne, mycoses, warts and rosacea, respectively. The quality of life, measured by EQ-5D, was significantly more reduced in patients with acne than in those with other skin diseases.
Limitations: Questionnaire-based study.
Conclusion: The main interest of this study was the assessment based on a large and representative sample of the population. Pruritus and (to a lesser extent) pain were found to be common not only in classic pruritic skin diseases but also in acne, rosacea or warts. These symptoms must be systematically sought, especially since new therapeutic possibilities are emerging.
PP81: Psychosomatic aspects of pruritic dermatoses (Psoriasis, Eczema, Atopic Dermatitis). Case reports
Nina O. Otarashvili2, Natia A. Khutsishvili1,2, M.B. Jaiani1, T.E. Gviniashhvili1,2
1Tbilisi State Medical University, Tbilisi, Georgia, 2Curatio Clinic, Tbilisi, Georgia
Background: Chronic itchy skin diseases are common in a dermatologist’s every day practice. Varied lesions with different distribution, annoying pruritus appended with stress are of main complaints faced by a clinician. Meanwhile, stress may be an added concern to the skin symptoms, but inversely it can be an exacerbating factor of cutaneus disorders. Because skin problems are hard to hide and itch just aggravates the situation, such chronic conditions lead patients to psychological distress.
Objective and Aim: To outline the importance of collaboration of a dermatologist, a psychologist and a neurologist while dealing with pruritic skin disease, particularly the chronic one.
Methods: A review of the data from several studies addressing psychological distress in the patients with psoriasis, eczema, atopic dermatitis with one case study for each condition.
Results/Conclusions: Depression, anxiety, suicidal thoughts and other mental disturbances are frequent accompanying factors of chronic itchy dermatological conditions. All patients involved in the study had better results with Standard dermatological treatment in combination with Psychotherapy. When presented to such disorders the dermatologist ought always to evaluate the level of psychological distress in patients and take into account the possible good outcome of the involvement of the psychology specialists.
PP82: Itch in superficial dermatophytoses: clinical study based on epidemic-like scenario in India
Shyam B. Verma1, Resham Vasani2, Radomir Reszke3, Łukasz Matusiak3, Jacek C. Szepietowski3
1Nirvan Skin Clinic, Vadodara, India, 2Bhojani Clinic, Mumbai, India, 3Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Wroclaw, Poland
Itch is an integral part of clinical picture of superficial dermatophytoses which constitute a common and growing problem in India. The study aimed to evaluate the prevalence, intensity and clinical characteristics of itch in superficial dermatophytosis. The data concerning disease history and clinical type of dermatophytosis was obtained. The presence and various characteristics of itch were documented. Numerical Rating Scale (NRS) was utilized to assess the worst intensity of itch during the last 3 days and during the course of the disease. 4-Item Itch Questionnaire (4IIQ) was utilized to assess itch extent, intensity, frequency and associated sleep impairment, while quality of life (QoL) impairment was assessed via Dermatology Life Quality Index (DLQI). Ninety-nine patients with direct microscopic confirmation of dermatophytosis were included in the study. In 46.5% of subjects, the coexistence of tinea corporis and tinea cruris was noted, followed by tinea cruris (25.2%) and tinea corporis (13.1%). The majority of patients reported itch in the last 3 days (99%) and complained of itch limited to skin lesions (89.9%). According to NRS, the mean intensity of worst itch in the last 3 days was 6.8±1.8 points. Severe and very severe itch was reported by 74.7% of patients. Itch was an isolated sensation in 34.3% of subjects, while 46.9% reported associated burning sensation. Itch was frequently exacerbated by sweating, hot temperature and wearing tight clothes. Difficulties in falling asleep and sleep awakenings were reported by 34.3% and 54.6% of subjects, respectively. Itch negatively influenced the well-being of patients and its intensity correlated with QoL impairment. In conclusion, itch is an important symptom in superficial dermatophytoses and is associated with negative impact on sleep and carries a significant psychosocial burden. Acknowledging its presence is necessary in a holistic approach to these patients.
