ISSN 0001-5555 ActaDV Volume 100 2020 Theme issue

Advances in Dermatology and Venereology

A Non-profit International Journal for Interdisciplinary Skin Research, Clinical and Experimental Dermatology and Sexually Transmitted Diseases

Frontiers in Dermatology and Venereology - A series of theme issues in relation to the 100-year anniversary of ActaDV

Official Journal of - European Society for Dermatology and Psychiatry

Affiliated with - The International Forum for the Study of Itch

Immediate Open Access

Acta Dermato-Venereologica

www.medicaljournals.se/adv ACTA DERMATO-VENEREOLOGICA The journal was founded in 1920 by Professor Johan Almkvist. Since 1969 ownership has been vested in the Society for Publication of Acta Dermato-Venereologica, a non-profit organization. Since 2006 the journal is published online, independently without a commercial publisher. (For further information please see the journal’s website https://www. medicaljournals.se/acta)

ActaDV is a journal for clinical and experimental research in the field of dermatology and venereology and publishes high- quality papers in English dealing with new observations on basic dermatological and venereological research, as well as clinical investigations. Each volume also features a number of review articles in special areas, as well as Correspondence to the Editor to stimulate debate. New books are also reviewed. The journal has rapid publication times.

Editor-in-Chief: Olle Larkö, MD, PhD, Gothenburg Former Editors: Johan Almkvist 1920–1935 Deputy Editors: Sven Hellerström 1935–1969 Anette Bygum, MD, PhD, Odense Nils Thyresson 1969–1987 Magnus Lindberg, MD, PhD, Örebro Lennart Juhlin 1987–1999 Elisabet Nylander, MD, PhD, Umeå Anders Vahlquist 1999–2017 Kaisa Tasanen-Määttä, MD, PhD, Oulu Artur Schmidtchen 2018–2019

Section Editors: Tasuku Akiyama, Miami (Neurodermatology and Itch - Experimental) Annamari Ranki, Helsinki (Cutaneous lymphoma) Nicole Basset-Seguin, Paris (Skin cancer) Artur Schmidtchen, Lund (Wound healing and Innate immunity) Veronique Bataille, London (Melanoma, Naevi, Photobiology) Matthias Schmuth, Innsbruck (Genodermatoses and Keratinizing disorders, Josip Car, Singapore (Health Services Research and e-Health) Ichthyosis and Retinoids) Brigitte Dréno, Nantes (Acne and Rosacea) Lone Skov, Hellerup (Psoriasis) Regina Fölster-Holst, Kiel (Paediatric dermatology, Atopy and Parasitoses) Enikö Sonkoly, Stockholm (Psoriasis and related disorders) Jürg Hafner, Zürich (Skin cancer, Skin tumours, and Melanoma) Jacek Szepietowski, Wrocław (Psychodermatology) Jürgen Harder, Kiel (Cutaneous innate defense, Skin microbe interactions) Elke Weisshaar, Heidelberg (Itch and Neurodermatology) Roderick Hay, London (Cutaneous Infections) Margitta Worm, Berlin (Atopic dermatitis and Immunology) Kristian Kofoed, Copenhagen (STD and Microbiology) Claus Zachariae, Hellerup (Contact dermatitis, Acute dermatology) Veli-Matti Kähäri, Turku (Skin cancer) Magnus Ågren, Copenhagen (Wound healing & Extracellular matrix) Dennis Linder, Graz/Padua (Psychoderm., Dermato-epidemiology,­ e-Health)

Advisory Board: Masashi Akiyama, Nagoya Rudolf Happle, Freiburg Lisa Naysmith, Edinburgh Mona Ståhle, Stockholm Wilma Bergman, Leiden Lars Iversen, Aarhus Jonathan Rees, Edinburgh Sonja Ständer, Münster Tilo Biedermann, Munich Peter van de Kerkhof, Nijmegen Jean Revuz, Paris Jouni Uitto, Philadelphia Magnus Bruze, Malmö Irene Leigh, Dundee Johannes Ring, Munich Shyam Verma, Vadodara Earl Carstens, Davis John McGrath, London Matthias Ringkamp, Baltimore Gil Yosipovitch, Miami Thomas Diepgen, Heidelberg Maja Mockenhaupt, Freiburg Inger Rosdahl, Linköping Giovanna Zambruno, Rome Charlotta Enerbäck, Linköping Dedee Murrell, Sydney Thomas Ruzicka, Munich Christos C. Zouboulis, Dessau Kilian Eyerich, Stockholm

All correspondence concerning manuscripts, editorial matters and subscription should be addressed to: Acta Dermato-Venereologica S:t Johannesgatan 22, SE-753 12 Uppsala, Sweden Editorial Manager, Mrs Agneta Andersson Editorial Assistant: Ms Anna-Maria Andersson Please send an E-mail Please send an E-mail

Information to authors: Acta Dermato-Venereologica publishes papers/reports on scientific investigations in the field of dermatology and venereology, as well as reviews. Case reports and good preliminary clinical trials or experimental investigations are usually published as Short Communications. However, if such papers are of great news value they could still be published as full articles. Special contributions such as extensive feature articles and proceedings may be published as supplements to the journal. For detailed instructions to authors see https://www.medicaljournals.se/acta/instructions-to-author. Publication information: Everything is Open Access and no subscription fee. For publication fees: see https://www.medicaljournals.se/acta/ instructions-to-author.

Indexed in: See https://www.medicaljournals.se/acta/about/adv. Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Derm Venereol 2020;24(inpress). This isan open access article under the CC BY-NC license.www.medicaljournals.se/acta pdf) andregistrationform(https://medicaljournals.se/actadv100/registration.php). The registrationforthissymposium isopen.Formoreinformation(https://medicaljournals.se/acta/Acta100Year. 1 ActaDV 100years– An incompletehistory mercial publisher. Foran historic review see Vahlquist A. entirely in-house without any dependency on a com produced and society non-profit a by own publication, the journalisanonline,openaccessandpeer-reviewed mainly from Europe. Today, 100 years and 6 editors later, journal (German, French, English) with contributions Johan Almkvist. To aminortri-lingual itwas beginwith, and ProfessorInstitutet, Syphilidology at Karolinska founded inStockholmbytheChairmanofDermatology In 1920,Acta Dermato-Venereologica ( and Venereology” The celebrationscompriceasymposiumandseriesofthemeissuesjointlycalled”Frontiers in Dermatology top 10inthefield. and theimpactfactor3.4–4.2inrecentyears,i.e.among around theworld. The acceptancerateisaround50% ActaDV releases250–300papers submittedfromall Journal Compilation ©2020ActaDermato-Venereologica. Vahlquist A. ActaDV 100years– An incomplete history. ForumforNord C P C 9.00–10.30 13.00–14.10 14.30–16.00

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D A e: n: O n: A c a t t a D e n l : 15 ” ” ” ” ” ”Is permanentcureforgenodermatosesinsight”,JouniUitto ” ” le L der A C M S Where are we with prevention of atopic dermatitis?”, Williams Hywel I P F t k c s er c o e o t in f h; s a t m s V aD l h r m r a M i r k b n a o ra ö a a cra V 100y a si o h n t t a m g s: N t o-V lq y 2020. ti in i t ActaDV) was a: N li c ui e 1 g s hin t rs inD . Annually, e y a en s ws inp t k e e g t n in f ws inep er a r d b h ; a P e e s o l li n hi a e FOREWORD log a e s c rma ur t c t e h er t : S face i idemio io ic s og t in - o n a w t w en r o g di s: Ap ic p e l esi s n og di i l s log publish aseriesofconnectedthemeissueswithcontri from EuropeandtheUSA (seefullprogrambelow),and in Dermatologyand Venereology” withinvitedspeakers birthday, nothing ofthishadbeenpossible. and the skilful work of the editorial office without which the themeissues,speciallyappointededitors, thank alltheauthorswhokindlyacceptedtocontribute nizer of the centenary celebrations, I wish to sincerely in Dermatologyand Venereology. these undertakings will help to spur the scientific interest leaders aroundtheworld(seenextpage).Itishopedthat butions from the speakers and other invited key-opinion- l ce s er s a e o y a h S a r t en s As partofthecelebrationjournal’s 100years On behalfoftheeditorialboardandasprincipalorga io s y a n p es le nd V d t r e o i ” b c n o Society for Publication of ActaDermato-Venereologica t , ciet t y n ra ug h d t Former Editor-in-Chief andcurrent Chairman of the L i v era e t e e h en h e i o y o ” ne ” ActaDV willorganize asymposium”Frontiers , era t j , p a B A A G ts 100-y y” u r f M n n i p , e s l Y d ge r y” t inA J o u er o l l , o e c n J i og s V k s k dicin a u Uppsala inDecember2019 i n a S p t Ol l h y er i a o f e a N r a h v a t l -T ic n B e L a i l r a q t Anders Vahlquist e r a c u e u , S y ” h , w a d i nni a s R r er r t t t k o k o o m ö n-B er d c v er a k er n h i i c s s o k H h a lm, S r o y w p a y i w t h asy e den m p osi um 1 - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Blistering skindisorders Psoriasis Forthcoming issues Itch andpruriticdisorders Current issue Cutaneous andgenitalinfections Atopic dermatitis Skin malignancies Genodermatoses • • • • • • • • • • • • • • • • Pustular Psoriasis:theDawnofaNewEra,H.Bachelez Psoriasis andCo-morbidity, M. Amin, E.B.Lee,T-F. Tsai, J.J.Wu Psoriasis and Treatment: Past,Presentand Future Aspects C.Reid,C.E.M.Griffiths The Woronoff RinginPsoriasisandtheMechanismsofPostinflammatory Hypopigmentation,J.Prinz Psoriasis andGenetics,N.Dand,S.Mahil,F. Capon,C.H.Smith,M.A.SimpsonandJ.Barker Bullous DrugReactions,M.Mockenhaupt Drug DevelopmentinPemphigoidDiseases,K.Bieber, R.J.Ludwig Skin Fragility:PerspectivesforEvidence-based Therapies, L.Bruckner-Tuderman Current ConceptsofDermatitisHerpetiformis,T. Salmi,K.Hervonen Collagen XVIIProcessingandBlisteringSkinDiseases,W. Nishie A.G.S. Zink,S.Ständer Challenges inClinicalResearchandCarePruritus,M.P. Pereira, C.Zeidler, M.Storck, K. Agelopoulos, W.D. Philipp-Dormston, A NewGenerationof Treatments forItch,E.Fowler, G.Yosipovitch Itch andPsyche:Bilateral Associations, R.Reszke,J.C.Szepietowski Non-dermatological ChallengesofChronicItch,A.E.Kremer, T. Mettang,E.Weisshaar Mechanisms andManagementofItchinDrySkin,C.SagitaMoniaga,M.Tominaga, K.Takamori The ChallengeofBasicItchResearch,E.Carstens,T. Follansbee,M.I.Carstens Theme editor:KaisaTasanen Theme editors:LoneSkovandEniköSonkoly Theme editors:ElkeWeisshaar, Tasuku Akiyama andJacek Szepietowski Content detailsTBA Theme editors:RoderickHayandKristianKofoed Content detailsTBA Theme editors:MagnusLindberg andCarl-Fredrik Wahlgren Content detailsTBA Theme editors:Veronique Bataille andNicoleBassetSeguin Content detailsTBA Theme editors: Anette BygumandMatthiasSchmuth Centenary theme issuesinVolume 100ofActaDermato-Venereologica Frontiers inDermatologyandVenereology An overview

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV lopoulos, W.D. Philipp-Dormston, A.G.S. Zink,S.Ständer Challenges inClinicalResearchandCarePruritus, M.P. Pereira, C.Zeidler, M.Storck, K. Age A NewGeneration of Treatments forItch,E.Fowler, G.Yosipovitch Itch andPsyche:Bilateral Associations, R.Reszke,J.C.Szepietowski Non-dermatological ChallengesofChronicItch,A.E.Kremer, T. Mettang,E.Weisshaar Mechanisms andManagementofItchinDrySkin,C.SagitaMoniaga,M.Tominaga, K.Takamori The ChallengeofBasicItchResearch,E.Carstens,T. Follansbee,M.I.Carstens TABLE OF CONTENTS Elke Weisshaar, Tasuku Akiyama andJacekSzepietowski Itch andPruriticDisorders Theme Editors: - 45–51 36–44 27–35 21–26 9–20 2–8 Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV doi: 10.2340/00015555-3343 L 95616 USA. E-mail:[email protected] Behavior, University of California, Davis, 1 Shields Avenue, Davis, CA Corr: Acta DermVenereol 2020;100:adv00023. Accepted Oct15,2019;PublishedJan9,2020 peptide; alloknesis. Key words: itch; pain; labeled-line coding; gastrin releasing itch. relieve chronic targets for development of therapeutic strategies to naling pathways.advances provide Theserecent novel inhibition allowingis reduced, touch to excite itch-sig neuropeptide NPY-mediated itch, Y(NPY).Inchronic byinhibitorykept incheck interneurons expressing the can spinal access pathway,butarenormallyitch dicates afferents that low-threshold mechanosensory ormechanical touch-evoked evidencein Recent itch. A cardinalsymptom ofisalloknesis, itch chronic i.e., marcated inrodents, speciesdifferences. suggesting pathwaystaminergic itch-signaling whichislessde there is a dichotomy of histaminergic and non-his Inhigherprimates unresolvedchallenge. currently the ofissue a labeled line for itch- a long-debated but cloud findings These pain. elicits stimulation spread nerveendingselicits while itch ciceptive more wide­ based onthe observation that focalstimulation of no are asintensity orspatialcontrast, crimination,such dis ascapsaicin.Alternativetheoriesofitch-pain such ly all pruriceptive neurons alsorespond to algogens modulate segmental transmission.itch However,near­ interneurons releaseGABA,glycine and dynorphin to the to andthalamus. Spinal inhibitorynucleus parabrachial project and receptor (NK-1) P substance the ceptor connect (GRPR), which to neurons that express gastrin expressing releasing peptide (GRP) and its re neurons activate to cord spinal the into project fibers Their genes. itch-related neurons highlyexpressing of pruriceptivesensory studiesreveal3subsets cent Department of Neurobiology,PhysiologyandBehavior, University of California, Davis, USA Earl CARSTENS, The ChallengeofBasicItchResearch Centenary theme section:ITCHANDPRURITIC DISORDERS Acta DermVenereol 2020;100: adv00023 knowledge to theclinicaltreatment of Re itch. chronic in translatingcurrent as wellremainingchallenges reviewed, with an emphasis on the progress to date and pathwaysBasic mechanisms of itch signaling are a usefulfunctionbutinstead imposessuffering, highso > lasting However,itch chronic from theskinsurfaceorto digoutinvasiveparasites. organism to scratch away insects or plant spicules forthe signal awarning ike pain,acuteitchprovides Prof. Earl Carstens, Department of Neurobiology, Physiology and Taylor FOLLANSBEEand MirelaIODI CARSTENS 6 weeks does not serve not does weeks 6 This isan open access article under the CC BY-NC license. www.medicaljournals.se/acta REVIEW ARTICLE ------categorize 11 subpopulations ofdorsalrootganglion Single-cell RNA sequencing has beenusedrecentlyto (11–13).serotonin andchloroquine itchtransduction (10), andrecentreportsimplicate TRPV4 inhistamine, Many non-histaminergic itchmediatorsactvia TRPA1 1.7, 1.8) to initiate action potentials in the afferent fiber. activate voltagesensitivesodiumchannels(Nav thereby (8, 9),whichopenstodepolarizethenerveendingand TRPV1, theheat-andcapsaicin-sensitiveionchannel to linked receptors H4 and H1 histamine ator,at acting partial list. Histamine is the most well-known itch medi of pruriceptiveafferents intheskin.Fig.1providesa inthefreenerveendings nate receptorsthatareexpressed A wide varietyofitchmediatorsinteractwiththeircog schematic overview of itch processing is shown in from theperipheryintocentralnervoussystem. A understanding of how itch is transduced and transmitted our in decade past the in made been have strides Huge OVERVIEW OFITCHPATHWAY treatments forchronicitch(7). based onrecentresearchthathasledtoneweffective for translational itch research. Optimism iswarranted treatment strategies. This isoneofthegreatchallenges there is a pressing need to develop novel drugs and other types ofchronicitchareresistanttoantihistamines,so and economiccostsinthebillionsofdollars(1–6).Most the generalpopulationwithassociatedannualhealthcare dermatitis orpsoriasisaffect upwardsof10%ormore been estimatedthatitchyskinconditionssuchasatopic cioeconomic costs,andreducesthequalityoflife.Ithas as asymptom of chronic itch. challenges in understanding touch-evoked itch (alloknesis) histaminergic itch-signaling pathways? We also address peptide and itsreceptor);are there histaminergic and non- are there specific markers of itch (such as gastrin releasing ries explain the ability to distinguish between itch and pain; pathway separate from thatfor pain;can alternative theo are addressed include:isitchsignaledby a labeled-line the clinical treatment of chronic itch. Major questions that remaining challenges in translating current knowledge to itch signaling, emphasizing the progress todate as well This paper reviews the basic mechanisms and pathways of SIGNIFICANCE Journal Compilation ©2020ActaDermato-Venereologica. Fig. 1. - - -

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV spinal cord dorsal horn, where they release neuropeptides spinal corddorsalhorn,where theyreleaseneuropeptides research intomoreeffective treatmentsforchronicitch. is alreadyaddressingthechallenge oftranslatingbasic peripheral transduction ofitch and immune function cytokines (7).Clearly, improvedunderstandingofthe antagonists thatblockactivationofsensoryneuronsby sitization, leadingtothedevelopmentofbiologicsand IL-31 (19,20),IL-4andIL-13(21)initchsen plicated inchronicitch.Recent studies haveimplicated havebeenim In addition,neuroimmuneinteractions and somatostatinhaveallbeenimplicatedinitch(15–18). [BNP] andsomatostatin)(14).MrgprD, NP2 (MrgprA3), andNP3(brainnatriureticpeptide expressing genesassociatedwithitch:NP1(MrgprD), (DRG) cells,with3largely nonpeptidergic (NP)groups SP: substanceP;Sst:somatostatin;TLR:toll-like receptor;TLSP: thymic stromallymphopoietin. B4; Mrgpr: Mas-related G-protein coupled receptor; PAF: platelet activating factor; PAR: protease-activated receptor; SI: primary somatosensory cortex; CGRP: calcitoningene related peptide; Dyn: dynorphin; Glu: glutamate; Gly: glycine; GRP: gastrin releasing peptide; IL: interleukin; LTB4: leukotriene pathways. of itch-signaling 1. Schematic Fig. Pruriceptive afferent fibers transmit signals into the into signals transmit fibers afferent Pruriceptive 5-HT: 5-hydroxytryptamine (serotonin); ACC: anterior cingulate cortex; BNP: brain natriuretic peptide; MrgprA3, BNP - - 35). Usingadouble-labelstrategy, weobservedsimilar responding tothealgogenscapsaicin andmustardoil(34, to intradermal injection of pruritogens, with most also and spinoparabrachial projection neurons in rats respond spinothalamic identified antidromically of majority A projection neuronsexpresstheNK-1receptor(32,33). somatosensory thalamus. A highpercentageofascending itch-signaling pathwaystotheparabrachialnucleusand 1). Projectionneuronsultimatelygiverisetoascending pressing GABA,glycineanddynorphin(28–31)(Fig. P (26,27), as well as itch-inhibitory interneurons ex excitatory interneuronsthatexpressGRP andsubstance glutamate (see below). The spinal circuitry includes and somatostatin(25)aswelltheneurotransmitter (GRP) (22,23),substanceP (23), neuromedinB(24), including BNP (17),possiblygastrinreleasingpeptide Challenge ofbasicitchresearch Theme issue: Itch and pruritic disorders 3 - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue: Itch and pruritic disorders Fig. 2. Itch theories. itch sensation(40).Morerecentstudiessuggestthat tern closelyparalleledthetimecourseofconcomitant pat firing potential action the that such histamine, of microneurography respondedto cutaneous application by recorded C-fibers insensitive mechanically that was but never transitioned to pain (39). A seminal observation increased asafunctionofincreasingstimulusfrequency surface reported that the intensity of the evoked itch using electricalstimulationatdiscretesitesontheskin itch via a specific “labeled of line” pathway.sensation a An older elicits study fibers afferent primary sensitive pain andothersensoryqualities. conveyed tothebrainandhowitisdiscriminatedfrom emingly disparate observations to understand howitch is challenge ofbasicitchresearchistoreconcilethesese that can decode activity in non-selective neurons. A great other dysestheticsensoryqualities)bysomemechanism plying thatitchmustbedistinguishedfrompain(and im neurons, itch-specific any if few be to appear there capsaicin, mustardoil,and other noxiousstimuli. Thus, pruritogens invariablyalsorespondtoalgogenssuchas cord and brain, it is evident that neurons that respond to ripheral andsecond-orhigher-order neuronsinthespinal On the otherhand,based on neural recordings from pe pathway for itch transmission (discussed further below). sion involving the neuropeptide GRP provides a specific On the one hand, there is evidence that spinal transmis IS THERE ALABELEDLINEFOR ITCH? has onlybeguntobeexperimentallyaddressed(37,38). modulatory influences from the brainstem, although this itch-signaling circuitryisverylikelyunderdescending mine, chloroquineorcapsaicin(36).Finally, thespinal marker, c-fos,followingintradermalinjectionofhista spinoparabrachial neuronsthatco-expresstheactivity proportions ofretrogradelylabeledspinothalamicand 4 There ismuchevidencethatactivationofpruritogen- E. Carstensetal. A: selectivity (similar to population coding). B: intensity theory. See text for explanation. +: excitatory synapse; –: inhibitory synapse. ------theory, which is similar to the selectivity theory ( selectively signalitchbutnotpain. cess circuitsathigherlevelsofthenervoussystemthat neurons signalpain. Note that this idea still embodies contrast, pruritogen-insensitivebutalgogen-sensitive In 2A). (Fig. mechanisms central itch-specific access signal itch,wherebythesenon-selectivespinalneurons algogen-sensitive DRGandspinaldorsalhornneurons well ascapsaicin(45). We postulated thatpruritogen-and triangular thalamicnucleirespondedtopruritogensas of neuronsintheventralposteriormedialand dorsal hornneurons(44).Similarly, highpercentages superficial for true was same The 43). (42, oil mustard itch mediatorsadditionallyrespondedtocapsaicinand found thatmostifnotallneuronsrespondedto Using calcium imaging of DRG sensory neurons, we are notexclusivelyactivatedbyitchystimuli,theyac implies thatalthoughtheMrgprA3-expressing afferents activated by pruritic, algogenic or artificial stimuli. This nerve endingselicitsitch,regardlessofwhethertheyare findings indicate that activation of MrgprA3-expressing also eliciteditch-relatedscratchingbehavior(27). These activation ofMrgprA3-expressing peripheralafferents indicating that they are not itch-specific (41). Optogenetic to chloroquinebutalsocapsaicinandotherchemicals, MrgprA3-expressing sensory nerves responded not only that isnormallyelicitedbycapsaicin(41).Moreover, elicits itch(scratching)ratherthanthepainbehavior TRPV1-null mice,capsaicinactivationoftheseneurons into sensory neurons expressing MrgprA3 in otherwise and heat-sensitivereceptor)isgeneticallyengineered drug chloroquine(15). When TRPV1 (thecapsaicin nerve endingsthatrespondtotheitchyantimalarial insensory receptorexpressed related G-protein-coupled pruritogenic stimuli.Forexample,MrgprA3 isaMas- though theafferents respondtoalgogenicaswell activation of specific primary afferents elicits itch, even This concept is also reflected in a “population coding” Fig. 2 A). -