PP83: A rare association and sequential development of pyoderma gangrenosum and livedoid vasculitis
Min Seok Ham, Soo Hong Seo, Young Chul Kye, Hyo Hyun Ahn
Department of Dermatology, College of Medicine, Korea University, Seoul, Republic of Korea
Leg ulcers may be associated with various diseases. But the diseases are clinically and pathologically different. Among them, Pyoderma gangrenosum is a neutrophilic dermatosis that is often diagnosed clinically. It typically manifests as rapidly progressing, well-defined, painful ulcerations with ragged, violaceous, and undermined edges. Otherwise, Livedoid vasculitis is a rare, chronic, recurrent disease lead to local skin ulcer formation. In the acute stage, ulcerations develop with necrotic areas as the result of cutaneous ischemia. Association of the two different disease entities is rare and very few cases have been reported. We report case of 64-year-old female who presented with well-defined multiple ulceration lesions on the both lower leg which diagnosed with pyoderma gangrenosum. After systemic steroid therapy, the lesions improved. Then, the patient presented with asymptomatic crusted ulceration and atrophied blanches on both lower leg 3 years later. In the laboratory test, antiphospholipid antibody and autoantibodies test were negative and histopathological study revealed fibrin thrombi in superficial dermal vessels. Under the diagnosis of livedoid vasculitis, treatment was initiated with oral pentoxifylline and aspirin. Skin lesions improved and there were no signs of recurrence so far. Herein we report a rare case of association and sequential development of pyoderma gangrenosum and livedoid vasculitis.
PP84: Dry skin-associated pruritus in ulcerative colitis patients: Implication of unnoticed complication
Shiho Iwamoto1,2, Mitsutoshi Tominaga1,3, Yayoi Kamata1, Tomohiro Kawakami2, Taro Osada2, Kenji Takamori1,3,4
1Juntendo Itch Research Center (JIRC), Institute for Environmental and Gender Specific Medicine, Juntendo University Graduate School of Medicine, Japan, 2Division of Gastroenterology, Juntendo University Urayasu Hospital, Japan, 3Anti-Aging Skin Research Laboratory, Juntendo University Graduate School of Medicine, Japan, 4Department of Dermatology, Juntendo University Urayasu Hospital, Japan
Ulcerative colitis (UC) is chronic relapsing inflammatory disease with unclear etiology. We have frequently treated UC patients complaining of pruritus and skin dryness, but clinical and scientific evidence for this condition is lacking. We examined the incidence of pruritus complicated with dry skin in UC patients during the winter season in Japan. The correlation between pruritis severity and UC activity level was analyzed statistically. Pruritus in 63 UC out-patients and 39 healthy volunteers (HV) was assessed using visual analogue scale (VAS) score. Some 70% of UC patients reported mild to very severe pruritus. The mean VAS score was significantly higher in UC that HV group. Skin barrier condition was examined on forearm skin by measuring transepidermal water loss (TEWL) and stratum corneum (SC) hydration. TEWL value was higher in UC than HV, whereas SC hydration was similar in both. Moreover, disease activity in UC patients was classified by Total Partial Mayo Index Score. VAS score in mild to moderate active phase of UC patients was significantly higher than that in remission phase. These findings suggest that UC patients frequently show a symptom of pruritus with dry skin. This may provide predictive and therapeutic implications for application to UC.