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV receptor antagonistsofGRP (RC-3095),substanceP itch. We found that individual intrathecal delivery of have alsobeenimplicatedin thespinaltransmissionof P (17),glutamate(50)andsubstance peptide (BNP) (51) studies toresolve. theories ofitch-paindiscriminationthatrequiresfuture itch-specific or signal both itch and pain, a challenge to whether GRP- and GRPR-expressing spinal neurons are to as evidence conflicting is there Thus, (49). neurons dorsal hornneurons,includingspinothalamicprojection spinal in pruritogens to compared rates firing higher In general, capsaicin and mustard oil elicited consistently the pruritogensSLIGRL,chloroquineor histamine (27). expressing spinalneurons compared tothoseelicited by deed, capsaicin elicited much higher firing rates in GRP- firing rate in a common population of spinal neurons. In itch is signaled by a lower firing rate and pain by a higher intensity theory of itch (Fig. 2B), which postulates that signals bothitchandpain. This isconsistentwiththe a common population ofGRP-expressing spinal neurons opioid mechanism that reduced pain but not itch, and that authors suggested that high-dose capsaicin triggered an administration oftheµ-opioidantagonistnaloxone. The (but notitch)responsesdecreasedandwererescuedby (licking). At higherdosesofcapsaicin(1–20µg),pain behavioral signsofitch(scratching)aswellpain administration ofcapsaicin dose-dependently elicited spinal neurons in otherwise TRPV1-null mice. Intrathecal genetically engineered TRPV1 into GRP-expressing behavioral signsofbothitchandpain(27). The authors activation ofGRP-expressingspinalneuronselicited expressed inspinalneuronsasitch-specificmarkers. pain (48). These datastronglysupportGRP andGRPR horn neuronselicitedbehavioralsignsofitchbutnot that chemogeneticactivationofGRP-expressingdorsal These findings were recently corroborated by the report pruritogen-evoked scratching but not pain behavior (47). attenuated significantly also neurons spinal expressing receptor (GRPR)(22).NeurotoxicdestructionofGRPR- not painbehavior, intransgenicmicelackingtheGRP but scratching, pruritogen-evoked in reduction nificant sig a by demonstrated first was itch GRPin Afor role SPECIFIC MARKER? IS GASTRIN RELEASING PEPTIDEANITCH- also bemaskedbystrongerpain. with theselectivitytheoryofitch.Itchperceptionmay itch-inhibitory interneurons (Fig. 2A) (46), consistent due totheabilityofnociceptivespinalinputactivate simultaneously. Inthiscase,painsensationdominates tions ofneurons,implyingthatitchandpainareelicited pain. Pain-evokingstimuliwouldactivatebothpopula separate, centrallabeledlinemechanismsforitchand Besides GRP, neuromedin B(24),brain natriuretic However, another recent study reported that selective - - - nociceptive nerve endings in the skin by either pruritoge that highlylocalizedactivationofaminimalnumber or nativecowhagespiculeintotheskin(54). This implies of either a single histamine-loaded, or capsaicin-loaded, (burning, stinging,pricking),wereelicitedbyinsertion itch, together with sub-dominant nociceptive sensations of sensation dominant a that finding the is mechanisms A further complication to our understanding of itch SPATIAL CONTRAST THEORY OFITCH the transmissionofitchsignals. provide pointsofinterventioninthespinalcordtoblock neurotransmitter inhistaminergic itch(52). studies These histamine, implicating glutamate as the primary spinal pletely abolishedscratchingandneuronalresponsesto ment ofcowhagespiculesactivated largely separatepo well, sinceintradermalinjections ofhistamineorplace cowhage-sensitivity applies tonon-humanprimatesas nociceptors (56,59). The dualityofhistamine-and Cowhage excitesmechanically sensitivepolymodal spicules ofcowhage,whichcontainproteases(57,58). In contrast,non-histaminergic itchcanbeelicitedby 56). (40, above mentioned afferents C-fiber insensitive itch is mediated bythe histamine-sensitive, mechanically ergic andnon-histaminergic. Inhumans,histaminergic It isadogmathattherearetwotypesofitch,histamin ITCH: SPECIES DIFFERENCES? HISTAMINERGIC VS. NON-HISTAMINERGIC localized patternsofactivationnociceptiveC-fibers. remains toexplainhoweitheritchorpainresultsfrom spared fibers elicits asensation of itch (55). The challenge most but not all C-fibers, such that activation of the few following nerveinjurythatresultsindegenerationof suggested asapossiblemechanismofneuropathicitch via theactivationofmanynociceptors. This conceptwas itch for pattern specific a of disruption to due possibly (e.g., byintradermalinjectionofcapsaicin)ispainful, a greaternumberofnerveendingsoverbroaderarea nociceptive nerveendingsisitchy, whileactivation of theory ofitch,whichholdsthatlimitedactivation nant sensation of itch. This supports the “spatial contrast” nic or algogenic chemicals is sufficient to elicit a domi neuropeptides to different extents. CNQX almost com ways for itch, each utilizing these neurotransmitters/ path­ spinal parallel be may there that suggest findings of BNP orGRP, butlesscommonlytoboth(53). These or chloroquine,somerespondedtointrathecaldelivery to intradermalhistamine responsive dorsal hornneurons This issupportedbyanotherstudyreportingthatof antagonists completelyinhibitedtheseresponses(52). responses tochloroquine,whileacombinationofall3 partially reducedscratchingbehaviorandspinalneuronal (L-733060) orthe AMPA glutamatereceptor(CNQX), Challenge ofbasicitchresearch Theme issue: Itch and pruritic disorders 5 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue: Itch and pruritic disorders excitatory synapse;–:inhibitorysynapse. +: receptor; Y-1 neuropeptide Y;NPY-1R: NPY:neuropeptide gastrin releasing peptide receptor; NK-1R: neurokinin-1 receptor; text for explanation. GRP:gastrin releasing peptide; GRPR: of itch Fig. 3.Schematic mechanical (alloknesis).See receptor agonistsreducedtouch-evokedscratching(66), evoked scratching(65),andintrathecaldeliveryofNPY-1 Y (NPY)–expressingneuronsledtoincreasedtouch- (64). Chemogeneticsilencingofspinalneuropeptide elicits immediatescratchbouts–amodelofalloknesis injection ofhistamineandotherpruritogens,lighttouch intradermal following However, itch. of signs havioral mice, lightlytouchingtheskindoesnotelicitanybe or punctatemechanicalstimulus).Inhealthynormal itch), andhyperknesis(increaseditchtoanormallyitchy taneous”) itch,alloknesis(mechanicalortouch-evoked Cardinal symptoms of chronic itch are ongoing (“spon ALLOKNESIS THE CHALLENGEOFCHRONIC ITCHAND models fortranslationtohumanitch. rodent of limitations the understand to is field the for non-human primatescomparedtorodents. A challenge ergic pathways may be more segregated in humans and These dataimplythathistaminergic andnon-histamin thalamic neurons did not respond to chloroquine (45). it isnotedthatalarge numberofhistamine-responsive additionally testedwithhistamineresponded,although thalamus, all 7 chloroquine-responsive neurons that were also respondedtohistamine(63).Inratsomatosensory revealed that 47–71% of chloroquine-responsive neurons (41). Recordings from mouse spinal dorsal horn neurons 78% (7/9)respondedtobothhistamineandchloroquine from identified MrgprA3-expressing DRG cells in mice, also responded tohistamine. Using invivorecording (61) or17–23%(62)ofchloroquine-responsivecells cells, it was variously reported that 100%(15),50% imaging of mouse DRG and trigeminal ganglion (TG) and non-histaminergic itchmediators.Usingcalcium and secondarysensoryneuronsresponsivetohistamine in rodentsthereappearstobegreateroverlapprimary pulations of spinothalamic tract neurons (60). However, 6 E. Carstensetal. - - - under conditions inwhichMerkel cell-SAI inputisre neurons todrivethemechanicalitch-signalingpathway chanoreceptor activationofNPY-1 receptor-expressing 3). NPY-mediated inhibitioncan be overcomebyme a pathwayindependentofthatforchemicalitch(Fig. receptor, implying thatmechanical itch is transmitted via following ablation of spinal neurons expressing the NK-1 mechanical itch(68).Mechanicalwasnotaffected tion ofneurons expressing the NPY-1 receptor promotes transmission. Itwasveryrecentlyreportedthatactiva excite NPY-expressing interneurons to inhibit spinal itch cells connected to slowly adapting type I(SAI)afferents alloknesis in dry skin (67). This suggests that Merkel while chemogenetic activation of Merkel cells prevented skin conditions,wasassociatedwithincreasedalloknesis, channel piezo2,asoccurredinagedmiceorunderdry and reduced expression of the mechanotransduction 3). A reductioninthenumberofcutaneousMerkelcells of GRP-GRPRsignalinginthespinalitchcircuit(Fig. independentof,orconvergeschanical itchis downstream saporin. This impliesthattheeffect oflow-threshold injection ofsubstanceP-saporinbutnotbombesin- abolished inOVA-treated micethatreceivedintrathecal not hyperknesis or spontaneous scratching, was nearly behavior, alloknesis and hyperknesis (32). Alloknesis, but kines, and importantly, increased spontaneous scratching skin hyperplasiaandlesions,increasedIgG Th2 cyto atopic dermatitis-likeconditioninmice,characterizedby Repeated topicalapplicationofovalbumininducedan cluding atopicdermatitis,psoriasisandothers(69,70). mimic varioustypesofchronicitchandalloknesis,in duced (Fig.3). or ablatingGRPR-expressingneurons,implyingthatme mechanical stimulation,wasattenuatedbyantagonizing Scratching elicitedbyintradermalchloroquine,butnot inhibit itchelicitedbylow-thresholdmechanoreceptors. implying thattheNPY-expressing neuronsnormally A numberofanimalmodelshavebeendevelopedto ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV REFERENCES Institutes ofHealth(AR057194). Institute of Arthritis, Musculoskeletal and Skin Diseases, National The author’s workhasbeensupportedbyagrantfrom theNational ACKNOWLEDGMENTS arguments favoringbothconcepts. This debatecontinuesunresolveduptothepresent,with neurons. non-specific of population common a by or and painaresignaledbyseparatelabeled-linepathways has beendebatedformorethan100yearswhetheritch more canbeexpectedinthenearfuture.Nevertheless,it to the treatment of chronic itch are already being used and strong interestinitchresearch,severalnovelapproaches the remarkableprogressofpastdecadeandcurrent into clinicaltreatment.Given ofitchsignaling knowledge discriminated from pain, and to translate our increasing arising frombasicitchresearch to explainhowitch can be The preceding text has identified a number of challenges CONCLUSIONS targeting spinalNPY1receptors. pathways and potential anti-alloknesis interventions mechanosensory input interacts with spinal itch-signaling low-threshold how understand better to is field the to suffering frommanytypesofchronicitch,achallenge and mechanically-evokeditchbehavior(66). intrathecal NPY agonistssuppressedbothchemically- connecting NPY-1R toNK-1R).Consistentwith this, the chemicalitch-signalingpathway(Fig.3;dashedline the idea thatmechanoreceptive input converges onto requires NK-1receptor-expressing neurons,supporting occurred downstreamofGRPR-expressingneuronsbut mechanoreceptor inputtoinhibititchsignalingneurons 7. 6. 5. 4. 3. 2. 1. Given that alloknesis isquite bothersome to patients Yosipovitch G, Rosen JD, Hashimoto T. Itch: From mechanism Thorpe KE, Florence CS, Joski P. Which medical conditions Bickers DR, LimHW, MargolisD, Weinstock MA,GoodmanC, Krueger GG,BergstresserPR,LoweNJ, Voorhees JJ, W. G. Michalek IM, Loring B, John SM. A systematic review of Drucker AM, Wang AR, Li WQ, Sevetson E, Block JK, Qureshi Silverberg JI, Hanifin JM. Adult eczema prevalence and as and prevalence eczema Adult JM. Hanifin JI, Silverberg to (novel) therapeutic approaches. J Allergy Clin Immunol Clin Allergy J approaches. therapeutic (novel) to (Millwood). SupplWeb Exclusives, W4–437–45. account for the rise in health care spending? Health Aff Dermatol 2006;55: 490–500. and the Society for Investigative Dermatology. J Am Acad Academyproject oftheAmerican Association ofDermatology Faulkner E,etal.Theburdenofskindiseases:2004:Ajoint Psoriasis. JAmAcadDermatol 1984; 11: 937–947. Venereol 2017;31: 205–212. worldwide epidemiology of psoriasis. J Eur Acad Dermatol 137: 26–30. the National Eczema Association. J Invest Dermatol 2017; AA. Theburdenofatopicdermatitis:summaryareportfor 2013; 132:1132–1138. factors: A sociations withasthmaand otherhealthdemographic

US population–based study. J Allergy Clin Immunol - 12. 11. 10. 28. 27. 26. 16. 25. 19. 15. 24. 22. 18. 14. 13. 23. 21. 20. 17. 9. 8. Chen Y, Fang Q, Wang Z,ZhangJY, MacLeodAS, HallRP, et Akiyama T, Ivanov M, Nagamine M, Davoodi A, Carstens MI, Wilson SR, Gerhold KA, Bifolck-Fisher A, Liu Q, Patel KN, Imamachi N,ParkImamachi AndersonDJ, LeeH, GH, MI, Simon Shim WS, Tak MH, Lee MH, Kim M, Kim M, Koo JY, et al. Akiyama T, CarstensM, E. Transmitters andpat Sun S, Xu Q, Guo C, Guan Y, Liu Q, Dong X. Leaky gate Gutierrez-Mecinas M, Bell AM, Marin A, Taylor R, Boyle KA, Liu Q, Sikand P, Ma C, Tang Z, Han L, Li Z, et al. Mecha Stantcheva KK,Iovino C,Castaldi Martinez R, L,Dhandapani Cevikbas F, Wang X, Akiyama T, Kempkes C, Savinko T, Antal Liu Q, Tang Z, Surdenikova L, Kim S, Patel KN, Kim A et al. Wan L,JinH,LiuXY, Jeffry J, Barry DM, ShenKF, etal. Sun YG, Chen ZF. A gastrin-releasing peptide receptor medi Huang J, Polgár E,SolinskiHJ, Mishra SK,Tseng PY, Iwagaki Usoskin D, Furlan A, Islam S, Abdo H, Lönnerberg P, Lou Kim S, Barry DM, Liu XY, Yin S, Munanairi A, Meng QT, et al. Akiyama T, Tominaga M, Davoodi A, Nagamine M, Blansit K, Oetjen LK, Mack MR, Feng J, Whelan TM, Niu H, Guo CJ et al. Cevikbas F, Kempkes C, Buhl T, MessC,Buddenkotte J, Stein Mishra SK, HoonMA.Thecellsandcircuitryforitchresponses al. Transient receptor potential vanilloid 4 ion channel fun scratching. J Invest Dermatol 2016; 136:154–160. Ikoma A, et al. Involvement of TRPV4 in serotonin-evoked Neurosci 2011; 14: 595–602. Mas-related Gprotein-coupledreceptor-mediated itch.Nat Dong X, et al. TRPA1 is required for histamine-independent, mechanisms. Proc Natl Acad Sci 2009; 106: 11330–11335. generate behavioral responsestopruritogensviamultiple afferents primary TRPV1-expressing Basbaum AI,etal. 27: 2331–2337. of phospholipaseA2and12-lipoxygenase. JNeurosci2007; TRPV1 mediates histamine-induced itching via the activation 2018; 142:1375–1390. spinal cord.Neuron 2017; 93: 840–853. model: intensity-dependent coding of pain and itch in the and pruritic stimuli.Pain 2017;158:440–456. spinal dorsal horn including cells that respond to noxious superficial mouse the in neurons excitatory of population Furuta T, et al. Preprotachykinin A is expressed by a distinct 2016; 17: 585–600. marked by Ret EMBORep and expression. somatostatin L, Nocchi L, et al. A subpopulation of itch-sensing neurons IL-31neuron–expressed sensory A al. et A, medi receptor 1353–1365. 2009; 139:Cell pruritus. chloroquine-induced mediating receptors itch are Mrgprs GPCR neuron-specific Sensory 2017; 7:15466. Distinct rolesof NMB andGRPinitchtransmission. SciRep and pain. Nature Neuroscience2018;21: 707–716. N, etal.Circuitdissectionoftherolesomatostatininitch 18: 145–153. large-scale single-cell RNA sequencing. Nat Neurosci 2015; D, et al. Unbiased classification of sensory neuron types by Facilitation ofTRPV4by TRPV1isrequiredforitchtransmis pruriceptors. J Neurophysiol 2013; 109: 742–748. peptide as neurotransmitters released by primary afferent Horwitz A,etal.Roles forsubstance Pand gastrin-releasing to mediatechronic itch. Cell 2017; 171:217–228. Sensory neurons co-opt classical immune signaling pathways in mice. Science 2013;340: 968–971. 9: ra71. sion insomesensoryneuronpopulations. Sci Signal2016; histaminergic itch.JBiol Chem2016; 291: 10252–10262. ctions asapruriceptorinepidermalkeratinocytes toevoke 700–703. ates the itch sensation in the spinal cord. Nature 2007; 448: CRC Press;2014,Ch.11. editors. Itch: Mechanisms and Treatment. Boca Raton (FL): Neuroimmune Communication. In: Carstens E, Akiyama T, hoff M. Role of Interleukin-31 and Oncostatin M in Itch and and T ates 14532–14537. nisms of itchevoked by beta-alanine. J Neurosci2012; 32: TRPA1. J Allergy Clin Immunol2014; 133: 448–460. epr eldpnet th Ivleet f TRPV1 of Involvement itch: cell–dependent helper Challenge ofbasicitchresearch Theme issue: Itch and pruritic disorders 7 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV 49. 41. 48. 40. 47. 39. 46. 38. 31. 45. 37. 34. 30. 44. 43. 42. 36. 35. 33. 32. 29. Theme issue: Itch and pruritic disorders 8 Davidson S, ZhangX,Khasabov SG, MoserHR,HondaCN, Q, L,MaC,Liu Han Weng HJ, Y, Cui Tang Asubpopu Z,etal. Albisetti GW, Pagani M,Platonova E,HösliL,Johannssen Schmelz M, Schmidt R, Bickel A, Handwerker HO, Torebjörk Sun YG,ZhaoZQ, MengXL,YinJ, LiuXY, ChenZF. Cellular Tuckett RP. Itch evoked by electrical stimulation of the skin. Ross SE, Mardinly AR, McCord AE, Zurawski J, Cohen S, Gao ZR, Chen WZ, Liu MZ, Chen XJ, Wan L, Zhang XY et al. Foster E,WildnerH,Tudeau L,HaueterS, Ralvenius WT, Lipshetz B, Khasabov SG, Truong H, Netoff TI, Simone DA, CarstensM,AkiyamaCarstens E,Iodi T, Davoodi A,Nagamine Jansen NA,GieslerGJ. Response characteristics ofpruricep Kardon AP, Polgár E,HachisukaJ, Snyder LM,CameronD, Akiyama T, Merrill AW, Carstens MI. Carstens E. Activation Klein A,CarstensMI,E.Facial injectionsof pru Akiyama T, CarstensMI,E.Facial injectionsofpru Akiyama T, CurtisE,Nguyen T, CarstensMI,E. Moser HR, Giesler GJ. Characterization of pruriceptive tri Cameron D, Polgár E,Gutierrez-Mecinas M,Gomez-Lima M, Akiyama T, Nguyen T, Curtis E, Nishida K, Devireddy J, De Braz JM,Juarez-Salinas D, Ross SE,Basbaum AI.Transplant J Neurosci 2019; 39:2238–2250. neuronstransmitexpressing signals. butnotpain itch spinal HC, Fritschy JM, et al. Dorsal horn gastrin-releasing peptide 1997; 17: 8003–8008. Neurosci J skin. human in itch for C-receptors Specific HE. basis of itchsensation.Science 2009; 325: 1531–1534. J Invest Dermatol 1982; 79: 368–373. 2010; 65: 886–898. spinal cord and elevated itch in Bhlhb5 mutant mice. Neuron Jung C,etal.Lossofinhibitoryinterneuronsinthedorsal 2019; 101:45–59. the itch-scratching cycle viadescendingregulation.Neuron Tac1-Expressing neuronsintheperiaqueductalgray facilitate establish glycinergic dorsal horn neurons as key compo Jegen M, et al. Targeted ablation, silencing, and activation 1119–1134. 120: 2018; Neurophysiol J rats. in stimuli pain-producing Giesler GJ Jr. Responses of thalamic neurons to itch- and itch and pain transmission. Itch2018;3:e16. M. Opposingeffects ofcervicalspinalcoldblockon spinal 2014; 82: 573–586. inhibit itchinthedorsalhornofspinalcord.Neuron Savage S, et al. Dynorphin acts as a neuromodulator to 29: 6691–6699. agonist and5-HT: potentialrole in itch.JNeurosci2009; a by mouse PAR-2 the in neurons horn dorsal superficial of Neurol 2016; 524: 244–256. trigeminoparabrachial projectionneuronsinmice.JComp Anatomical evidence of pruriceptive trigeminothalamic and neurons in the mouse. Pain 2015; 156: 2061–2071. Watanabe M,Todd AJ. Theorganisation ofspinoparabrachial neuropathic itch. J Clin Invest 2014;124:3612–3616. restoration ameliorates controls cordinhibitory ofspinal 2011; 106:1078–1088. and trigeminalsubnucleuscaudalisneurons.JNeurophysiol rats andexcite overlapping populationsofprimary sensory or ritogens behavior algogens distinct elicit responses in Neurophysiol 2010; 104:2442–2450. of primaryandsecond-ordertrigeminalneuronsinmice.J ritogens and algogens excite partly overlapping populations 2013; 16: 174–182. lation of nociceptors specifically linked to itch. Nat Neurosci 111: 1574–1589. geminothalamic tract neuronsinrats. JNeurophysiol 2014; the rat. JNeurophysiol 2015;113:58–70. tive andnociceptive trigeminoparabrachial tract neuronsin 2015; 156:1240–1246. Pain itch. chronic receptorsin that expressneurokinin-1 lahanty J, et al. A central role for spinal dorsal horn neurons 1289–1304. 85: 2015; Neuron itch. and pain for gate spinal a of nents 6: 1–10. by scratching PLoSOne2011; andothercounterstimuli. hways mediating inhibition of spinal Itch-Signaling neurons E. Carstensetal. ------58. 57. 50. 56. 55. 54. 70. 53. 69. 66. 52. 68. 65. 60. 51. 67. 64. 63. 62. 61. 59. Reddy VB, IugaAO, ShimadaSG,LaMotteRH,LernerEA. Shelley WB, Arthur RP. Mucunain, the active pruritogenic Koga K,ChenT, LiXY, Descalzi G,LingJ, GuJ, etal.Gluta Namer B, Carr R, Johanek LM, Schmelz M, Handwerker HO, Steinhoff M, Oaklander AL, Szabó IL, Ständer S, Schmelz M. LaMotte RH, Shimada SG, Green BG, Zelterman D. Pruritic Kim D, Kobayashi T, NagaoK.Research techniquesmade Kusube F, Tominaga M,Kawasaki H,Yamakura F, NaitoH, Bautista DM, WilsonSR,HoonMA.Why wescratch anitch: Gao T, Ma H, Xu B, Bergman J, Larhammar D, Lagerström Akiyama T, Tominaga M,Takamori K,CarstensMI, Acton D, Ren X, Di Costanzo S, Dalet A, Bourane S, Bertocchi Bourane S, Duan B, Koch SC, Dalet A, Britz O, Garcia- Davidson S, ZhangX,Yoon CH,Khasabov SG,SimoneDA, Carstens EE,MI,SimonsCT, JinksSL.Dorsal horn Feng J, LuoJ, Yang P, Du J, KimBS, HuH.Piezo2 channel- Akiyama T, Carstens MI, Ikoma A, Cevikbas F, Steinhoff M, Akiyama T, Tominaga M,Takamori K,CarstensMI, Roberson DP, Gudes S, Sprague JM, Patoski HA, Robson VK, Akiyama T, Tominaga M, Davoodi A, Nagamine M, Blansit K, Johanek LM, Meyer RA, Friedman RM, Greenquist KW, Shim Cowhage-evoked itch is mediated by a novel cysteine pro proteinase of cowhage.Science 1955; 122:469–470. man. JNeurophysiol 2008;100:2062–2069. Ringkamp M. Separate peripheral pathways for pruritus in J Neurophysiol 2012; 108: 1711–1723. physiological properties and projection targets in the primate. Simone DA, etal.Pruriceptive spinothalamic tract neurons: Neuropathic itch.Pain 2019; 160:S11–S16. of cowhage.JNeurophysiol 2009; 101: 1430–1443. and nociceptive sensations and dysesthesias from a spicule 2019; 139:984–990. JInvest dermatitis. mousemodelsofatopic simple: Dermatol 2016; 627:51–60. dorsal horn neurons in spinal itch transmission. Neurosci Let natriuretic peptide- and gastrin-releasing peptide-responsive Ogawa H, et al. Electrophysiological properties of brain- 17: 175–182. the molecules, cells and circuits of itch. Nat Neurosci 2014; MC. TheNeuropeptideYSystem Regulates Both Mechani nonhistaminergic itch. Pain 2014;155:80–92. peptide as spinal neurotransmitters of histaminergic and E. Roles of glutamate, substance P, and gastrin-releasing Cell Rep 2019;28: 625–639. form an essential excitatory pathway for mechanical itch. I, et neuropeptide Y1 receptor-expressingal. Spinal neurons 350: 550–554. subpopulation of spinal cord interneurons. Science 2015; Campmany L, et al. Gate control of mechanical itch by a cowhage activate separate populationsof primate spinot GJ Giesler Jr. The itch-producing agents histamine and rats. Neuroreport2010; 21: 303–308. neurons expressingNK-1 receptorsmediatescratching in itch. Science 2018;360: 530–533. Merkel cell signaling modulates the conversion of touch to J Invest Dermatol 2012; 132: 1886–1891. Carstens E. Mouse model of touch-evoked itch (alloknesis). E. Role of spinal bombesin-responsive neuronsinnonhista Blasl F, etal.Activity-dependent silencingreveals functio Horwitz A, et al. Cross-sensitization of histamine-indepen nonhistaminergic itch. JNeurosci2008;28: 7659–7669. in afferents C-fiber polymodal for role A al. et J, Borzan B, in mammalianspinal cord. Mol Pain 2011; 7: 47. sensitive and insensitive itch-related synaptic transmission mate actsasaneurotransmitter peptide- releasing forgastrin 2405–2411. 