PP85: Papulosquamous eruptions on sun exposed areas in an old patient taking anti-hypertensive medication
Sung Jin Park, Min Seok Ham, Ji Hyuck Hong, Dae Yeon Kim, Soo Hong Seo, Young Chul Kye, Hyo Hyun Ahn
Department of Dermatology, College of Medicine, Korea University, Seoul, Republic of Korea
Drug-induced cutaneous eruption is one of the commonly encountered complaints at clinics. It ranges from common nuisance eruptions to rare, life-threatening diseases accompanying systemic symptoms. Among many types of drug eruption, papulosquamous type includes drug-induced cutaneous lupus, which often accompanies systemic symptoms like arthralgia, with frequent positive immunologic test results. Classic drug-induced lupus erythematosus is characterized by systemic disease with lack of cutaneous involvement, whereas anti-SSA antibody positive subset of drug-induced lupus is characterized primarily by cutaneous disease. The most common drugs associated with this subtype are anti-hypertensive drugs and systemic antifungal drugs. A 72-year-old female presented with itchy erythematous hyperkeratotic plaques on face, upper trunk and upper extremities, first appearing a year ago. She was under many medications including anti-hypertensive drug. We took a skin biopsy, which showed interface dermatitis with vacuolar alterations, as well as superficial perivascular inflammatory cell infiltration, which was suggestive of acute cutaneous lupus erythematosus. Further immunologic laboratory test was done afterwards, which turned out to be fluorescent antinuclear antibody with anti-SSA antibody positive. Patient refused additional evaluation and moved to another clinic. At there, after the oral hydroxychloroquine therapy with discontinuation of anti-hypertensive drug, the lesion gradually improved. The patient had dry eye and dry mouth, but didn’t have other systemic symptoms like polyarthralgia. Despite cause not clear, clinical improvement following discontinuation of drug and immunologic lab result shows the possibility of patient’s lesion as cutaneous manifestation of drug-induced lupus. Hence, thorough review of possible causative drug may be crucial for any patient with cutaneous eruption visiting the clinic.
PP86: Using low-level laser therapy for treatment of itch and hair loss in a patient with scarring alopecia
Nooshafarin Kazemikhoo1,2, Niluka Dilrukshi Paththinige1,3, Dedee Murrell1,3
1Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia, 2Skin and Stem cell Research Centre, Tehran University of Medical Sciences, Tehran, Iran, 3Department of Dermatology, St. George Hospital, Sydney, NSW, Australia
Background: Low-level laser therapy (LLLT) has anti-inflammatory effects, stimulates cellular activity and promotes tissue regeneration. Laser light may induce the proliferation of follicular stem cells and follicular angiogenesis.
Case Report: A 77-year-old lady with polymyalgia rheumatica, on leflunomide 20 mg daily and prednisolone 3 mg daily presented with itchy erosions on scalp with scarring alopecia and excoriated papules over her body since 2012. A scalp biopsy showed fibrosing alopecia with negative direct immunofluorescence. Lupus and bullous pemphigoid serology were negative. Initially she was treated with Plaquenil, topical Diavobet, clobetasol, UVB therapy and acitretin without much response. Involved areas of the scalp were treated 2 times a week for 10 minutes with CL2 matrix emitter (Azor-2K Russia), continuous combined Red (660 nm) + Infra-red (850 nm) for alopecia area and erosions were treated with 660 nm, Pavg=100 mW, 1 J/cm2 (Spectroanalytic Irradia AB). VAS score for itching was 10 at baseline, 2 after 5 sessions and 0 after 10 sessions (T10, week 5). 90% of the erosions had healed at T10. Interestingly, hair began to regrow over affected areas and SALT (Severity of alopecia tool) score at baseline was 47% and 24% at T10.
Discussion: This case demonstrates that LLLT can be useful in treating Itch with uncertain origin due to its anti-inflammatory effects. Although previous studies showed the effects of LLLT in hair growth in non-scaring alopecia, this is the first case report to show its effectiveness in scarring alopecia.
PP87: Global management and spatial modeling of skin cancer: Toward modeling safe lifestyle and reduce risk factors effects
Mahdi Arabi1, Roghayeh Jahdi2, Maryam Shahabi, PhD3
1Shahid Rajaee Teacher Training University, Tehran, Iran, 2University of Mohaghegh Ardabili, Ardabil, Iran, 3Department of Medical Education, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
Background: Skin cancers are multifactorial diseases and caused by the interaction of internal and external factors; UV rays has been identified as the main cause of skin cancer; other UV effects: aging skin, erythema, skin ulcers and various types of skin inflammation, DNA damage, and immune suppression.