138: 2018; Dermatol Invest J Itch. Histaminergic and cal minergic itch. J Neurophysiol 2014; 112:2283–2289. 2013; 16: 910–918. nally distinct itch-generating sensory neurons. Nat Neurosci 2012; 226:305–312. dent itchinmouseprimarysensoryneurons.Neuroscience halamic tract neurons. J Neurosci 2007; 27: 10007–10014. 2008; 28: 4331–4335. tease: aligand of protease-activated receptors.JNeurosci ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV corneum (SC)islargely responsible forthebarrierfun the most superficial layer of the skin, of which the stratum barrier functionoftheskinisexertedbyepidermis, This isan open access article under the CC BY-NC license.www.medicaljournals.se/acta 1 somatosensory sensationof itch,especiallychronicitch the with associated closely is and surface, fissured and Dry skinischaracterized by ascaly, rough,cracked, DRY SKIN excessive waterlossandleadstoskindryness(1,2). of waterintheSC.Impairedskinbarrierintegritycauses moisturizing factor, which has a key role in the absorption barrier againstdiffusion ofwateracrosstheSC,andnatural of SChumidity:intercellularlipids,whichformthemain ction. There are2elementsimportantforthemaintenance S Japan. E-mail:[email protected] Graduate School of Medicine, 2-1-1 Tomioka, Urayasu, Chiba 279-0021, tute for Environmental and Gender Specific Medicine, Juntendo University Corr: Acta DermVenereol 2020;100:adv00024. Accepted Oct15,2019;PublishedJan9,2020 mouse model. Key words: tic strategiesforitchindryskinconditions. theupdatedpathogenesissummarizes andtherapeu havethusfor itching beendeveloped. Thisreview and sensitization of Several itch. thera­ and non-neuronal cellsintheinitiation, modulation, been acquiredinto the neurones interplay between a histamine-independentpathway.Newinsights have thehypothesissupporting is itch that dryskin-induced kines, areresponsible for itch and its hypersensitivity, ceptor family, transient receptor potential, and chemo and mas-related receptors,G e.g. protein-coupled re by water model have revealed that many mediators studies using Animal the acetone and ether followed is amixture of acetone andetherfollowed bywater. ofvestigate itch mechanisms associated with dry skin Catharina Mechanisms andManagementofItchinDrySkin and treatments. One ofthe basicmouseand treatments. models to in as kidney diseases, with an unclear pathomechanism as atopic dermatitis,such andsystemicdisorders,such accompanies pathological conditions, dryskin-based Chronic itch is a burdensome clinical problem that often Juntendo University Graduate School of Medicine, and Journal Compilation ©2020ActaDermato-Venereologica. Juntendo Itch Research Center (JIRC), Institute for Environmental and Gender Specific Medicine, Specific Gender and Environmental for Institute (JIRC), Center Research Itch Juntendo logical barrieragainsttheexternalenvironment. The kin, the body’s largest organ, serves as a first physio Mitsutoshi Tominaga, Juntendo Itch Research Center (JIRC), Insti- (JIRC), Center ResearchTominaga, Itch Mitsutoshi Juntendo Sagita MONIAGA dry skin; hypersensitivity; itch; sensory neuron; 1 , Mitsutoshi TOMINAGA Centenary theme section:ITCHANDPRURITIC DISORDERS peutic options 3 Department of Dermatology, Juntendo University Urayasu Hospital, Chiba, Japan REVIEW ARTICLE 1,2 and Kenji TAKAMORI ------are notfullyeffective inmanydermatologicalandsyste levels. All ofthese factors mayleadtoitchinduction(10). sebaceous and sweat glands; and (v ( and intercellular lipid matrix changes; (ii) pH variations; terations inthebarrierfunction ofSC,includingcellular skin changesintheelderlyarerelatedtoxerosis:(i ≥ aged individuals of 50% over conditions intheagedpopulationworldwide(8),affecting Aged skin.Xerosisisoneofthemostprevalentdryskin Disease-related dryskin comfortable, butalsoaffect patientspsychologically(7). manifestations ofdryskinarenotonlyphysicallyun clinical and signs The (1). used commonly are pH and tion, transepidermal water loss (TEWL), SC hydration, as filaggrin mutations (1, 5, 6). To assess skin barrier func exposure, temperature, humidity, and genetic factors, such which can be caused byenvironmental factors, such as sun tion ofdryskinisimpairedfunctionthebarrier, (histamine-independent) itch(2). The underlyingcondi dry skin is an important feature of antihistamine-resistant mic diseasescharacterizedbydryskin,suggestingthat however, antihistamines (histamine H diseases (CLD),anddiabetesmellitus(DM)(4). such aschronickidneydisease(CKD),liver cutaneous manifestationinpruriticsystemicdiseases, atopic dermatitis(AD),andpsoriasis,isacommon clinical manifestationofdermatoses,suchasxerosis, (3). Dryskinwithchronicitchisthemostcommon activity of iii) alterationsinSCproteases; (iv)reducedactivityof py, phospholipids, antioxidants, and emollients. for itchinghave thusbeen developed, suchasphotothera and central nervous system. Several therapeutic options itch signallingamong theskinnervous system, skincells, kinds of mediators, receptors, and channels are involved in to be the primary cause of itch induced by dry skin. Many ney diseases. A decline in skin barrier function is thought conditions, such as xerosis, atopic dermatitis, liver and kid 6 weeks, often accompanies pathological dry skin-based treatments are unclear. Chronic itch, which lasts more than life, and for which the pathomechanism and appropriate Itch isan unpleasant sensation thatmay disturbquality of SIGNIFICANCE Histamine is a well-known substance that induces itch; 1–3 Acta DermVenereol 2020;100: adv00024 2 Anti-aging SkinResearchLaboratory, doi: 10.2340/00015555-3344 65 years (9). Multiple Multiple (9). years 65 ) decreased oestrogen 1 -receptor blockers) -receptor blockers) ) al - - ­ - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue: Itch and pruritic disorders clinically apparentdryskin, patientswithdiabeteshave activity inpatientswithDM. Evenintheabsenceof reduced hydration of the SC and reduced sebaceous gland pruritus (21).Clinicalobservations aresupportedbya type 2DM,e.g.cutaneous infection,dryskin,and prise a broad spectrum of disorders in both type 1 and reflect itsdegreeinpatientswithCLD(20). opioids correlateswiththeseverityofpruritusandmay recently thattheplasmadynorphin A levelofendogenous ids, histamine,serotonin,andsteroids(19). We reported may beinvolved,includingbilesalts,endogenousopio substances (18). Several potentialitch-causing of 40.3% stood and often refractory to treatment, with a prevalence always correlatewithpruritus(17). bilayer abnormalities,anddrynessoftheskin,donot skin, such asthedegreeof hydration of the skin, lipid objective measurementsofthebarrierfunction suggested thatdryskincancauseitchinCKD;however, part, fordryskininuraemicpatients(16).Ithasbeen lities ofeccrinesweatglandsmay account, atleastin dialysis subjects(45%)(15). The functionalabnorma stages ofCKD,butit is morefrequentlydiagnosedin CLD, andDM(4).Skindrynessmayappearatdifferent manifestation in pruritic internal diseases, such as CKD, Systemic diseases.Dryskinisalsoacommoncutaneous states, especiallyinacuteandchronicphases. intraepidermal nerves fluctuate in different skin disease that thedensity, structure,andfunctionalproperties of sprouting of nerves is possible. Another possibility is ment membranewerereduced,increasedintraepidermal speculated that,althoughthenervescrossingbase nerves crossingthebasementmembrane. The authors epidermis, observedasadecreasednumberofcutaneous AD, butitwasnotrelatedtohyperinnervationinthe hyperesthesia inpatientswithchronicpruritus,suchas nerve elongationandsproutingin AD (13). a nerverepulsionfactor(NRF)),arerelatedtothisaberrant elongation factors(NEFs),andsemaphorin3A (Sema3A, amphiregulin (AR),and artemin (ARTN), which arenerve cause ofskinhyperesthesia.Nervegrowthfactor(NGF), SC, due to drying and inflammation, is considered to bea nerve intheepidermistoimmediatelyunderneath as such inflammation, sensory the of Elongation (5). AD an abnormalincreaseinsensitivitytostimuli)occurs cycle”. Skinhyperesthesia(askinconditionthatinvolves matitis (12). This vicious cycle is called the “itch-scratch the affected areaisscratched,thenfurtheraggravatesder induce itchmainlybyactingonthesensorynerves,and are releasedfromtheaffected area(5,11). Pruritogens pruritogens, suchascytokinesandchemicalmediators, the skin barrier, suchas AD and psoriasis. Inthese diseases, symptom indermatosescharacterizedbydysfunctionof diseases. skin Inflammatory 10 Skin disordersarecommoncomplicationsandcom The pathogenesisofpruritusinCLDispoorlyunder More recently, Pogatzki-Zahnetal.