Aim: Global skin cancer management: towards modeling safe lifestyles and reducing risk factors effects.
Methods: with the use of cohort study, more than 1000 articles that related to UV effects on skin cancer were selected, 283 articles directly analyzed in more specialized sections; then by meta-analytical methods classified; in order to make accurate studies, local, regional and global studies were conducted. In the end, statistical analysis and spatial analysis have been used and the spatial immunity model has been identified to control the risk of skin cancer factors.
Results: The most commonly repeated parameters identified in three following groups respectively: Environmental group: geographical area, latitude, Ozone depletion, Altitude, surface albedo, UV dose Cloudless and Cloud cover sky UVI. Individual features group: Demographic, hair color, eye color, skin color, education. Medical, Experimental, Molecular group: COX-2 enzymes, Prostaglandin E (PGE2), DNA damage, oxidative stress, MC1R gene, p53 growth inhibitory factor, skin pigmentation. Methodology used in articles was 40% document review and other methods questionnaires survey and experimental respectively. Among the highest repeated parameters: sunburn, history, job and tanning respectively. 41% of articles emphasize the increasing incidence of skin cancer worldwide. 34% prevention and screening, and in 17% sun protection behavior was assessed.
Conclusion: The risk factors for skin cancer risk are chains and strands. Scattered and Unsystematic studies are ongoing around the world. Due to the lack of specific standards, prevention methods and specific algorithms in each geographical area, the trend of skin cancer is still uncontrolled and has a sharp upward trend. This article focuses on the spatial modeling of skin cancer in order to manage it globally, and to control the effective parameters of skin cancer in order to change lifestyles.
PP88: Drug repurposing in netherton syndrome: Improvement of pruritus with novel systemic therapies
Kira Süßmuth1*, Heiko Traupe1, Henning Wiegmann1, Karin Loser1, Helmut Wittkowski2, Vinzenz Oji1
1Department of Dermatology, University Hospital Münster, Germany, 2Department of Pediatrics, University Hospital Münster, Germany
Netherton syndrome (NTS) is a syndromal ichthyosis caused by mutations in the SPINK5 gene encoding for a serine protease inhibitor. It affects the skin, hair and immune system. Patients suffer from chronic pruritus. We report on three patients with NTS treated with biologics. The first patient was a 12-year old female treated with 600 mg dupilumab followed by 300 mg every four weeks due to clinical similarities to atopic dermatitis (AD). After two months of treatment, scaling and erythema appeared less pronounced. The Netherton Area Severity Assessment (NASA) score decreased from 33 to 24.4. Pruritus intensity improved from 8 to 4 on the numerical rating scale (NRS, 0-10). The anti-pruritic effect lasted for three weeks after each injection and worsened afterwards (NRS 6). Attention deficit hyperactivity disorder (ADHS) diagnosed in this patient improved, so that systemic treatment for ADHS did not become necessary. The second patient was an 8-year old male who received dupilumab 300 mg every four weeks. The NASA score dropped from 50.5 to 46.3, however the perioral area worsened (new fissures/scaling). The average pruritus intensity improved from 8 to 4 (NRS), but was still intense at night (NRS up to 9). The third patient was a 14-year old female treated with ustekinumab 45 mg due to psoriasiform aspects of her condition. The skin clearly improved within four months. The NASA score dropped from 52.4 to 25.3. Pruritus changed from 8 to 3 (NRS), but the therapy had to be discontinued due to transaminase elevation. These clinical observations suggest that NTS patients can benefit from biologics when they suffer from severe pruritus. To obtain a full picture including safety issues systemic clinical trials are needed in the future.