(14)reportedskin C. S.Moniagaetal. Dry skin itch is a common Dry skinitchisacommon ------the AEW-treated mice had marked epidermal hyperpla treatment. The histopathologicalanalysisshowedthat increased, andSChydration wasdecreased,underthis consecutive days. TEWL andscratchingbehaviourwere performed twicedailyunderetheranaesthesiafor5–7 was placedonthesameareafor30s. Treatments were after treatment,cotton soakedwithdistilledwater AE (1:1) wasplacedontheshavedareafor15s.Immediately dermis (26,27).Overall,the AEW treatmentproduces epidermis, but no infiltration of inflammatory cells in the sia, parakeratosis, and infiltration of nerve fibres into the cotton (2 start oftheexperiment. To disruptthecutaneousbarrier, over therostralpartofbackatleast3daysbefore of dryskin-induced itch (26). The hair ofmice wasshaved one ofthemostwell-knownmousemodelsforstudy skin model with itch). The AEW-treated mouse model is Acetone/ether/water (AEW)-treated model(chronic dry important factorfortheregulationofitchindryskin(3). C). The increase in intraepidermal nerve fibres may be an penetration of nerve fibres into the epidermis (Fig. 1B and decreased (Tominaga etal.,unpublisheddata)beforethe Sema3A (whichinhibitsnervegrowth)expressionwas increased(3),but was promotenervegrowth) (which we foundthattheexpressionofepidermalNGFand AR in nerve fibre density in the epidermis (Fig.1A).Ofnote, the acetone-treatedmice,althoughtherewasanincrease behaviours orepidermalhyperplasiawereobservedin altered cutaneous barrier permeability. No scratching mice manifestthecharacteristicsofdryskinandhave by 48hafter the treatment. Thus, the acetone-treated normal to returned which treatment, after hour first the increase in TEWL andadecreaseinSChydrationduring We arapid foundthatacetone-treatedmicedisplayed from mastcellsintheskinofacetone-treatedmice(25). levels (3, 24). Others observed the release of histamine acetone treatmentinhibitedtheincreaseinthesemRNA of thebarrierimmediatelyfollowingdisruptionby restoration artificial the and epidermis, the in increased factors, suchasNGFandARTNgeneexpression,were demonstrated thatintraepidermalinnervation-related treated withsterilewater(3,24). balls for5min.Inthecontrolgroup,shavedareawas The shavedareawastreatedwithacetone-soakedcotton part ofthebackatleast3daysbeforeacetonetreatment. application. The hairofmiceisshavedovertherostral itch). Acetone-treated model(acutedryskinwithno Dry skinmousemodels having generalizedpruritus(23). levels were reported to result in a higher probability of glucose postprandial Higher (21). neuropathy diabetic common inpatientswithdiabeteswhohavedryskinor an impaireddesquamationprocess(22).Pruritusismore Analyses of experimental animals treated with acetone Analyses of experimental animals treated with acetone One mousemodeltoinducedryskinusesacetone × 2 cm) soaked in a mixture of acetone and ether 2 cm)soakedinamixtureofacetoneandether - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV due toEFA deficiency. HR-AD causes deterioration of the skin barrier function position of epidermal intercellular lipids (32). Therefore, changes inceramides,and reduced elaborationandde ported todepressskinbarrier functionduetostructural EFA(31). skin re dry was of deficiency symptoms the (EFA)-deficient diet. Feeding HR-AD with EFA inhibits acid fatty essential an is HR-AD that revealed analysis and serumIgEareobserved(30).Lipidcomposition epidermal hyperplasia,and increase in circulating T cells TEWL, andprolongedscratchingboutduration.Marked by adecreaseinskinwater-holding capacity, increasein mice exhibitedseveredryskinsymptomsaccompanied mouse models. Mice were fed HR-AD for 48 days. These diet (HR-AD) is one of the dry skin-based experimental Special diet food model. HR-1 hairless mice fed a special (27, 29),asdescribedlaterinthisreview. a greaterthannormaldurationand/ormagnitudeofitch) ceptive state,inwhichanormallypruriticstimuluselicits non-pruriceptive) andhyperknesis(theabnormalpruri ching behaviourevokedbyastimulusthatisnormally W/W (WBB6F1- mice cell-deficient mast between scratching was noapparentdifference in AEW-induced spontaneous in manychronicitchyconditionshumans(28). There (26), whichrecapitulatethedryskinsymptomspresent changes in gene expression in sensory nerves and the skin marked skinbarrierdysfunction,robustscratching,and epidermis anddermis(basementmembrane), respectively. (red antibody anti-nidogen an with stained was B panel in membrane basement The membrane). (basement dermis and epidermis the between border the indicate A panel in (blue). Thebroken lines DAPI by counterstained are Nuclei (green Sema3A (green NGF of expression Maximum antibody.C) (B,anti-PGP9.5 an dry skinmodelmice. Fig. 1. Alterations in nerve fibre distribution, and nerve growth factor (NGF) and Sema3A expression in the epidermis of acetone-treated This dryskinmodelalsoexhibitsalloknesis(scrat V ) andnormallitter-mates (WBB6F1- ) was decreased 24 h after acetone treatment (C). These expression levels gradually returned to normal by 168 h after the treatment. the after h 168 by normal to returned graduallylevels expression These (C). treatment acetone after h 24 decreased was ) (A) Sequential alteration of intraepidermal nerve growth in acetone-treated mice was examined by immunohistochemistry using +/+ ) (26). ) (26). Arrowheads ) was noted 16–24 h after the treatment (B). In contrast, the expression level of level expression the contrast, In (B). treatment the after h 16–24 noted was ) indicateepidermalnerve fibres(green).Scalebars:15μm. - - - - Using mensional extracellular matrix(ECM)barriers (Fig. 2). several MMPsforgrowth cones topenetratethe3-di process ofcutaneousnerve growthindryskinrequires metalloproteinaseMatrix (MMP)-2 andMMP-8.The regulation ofitching(34). endothelial cells, and may be indirectly involved in the also acton keratinocytes, immunecells, and vascular tinocytes (5, 13). These axonal guidance molecules may and AR, andNRFs,suchasSema3A, producedbykera regulated bythebalanceofNEFs,suchasNGF, ARTN The controlling mechanism of cutaneous nerve density is and AD (13),aswellindryskinmicemodels(3, 33). pruritic dermatologicaldiseases,suchassenilexerosis density hasbeenobservedintheskinofpatientswith dermal junctions. An increasedintraepidermalnerve most cutaneous nerve fibres terminate under dermoepi under terminate fibres nerve cutaneous most Nerve elongation and repulsion factors. In healthy skin, Sensory neurones resulting intheperceptionofitch(Fig.2). ascending sensorypathwaytothesomatosensorycortex, The evokedactionpotentialistransmittedthroughthe fibre afferents andthinlymyelinated Aδ-fibre afferents. on peripheral sensoryafferents, e.g.unmyelinated C- itch-inducing substancestotheircognatereceptors The sensationofitchisgeneratedbythebinding MECHANISMS OFITCHINDRY SKIN ). White and in vitro modelsofECM,wefound thatMMP-2 Mechanisms andmanagementofitchindryskin broken lines indicate the skin surface and the border Theme issue: Itch and pruritic disorders 11 - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue: Itch and pruritic disorders of consist fibres nerve peripheral epidermal elongated the in fibres. increase nerve An stimulate turn in which ferent cellpopulations in the different layersof the skin, sensory nervesinthedermis tocommunicatewithdif related peptide(CGRP)are neuropeptidesproducedby Peptidergic fibres. SubstanceP (SP) andcalcitoningene- a reversesignallingpathwayfortheseevents(38). Sema3A stimulation of growing nerve fibres may provide signalling inhibits integrin-mediated adhesion signalling, long-distance axonextension (37). As class 3 semaphorin and efficient for necessary is signalling ECM-integrin ting thatthecoordinatedactivationofneurotrophinand be required for efficient nerve fibre penetration, sugges may fibres nerve growing the surrounding components and up-regulationofMMPscorrespondingtotheECM by NGFanddown-regulatedSema3A. The selection expression ofMMP-2andMMP-8wereupregulated in nervegrowthwithinthedermis(36). The levelsof involved be to reported was fibres nerve by secreted into thebasementmembrane(35).Inaddition,MMP-8 localized onthegrowthconefunctionedinpenetration signalling, alongwithastrocytosisinthespinalcord.Moretreatmentsha itch in involved also are cluster) (NP C-fibres non-peptidergic the KCs, from released substances to addition In epidermis. the penetrate fibres nerve sensory more diseases, skin inflammatory accompanyingitch-scratchor skin the systemic dry in chronic cycle,as In such (C) phase. this in symptoms which leads to the penetration of nerve fibres into the basement membrane and their growth. Emollients and phospholipids are effective at(TSLP) and interleukin alleviating(IL)-33 released from KCs. NGF the also promotes matrix metalloproteinase (MMP)-2 and MMP-8 production in sensory nerve fibres, prominent and induces the elongation of cutaneous nerve fibres into the epidermis.is ThisKCs, by produced elongation(NEF) factor elongation nerve may epidermal an (NGF), alsofactor growth nerve conditions, beskin dry acute affectedin stimuli environmental During by (B) thymic junction. stromal dermo-epidermal lymphopoietin the under fibres nerve cutaneous the maintains It dominant. is (KCs), keratinocytes by mainly produced (NRF) factor repulsion nerve a Sema3A, skin, healthy In (A) itch. of recognition the in resulting cord, spinal the through brain the in cortex somatosensory the to their respective receptors/channels expressed in peripheral sensory afferents. Electric signalsgenerated in the peripheral nerve endings are transmitted itch. The of dryskin-induced perception and management Fig. 2.Mechanisms of itch starts when endogenous and exogenous itch mediators activate 12 C. S.Moniagaetal. - - ve beenconfirmedtobebeneficialinthiscondition. sis ofneurochemical criteria. The peptidergic neurones are out ( essential forthedevelopmentofGRPR factor Tlx3 inthespinalcordwasdemonstratedtobe response tomultiplepruritogens(41). The transcription scratching the in reduction significant in resulted rones rones. GeneticablationofGRP receptor(GRPR) Huang et al. (43)reportedthat et Huang Tlx3 conditionalknock subset ofpeptidergic dorsalrootganglion(DRG)neu small a in expressed specifically and signals itch relays specifically that neurotransmitter a as characterized is the AEW model(39, 40). epidermal peptidergic nerve fibres, has been reported in represent usually which C-fibres, SP/CGRP-containing peptidergic andnon-peptidergic mainlyon theba subsets into divided been have C-fibres fibers. Non-peptidergic chronic itchinthesemice. skin model,suggestingimpairment ofdryskin-induced scratched muchlesscomparedwithcontrolsinthedry expression inmost TrkA-lineage DRGneurones)mice The neuropeptidegastrin-releasing peptide (GRP) Tlx 3 F/F ; Nav1.8-Cre mice specifically lost Tlx3 lost specifically mice + neurones(42). + neu - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV initiation andmaintenance of chronicitch(55). TRPA1-dependent. These genes play diverserolesinthe whereas CCL27and Tenascin C(TNC)are scratch-and TRPA1, andare independentoftheitch-scratchcycle, tor CXCR2, lipocalin, Slc9a3r1, and S100A9 require independent changes: AQP3, IL-33, chemokine recep TRPA1 regulatesbothscratch-dependentandscratch- changes intheskin. Among thehumandiseasegenes, scratching, epidermalhyperplasia,andexpressional the dry-skin-evoked phenotypes, including et al.