PP89: A case of diffuse cutaneous eruption possibly induced by medication
Sung Jin Park, Min Seok Ham, Ji Hyuck Hong, Dae Yeon Kim, Soo Hong Seo, Young Chul Kye, Hyo Hyun Ahn
Department of Dermatology, College of Medicine, Korea University, Seoul, Korea
Drug-induced cutaneous eruption is one of the commonly encountered complaints at clinics. It ranges from common nuisance eruptions to rare, life-threatening diseases accompanying systemic symptoms. Among many types of drug eruption, papulosquamous type includes drug-induced cutaneous lupus, which often accompanies systemic symptoms like arthralgia, with frequent positive immunologic test results. Classic drug-induced lupus erythematosus is characterized by systemic disease with lack of cutaneous involvement, whereas anti-SSA antibody positive subset of drug-induced lupus erythematosus is characterized primarily by cutaneous disease. The most common drugs associated with this subtype are antihypertensive drugs and systemic antifungal drugs. A 72-year-old female presented with itchy erythematous hyperkeratotic plaques on face, upper trunk and upper extremities, first appearing a year ago. She was under many medications including anti-hypertensive drug. We took a skin biopsy, which showed interface dermatitis with vacuolar alterations, as well as superficial perivascular inflammatory cell infiltration, which was suggestive of acute cutaneous lupus erythematosus. Further immunologic laboratory test was done afterwards, which turned out to be fluorescent antinuclear antibody with anti-SSA antibody positive. Patient refused additional evaluation and moved to another clinic. At there, after the oral hydroxychloroquine therapy with discontinuation of anti-hypertensive drug, the lesion gradually improved. The patient had dry eye and dry mouth, but didn’t have other systemic symptoms such as polyarthralgia. Despite cause not clear, clinical improvement following discontinuation of drug and immunologic lab result shows the possibility of patient’s lesion as cutaneous manifestation of drug-induced lupus. Hence, thorough review of possible causative drug may be crucial for any patient with cutaneous eruption visiting the clinic.
PP90: Senile gluteal dermatosis causing chronic pruritus of the buttock: Report of three cases and review of the literature
Mihn-Sook Jue, Taehan Koo, Jiho Park, Min-Soo Kim
Department of Dermatology, Veterans Health Service Medical Center, Seoul, Republic of Korea
Senile gluteal dermatosis (SGD) is the hyperkeratotic lichenified skin lesions on the superior part and both sides of the anal cleft. These lesions are particularly prevalent in sedentary and elderly patients. The prevalence is not known but it is thought to be common in Asia and relatively rare in the West countries. However, only few reports have been discussed the SGD as an aspect of a cause of chronic pruritus of buttock. Three patients visited our clinic complaining of erythematous to brownish patch/plaque with yellowish crust on buttock. All patients complained sever pruritus of the lesions, sometimes interrupting sleep. Skin biopsies from 3 patients showed evidence of hyperkeratosis, acanthosis and vascular dilatation in the papillary dermis with sparse lymphohistiocytic infiltration. Based on the clinical and histopathological findings, the diagnosis of SGD was made. They were treated with intralesional triamcinolone acetonide injection and the skin lesion and pruritus are gradually improved. Most patients with SGD had either mild symptoms or were asymptomatic. But various symptoms such as vague discomfort, mild itching, prickling, and pain may be associated. These symptoms can lead to chronic discomfort and can lead to serious complications such as ulceration and infection. We herein report 3 cases of SGD and review the literature to investigate the prevalence and clinical manifestations of SGD in elderly Korean.
PP91: Glossodynia and glossopyrosis
Andrey Lvov, Svetlana Bobko, Dmitry Romanov
Moscow Scientific and Practical Center of Dermatovenereology and Cosmetology, Moscow, Russia
The variety of skin sensations associated with mental disorders is rather wide and cause problems in diagnostics and treatment. Recently the application of patients with complains on itch of the skin and mucous membrane becomes more and more often. Glossalgia and glossopyrosis or Burning mouth syndrome is associated with dysgeusia, paresthesia, dysesthesia, xerostomia. Skin with a greater density of epidermal innervation is more susceptible for the development of cutaneous sensory disorder (Gupta M.A. et al, 2013). Glossodynia (ICD-10: K14.6, F45.4 and F22.0 DSM-IV-TR: 307.8 pain disorder with psychological factors) involves dysesthesias with burning pain or tingling in the tongue and other parts of the oral mucosa. The complaints in the mouth show no organically confirmable pathology. Burning mouth syndrome may be associated with higher scores for depressive and anxiety symptoms (Davies S.J. et al, 2016). Special questionaire of neuropathic and psychological components for primary burning mouth syndrome showed that 31% of 35 patients had neuropatic pain, 34,3% - anxiety and depressive disorder according to HARDS (Sevrain M. et al Am J Clin Dermatol 2016). About 50% of patients with glossodynia present deviant personality disorders (Huang et al,1996). The use of antidepressants (mirtazapine), sometimes tricyclic antidepressants like doxepin, neuroleptics is recommended in literature (W. Huang et al, 1996). In 51 patients with psychogenic origin of burning mouth syndrome use of selective serotonin reuptake inhibitors was effective (Fleuret C. et al, Dermatology, 2014). The use of gabapentin is possible in patients with glossodynia (F. Meiss et al, 2004). Among the therapeutic approaches clonazepam, psychotherapy, capsaicin are also mentioned (Liu YF. et al, 2017, Vellappally S., 2016). In 2016-2019 33 patients (average age 51.07 y old) applied with complains on different sensations of the skin and mucous membrane without or with rash on skin. The patients were consulted by stomatologists, allergologists and other specialist and directed to our center. Dermatovenereologist and psychiatrist in detail examined the patients. Among the diagnosis 24 patients had glossalgia, 5 patients had urticaria, 2 patients - somatoform itch and 2 patients - amplified itch at the base of atopic dermatitis. Psychiatric equivalents of itch and other sensations (burning, tingling, tickling, pricking, prickling, tightness, stinging and others) were widely presented and were the sign of different psychodermatological interventions. The manifestation of rash as a variant of psychogenic «pseudoallergic reactions» in form of urticum, papules was noticed. The use of psychotropic drugs (antipsychotics and others) is necessary in such cases and shows its efficacy.
PP92: Comparative study of 70% glycolic acid versus 35% TCA versus 1% tretinoinpeel for the treatment of melasma
Neerja Puri, MD
Consultant Dermatologist, Punjab Health Systems Corporation, India
Introduction: Chemical peels in melasma create an injury of specific skin depth thus improving surface texture and appearance.
Aims and Objectives: The aim of our study was to compare the efficacy and side effects of 70% glycolic acid versus 35% TCA versus 1% tretinoinpeel for the treatment of melama in sixty Indian female patients.
Material and Methods: We selected 60 female patients of melasma for the study. The patients were divided into three groups of 20 patients each. InGroup I patients 70% Glycolic acid peel was used, in Group II patients 35% TCA peel was used and in Group III patients 1%tretinoin peel was used.
Results: In group I (Glycolic acid group) patients, 65% reduction of MASI score was seen, in group II (TCA group) 59% reduction of MASI score was seen, whereas in group III (Tretinoin group) patients 50% reduction in MASI score was seen. There was no statistically significant difference in reduction of MASI scores at the end of six peels after 12 weeks in all the three groups (P>0.05). Erythema was seen in 3 patients in TCA group and 1 patient each from glycolic acid group and tretinoin group. Post inflammatory hyperpigmentation was seen in 2 patients with TCA peel and in none of the other two groups.
Conclusions: Considerable reduction of MASI scores was achieved in all the three groups with variable side effects.