(55)foundthatfunctional TRPA1 isrequiredfor pruritogens, chloroquineandBAM8-22(49,54). Wilson itch behaviourdownstreamof2histamine-independent neuroneactivationandindependent itch,e.g.sensory was previously reported to mediate acute histamine- The ionchannel TRP subfamily A member1(TRPA1) channels areknownaspolymodalcellularsensors. Transient receptor potential family (TRP). The TRP pH areinvolvedindryskin-relateditch. knockout mice (52), suggesting that fluctuations in skin were inhibitedinacid-sensingionchannel3(ASIC3) The increasesinexpressionofMrgprA3 andMrgprC11 that MrgprA3 functionsindryskin-relateditch(53). ced chronicitchinducedby AEW treatment,suggesting Moreover, the ablation of MrgprA3 dry skinmodelmicethaninwater-treated controls(52). and MrgprC11 wasfoundtobehigher in AEW-treated (49–51). The expressionofmRNAsencodingMrgprA3 cently suggestedtobeinvolvedinthetransmissionofitch in theDRGandtrigeminalganglia(TG),werere are expressedonlyonsmall-diametersensoryneurones (48). MrgprA3, MrgprC11, andMrgprD inmice,which subfamilies: MrgprA, MrgprB, MrgprC, andMrgprD-G The Mrgpr familyinmicecanbegroupedintoseveral Mas-related protein-coupled G receptor (Mrgpr) family . endogenous agonistsofthisreceptorinchronicitch(27). responses tothePAR-2 agonist,implicating arolefor larger significantly exhibited mice AEW-treated from the dryskinareaorsystemically. Inaddition,DRGcells attenuated byaPAR-2 antibodyeitherdeliveredlocallyto significantly was animals skin-treated dry in behaviour sidered involved in itch (27,47).Spontaneous scratching CGRP not but fibres, intraepidermal reported that AEW treatmentincreasednon-peptidergic and CGRP involvement in the AEW model, a recent study tin B4(IB4)(44).OnthecontrarytopreviousreportsofSP by thepurinergic receptorandtheplantlectinisolec P2X3 whereas non-peptidergic neuronesarecommonlylabelled mostly marked by neuropeptides, including SP and CGRP, keratinocytes, mastcells,andmacrophages,arecon other than PAR-3 are expressed in cutaneous nerve fibres, 4 members:PAR-1, PAR-2, PAR-3, andPAR-4. PARs Protease-activated receptors (PARs). PARs of consist imiquimod-induced psoriasismousemodel(46). dry skin itch (45),asisobserved in itch behaviour ofthe that a specific subset of non-peptidergic fibres functionin + DRG neurones redu + fibres, suggesting suggesting fibres, AEW-evoked - - - - - a heat-sensitivecationchannelthatisselectivelyexpres were previouslyassociatedwithnon-peptidergic noci (including NP1-3),expressedMrgprd andP2rx3,which with peptidergic nociceptors. The third,theNP cluster (Ntrk1) andCGRP, which werepreviouslyassociated cluster (includingPEP1-2),expressedSP (Tac1), TRKA with myelinatedDRGneurones. The second,thePEP previouslyassociatedparvalbumin (Pvalb),andwas (Nefh)and chain heavy neurofilament expresses which NF1-5), (including cluster NF the is cluster first The cells ofsensoryneuronesfrommouselumbarDRGs. damentally distincttypesofsensoryneurones)insingle into 11reported 4neuronalclusters(furtherdivided fun NP clustersofsensoryneurones. Usoskinetal.(57) tion and/orenhancementofitchindryskin. channel. This mayalsobepartlyinvolvedintheinduc in theskinof AEW modelmiceduetoexpansionofthis innervation density of TRPV1-expressing sensory fibres pain sensations(56). Yu etal.(28)reportedanincreased and DRG,whichplaysanimportantroleinthermal sed inapopulationofprimarysensoryneurones TG revealed that TRPV4 is selectively expressed by epi (60) al. et Luo 59). (58, (5-HT) 5-hydroxytryptamine acute itch elicited byexogenously applied histamine and V member4(TRPV4)wasreported tobeinvolvedin Transient receptorpotentialcationchannelsubfamily Keratinocytes related tothepathomechanismofdryskin-induceditch. new types and classification of neurones may be closely and serotonin,mayengageNP3neurones(57). These chronic states of inflammatory itch, as well as histamine as IL-31 and cysteine leukotrienes, which are linked to may betunedtoNP2neurones,andmediators,such chloroquine andhistamineassociatedwithacuteitch cholestatic disordersmaybetunedtoNP1neurones, response profiles: lysophosphatidic acid associated with least 3classesofitchresponsiveneuroneswithunique and PEP2. Thus, theirdatasupporttheexistenceofat serotonin receptors(Htr1f, mine receptors(Hth1)werefoundinNP2andNP3, Hista NP3. in P2X3 of level low a and markers, Sst) peptide, neurotensin,andsomatostatin(Nppb,Nts, ( (IL)-31 (Il31raandOsmr)-cysteineleukotriene rones (Mrgpra3 andMrgprx1) inNP2,andinterleukin Lpar5) intheNP1class,chloroquine-responsiveneu lysophosphatidic acid–responsiveneurones(Lpar3and detected They itch. inflammatory transduce and sense were reportedtofunctioninitch,andNP3islikely rones. Furthermore,NP1,NP2,andNP3neuronaltypes described inadistinctsubclassofunmyelinatedneu expression oftyrosinehydroxylase(Th)andhasbeen distinct exhibited cluster, TH the fourth, The ceptors. Cysltr2)-responsive neurones, neuropeptides natriuretic TRP cation channel subfamily V member 1(TRPV1) is Mechanisms andmanagementofitchindryskin Theme issue: Itch and pruritic disorders Htr2a) werefoundinNP3 13 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue: Itch and pruritic disorders 10 (CXCL10)andC-X-C motif chemokinereceptor3 al. (68)reportedthatC-X-C motifchemokineligand et Qu (67). neuroinflammation disease-associated and cluding neuronaldevelopment, synaptictransmission, both physiologicalandpathological conditions,in nervous system,wheretheyregulateitsfunctionunder Chemokines. areexpressedinthecentral partly involvedintheinductionofitchdryskin(66). These datasuggestthatthespinalGRP/GRPRsystemis pathway. PI3Kγ the via itch transmit which afferents, is expressedbythecentralterminalsofDRGnociceptive tenuated thescratchingbehaviour, suggestingthatGRPR at route, systemic or intrathecal by inhibition PI3Kγ or related toitch.Inadryskinmodelofitch,GRPRblockade ling cascade,isactivateddownstreamofGPCRsand lipid kinasesthatparticipateintheintracellularsignal a PI3Kγ, (41). behaviour scratching induce sed inthespinalcord.IntrathecalGRP actsviaGRPRto tor (GRPR), a G Gastrin-releasing peptidesystem. The GRP anditsrecep Spinal cord of dryskinitself. by keratinocytesplayanessentialroleinthemechanism ACD, itishighlypossiblethat TSLP andIL-33produced the closerelationshipbetweenitchy-dryskinand AD or 33 productionfromkeratinocytes(64,65).Considering trauma totheskin,suchastape-stripping,promoteIL- stress tokeratinocytes,suchasthatnotedin AD, and revealed thathypo-osmotic model.Studies pruritus inthis present inprimarysensoryneuronesandfoundtolead neurones, whichinnervatetheskin)werefunctionally this study, IL-33 and its receptor ST2 (expressed in DRG in theskinofurushiol-challenged ACD modelmice.In released bykeratinocytesisakeycytokineup-regulated robust itchbehaviours(62). on asubsetof TRPA1-positive sensoryneuronestotrigger and TSLPTSLP actsdirectly releasefromkeratinocytes, calcium signallingpathwayasanessentialregulatorof ORAI1/NFAT the identified al. et Wilsonitch. promote directly withcutaneoussensoryneuronesvia TSLP to communicate it wasfurtherreportedthatkeratinocytes an important role in the development of AD (61).Ofnote, plays lymphopoietin (TSLP)producedbykeratinocytes thecytokinethymicstromal 2 activationinkeratinocytes, Previously, we demonstrated that, possibly through PAR- neous diseasescharacterizedbydryskinandchronicitch. receptors in AEW asdownstreamsignalling. 5-HT signalling secondary to activation of distinct 5-HT mice. Moreover, TRPV4-dependent chronic itch requires of TRPV4 inkeratinocytesreduceditch AEW-treated dermal keratinocytes in mice. Lineage-specific deletion 14 reported as itch-specific signalling molecules and expres Liu etal.(63)alsoreportedthatIL-33producedand AD andallergic contactdermatitis(ACD)arecuta C. S.Moniagaetal. αq -protein-coupled receptor (GPCR), were -protein-coupled receptor (GPCR), were member of member of ------and TLR4 (70, 71), and their important roles, such as spi that primarysensoryneuronesexpress TLRs, e.g. TLR3 produced aftertissueinjury. There isincreasingevidence via recognitionofexogenousandendogenousligands proteins that can mediateinnateandadaptiveimmunity Toll-like receptors (TLR). TLR are type Itransmembrane induced itch(69). an essentialroleinthepathogenesisofchronicdryskin- expressing astrocytesinthespinaldorsalhorn. TLR4 TLR4 mRNA andincreased TLR4 expressionin GFAP- AEW mousemodelexhibitedpersistentupregulationof nal cord glial activation in neuropathic pain (72, 73). The CXCR3 tion, AEW-induced astrocyte activation was reduced in (78). Zetachain-associated proteinkinase70(ZAP70), pathway wasreportedtofunction indryskinpruritus protein chain-associated Zeta 70.TheT-cell kinase signal Others central mechanisms(77). expression ofchronicitchindryskinviaperipheraland full the for required partly is signalling TNF-α/TNFR1 only in the spinal cord. Thus, these findings suggest that skin, DRG,and spinal cord, and TNFR1 expression mice. AEW treatment induced TNF-α expression in the (TNF-α antagonist), and in TNFR1/R2 double-knockout thalidomide (TNF-α-synthesis inhibitor) induced by AEW wasreducedbytheadministrationof receptors, TNFR1 and/or TNFR2 (76).Dryskinitch plasticity inthespinalcordandchronicpainviaits reported to play a central role in regulating synaptic was TNF-α (75). modulators and/or mediators itch key suggests thatcytokinesandchemokinesalsoserveas Tumournecrosisfactor-α (TNF-α). Emerging evidence alloknesis (74). and astrogliosis,whichmayunderliechronicitch signalling isimportantforspinalastrocyteactivation and alloknesis. These findings suggest that spinal TLR4 RS), a TLR4 antagonist,suppressed AEW-induced itch lipopolysaccharide fromRhodobactersphaeroides (LPS- the necktopreventscratching.Intrathecalinjectionof induced astrogliosis was abrogated byplacing collars on an essentialroleinspinalastrogliosisbecause AEW- ced AEW-induced itchandalloknesis.Scratchingplays redu L-α-aminoadipate inhibitor astroglial of injection liosis (GFAP upregulation)inthespinalcord.Intrathecal fewer scratchingresponsesthancontrolmice.Inaddi CXCL10 inthespinalcord,andCXCR3 AEW treatmentinducedtheexpressionofCXCR3and Ofnote, throughneuronalCXCR3. neurones DRG and CXCL10directlyactivatesasubsetofcutaneous (CXCR3) areincreasedintheDRGan ACD model, AEW. This model also induced TLR4-dependent astrog alloknesis, atouch-elicited itch in wild-typemice,after mice exhibitedsubstantialreductionsinscratchingand –/– mice, suggesting that the spinal CXCR3 plays plays CXCR3 thatthespinal mice,suggesting and etanercept –/– micehad –/– - - - -