PP93: Phase I, first-in-human study of the safety, tolerability and pharmacokinetics of Neu-P12, a Novel anti-itch drug candidate, in healthy male volunteers
A. Katz1, Y. Shefer1, N. Zisapel1, T. Chou2, B. van Baar3, P. Dogterom3
1Neurim Pharmaceuticals (1991) Ltd. Tel-Aviv, Israel, 2QPS Netherlands B.V., Groningen, The Netherlands, 3QPS, LLC, Newark DE, USA
Introduction: Neu-P12 is an inhibitor of Nav1.7 sodium channels and TRPV1 non-selective cation channels that are widely expressed in skin tissues and peripheral sensory nerve fibers and associated with pain and itch. Neu-P12 demonstrated a potential for the treatment of inflammatory and neuropathic pain in multiple different and relevant animal pain and itching models. The safety tolerability and pharmacokinetic profiles of Neu-P12 were evaluated in a phase I, first-in-human, randomized, placebo-controlled, double blind, escalating oral single-dose study, in healthy male volunteers.
Methods: Within each of 4 dosage groups of 8 subjects, 2 subjects were randomized to receive placebo and the remaining 6 subjects were randomized to receive a single dose of Neu-P12 (100, 300, 600, 900 mg per os).
Results: Neu-P12 was well tolerated. Overall, 5 subjects reported 10 adverse events, 9 of mild and 1 of moderate intensity. All Adverse events were considered unrelated to the drug and the incidence was similar between treatment groups, including placebo. There were no serious adverse events. The extent of systemic exposure to Neu-P12 (Cmax, AUC0-t, and AUC0-inf) increased in a dose-proportionate manner across all dose range. Maximum plasma concentrations of Neu-P12 were attained (tmax) at 3.5 to 4 h post dose; thereafter, plasma concentrations declined with a mean apparent terminal half-life of 6.9 - 16.3 h.
Conclusions: Overall, orally administered Neu-P12 was safe and well tolerated at all doses tested. Its pharmacokinetic properties are suitable for a drug candidate intended for the treatment of pain and itching.
PP94: Multiple dose study of safety, tolerability, pharmacokinetics, and pharmacodynamic activity of Neu-P12, a novel drug candidate developed for the treatment of itch, in subjects with scalp pruritus
Y. Shefer1, A. Katz1, L. Mircheva2, N. Zisapel1, Gil Yosipovitch3, V. Nankova2
1Neurim Pharmaceuticals (1991) Ltd, Tel Aviv, Israel, 2Convex CRO/Center for Early Phase Human Research, Sofia, Bulgaria, 3Miami Itch Center, University of Miami Miller School of Medicine, Florida, USA
Introduction: Neu-P12 is a novel investigational drug that is developed for the treatment of pruritus. Neu-P12 inhibits Nav1.7 sodium channels and TRPV1 non-selective cation channels. Nav1.7 and TRPV1 are widely expressed in skin tissues and peripheral sensory nerve fibers, and mediate the pain and itch response. In a series of in vitro and in vivo studies in various animal models, Neu-P12 demonstrated inhibition of pain and itching. The aim of this multiple dose study was to investigate the safety tolerability pharmacokinetics and pharmacodynamic activity of two topical formulations of Neu-P12 in patients with scalp pruritus.
Methods: Forty-two subjects with chronic scalp pruritus were randomized in 1:1:1 ratio to receive Neu-P12 (2%, 4%, and Placebo gels) twice daily, for 14 consecutive days. Safety, tolerability and anti-pruritus effects were assessed throughout the study. Pharmacokinetics studies were performed at Days 1 and 14. Anti-pruritus activity was evaluated using Numerical Rating Scale (NRS) 0-10 and 10 cm Visual Analog Scale (VAS).
Results: Neu-P12 was well tolerated with similar incidence between all treatment groups, including placebo. There were no serious adverse events. The systemic exposure following topical Neu-P12 was 20-150-fold lower than following oral intake. Evidence of anti-itch activity of Neu-P12 was indicated by a decrease of more than 50% in NRS and VAS scores throughout the treatment, particularly in subjects suffering from chronic scalp pruritus of either psychogenic or neuropathic source.
Conclusion: This study demonstrates a good safety and tolerability profile in the tested doses of Neu-P12 gel and provides preliminary evidence for anti-itch activity of Neu-P12 in Scalp Itch of psychogenic or neuropathic source.
Ahn, Hyo Hyun
Altunay, Ilknur K.
Andersen, Hjalte Holm
Ase, Ariel R.
Austen, Frank K.
Baar, van B.
Beebe, Jean S.
Berger, Timothy G.
Blythe, Joseph S.
Bushmakin, Andrew G.
Caceres, Ana I.
Cappelleri, Joseph C.
Carstens, Mirela Iodi
Chan, Kam Tim Michael
Chen, Suephy C.
Chestang, Justin A.
Cheung, Amy Ho Nam
Chiang, Michael C.
Chiu, Isaac M.
Choi, Yong Won
Chul Kye, Young
Chung, Bo Young
Chung, Jin Ho
Cohen, Arnon D.
Cruse, Glenn P.
Cunha, Paulo R.
Dalgard, Florence J.
Darriguade, Anne Sophie
De Villarreal, Joaquin
Della Giovanna, Patricia
Duffin, Kristina Callis
Dun, Nae J.
Ehrhardt-Humbert, Lauren C.
Evers, Andrea W.M.
Finlay, Andrew Y.
Garrec, Raphaele le
Gooderham, Melinda J.
Gviniashhvili, T. E.
Halvorsen, Jon Anders
Ham, Min Seok
Hartke, Timothy V.
Hong, Ji Hyuck
Huerta, Alvaro T.
Jemec, Gregor B.E.
Jensen, Liselotte E.
Jo, Han Heul
Johannssen, Helge C.
Jung, Min Je
Kang, Seok Young
Kang, So Min
Khutsishvili, Natia A.
Kiedrowski, Ralph von
Kim, Dae Yeon
Kim, Hee Joo
Kim, Hye One
Klein, Amanda H.
Kremer, Andreas E.
Kye, Young Chul
Laarhoven, Antoinette I.M. van
Lavrijsen, Adriana P.M.
Le Caër, F.
Lee, Dong Hun
Lee, Jong Yoon
Le-Gall Ianotto, Christelle
Legat, Franz Josef
Lin, Matthew J.
Lizzul, Paul F.
Lopez, Jorge Pinilla
Loriente, Diego Martin
Marron, Servando E.
Meeuwis, Stefanie H.
Meyer zu Hörste, Gerd
Middendorp, Henriët van
Miller, Paul E.
Mishra, Santosh K.
Mowla, Mohammad Rafiqul
Myers, Daniela E.
Neurath, Markus F.
Ng, Lai Guan
Ninaber, Maarten K.
Nocka, Karl H.
Otarashvili, Nina O.
Paller, Amy S.
Paps, Judy S.
Pariser, David M.
Park, Chun Wook
Park, Sung Jin
Paththinige, Niluka Dilrukshi
Paul, Julia C.
Peerdeman, Kaya J.
Pereira, Manuel P.
Polymeropoulos, Mihael H.
Ports, William C.
Rehman, Mati Ur
Rogers, John A.
Rosen, Jordan D.
Ross, Sarah E.
Rosso, Maria Victoria
Sagita Moniaga, Catharina
Salek, Sam S.
Sanders, Kristen M.
Seo, Soo Hong
Shah, Serena Maya
Sheahan, Tayler D.
Silverberg, Jonathan I.
Solinski, Hans J.
Spencer, Robert H.
Ständer, Hartmut F.
Stein Gold, Linda F.
Swerlick, Robert A.
Szepietowski, Jacek C.
Tey, Hong Liang
Thomaidou, Mia A.
Tsagareli, Merab G.
Tyring, Stephen K.
Veldhuijzen, Dieuwke S.
Verheyden, Matthew J.
Verma, Shyam B.
Vincent, Michael S.
Wee, Nic van der
Welsh, Sarah E.
Werth, John L.
Werth, Victoria P.
Wimalasena, Nivanthika K.
Woolf, Clifford J.
Zeilhofer, Hanns Ulrich