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV mice exhibited significantly larger responses to the PAR- conditions. Moreover, DRGcellsfrom AEW-treated skin dry PAR-2under 5-HTa and of agonist injections the numberofscratchingbouts evokedbyintradermal to itchprovocationoranactivelyitchyskinlesion(88). secondary when mechanism central a through fibres Aδ ctate stimuli (87). Hyperknesis may be mediated by type-I type ofafferents mediatethe mild itchresultingfrom pun hyperknesis arenotclear, anditremainsunknownwhich threshold toagivenstimulus(86). The mechanisms of itch tonormallyitch-provokingstimuliorlowered term encompassingthestateinwhichthereisenhanced umbrella an as proposed was “hyperknesis” term The Hyperknesis peripheral andcentralmechanisms. both via presumably (85), nalfurafine agonist κ-opioid nists, suchasnaloxoneandnaltrexone(26),the antago μ-opioid of injection subcutaneous by pressed sup significantly was treatment AEWafter scratching visual analoguescale(VAS) score(84).Spontaneous the κ-opioid system, concomitant with a decrease in the therapy downregulated the μ-opioid system and restored patients with AD, andthatpsoralen-ultraviolet A (PUVA) κ-opioid system was downregulated in the epidermis of pressive effects (18, 83). We previously reported that the activation of κ-opioid receptors is believed to have sup μ-opioid receptors is thought to induce pruritus, whereas (a receptor for nociceptin/orphanin FQ). Activation of nociception and enkephalins), for receptor (a δ-type β-endorphins), κ-type (KOR, for a receptor receptor for dynorphins), a (MOR, μ-type receptors, opioid of pes in TLR3 was TLR3-dependent. Spontaneousitchwaseliminated induced markedNGFupregulationintheskin,which the skin,butnotinDRGs.Moreover, AEW treatment elicited a marked 25-fold increase in TLR3 expression in sed by mastcells and keratinocytes (81). AEW treatment sensory nervesandDRGinmice. TLR3 isalsoexpres receptor inmurineitchsignalling,andisexpressedby Toll-like receptor 3. TLR3 wasfoundtobeanimportant increased secretionofIL-2andNGF(80). in dryskinprurituselderlypeople,probablydueto This studyrevealedthatincreasedZAP70isinvolved old AEW micecomparedwith5-month-old AEW mice. addition tothesecretionofIL-2andNGFin22-month- mice. ZAP70 expression was significantly increased, in neous scratchingcomparedwith5-month-old AEW 22-month-old AEW miceexhibited increasedsponta mote NGFsecretioninskin(79). After AEW treatment, as a T-cell receptor, mayinduceIL-2secretionandpro . Previous studies have identified 4 major ty major 4 identified have studies Previous Opioids. of chronicitch(82). dry skinareimportantfortheinductionandsensitization Akiyama et al. (27) reported a significant increase in increase significant a reported (27) al. et Akiyama –/– mice. Thus, TLR3 anditsupregulationinthe ------dry skinitch(29). presence ofalloknesisin this animal modelof chronic of aregion AEW treatmentinmice,suggestingthe mulation elicitedscratchingwhendeliveredattheedge neurones inthespinalcord.Innocuousmechanicalsti hold mechanoreceptorsexcitessensitized itch-signalling central mechanisminwhichtheactivationoflow-thres as itchy skin or alloknesis (90). Alloknesis may reflect a intradermal injectionofhistamine,aphenomenonknown surrounding asiteofexperimentalitch induced by the itch whendeliveredwithinaregionofnormalskin Innocuous mechanicalstimuliwerereportedtoelicit Alloknesis pathways. is consistentwiththesensitizationofitch-signalling which hyperknesis, reflects This skin. itchy chronic in enhanced is agonists, PAR-2 and 5-HT as such gens, highlight the importance of itch-responsive amygdala population oftheamygdala inadultmice. These results like behaviourandincreased neuroneactivityinasub acute itchstimuli,suchas histamine, inducedanxiety- of anxiety (95). Recently, Sanders et al. (96)reportedthat in AEW-treated micewithchronicitch. of the hypothalamic pituitary adrenal (HPA) axis function behaviour. They also demonstrated primary disturbance haviours were significantly related to the itch-associated chronic itchevolvesovertime. The moodimpairmentbe AEW treatment, suggesting that mood impairment due to weeks anddepression-likephenotypes3–4after that AEW micedevelopedanxiety-likesymptoms2–3 psychiatric illnesses (70%)(93). Zhao et al. (94)reported with highincidencesofsuicidalmotivation(21.1%)and chological burden produced by chronic itch was reported predominantly indermatologicalpatients(7). The psy ment ofmooddisorders,suchasanxietyanddepression, Chronic itchisclinicallycorrelatedwiththedevelop ITCH OFDRY SKIN AND ANXIETY critical inmodulatingtheconversionoftouchtoitch. that cutaneous Piezo2 channel-Merkel cell signalling is tected againstalloknesisindryskin. These datasuggest alloknesis. Chemogenetic activation of Merkel cells pro associated mechanosensitive Piezo2 channels produced cells. Targeted geneticdeletionofMerkelcellsandits loknesis in dry skin is associated with a loss of Merkel adapting afferents (91).Fengetal.(92)reportedthat al ported to make “synapse-like” contacts with type I slowly This impliesthatacuteitchelicitedbycertainprurito PAR-2 agonistinthismodelhavebeenreported(89). intradermal to neurones horn dorsal superficial lumbar 2 agonist and 5-HT. Furthermore, enhanced responses of Merkel cells,thetouchreceptorsinskin,werere The amygdala is the key brain region for the generation The amygdala is the key brain region for the generation Mechanisms andmanagementofitchindryskin Theme issue: Itch and pruritic disorders 15 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV and H cream, ontoacetone-induceddryskinreducedthenum of emollients, e.g. hydrophilic petrolatum and heparinoid In ourpreviousstudy, immediateanddelayedapplication Emollients innervation indryskinconditions. partly improveskinbarrierfunctionandepidermalhyper histamine-independent; however, antihistaminesmay pruritic conditions, AEW-induced itch is thought to be by acetonetreatment(99).Similartomanyintractable hyperplasia inmicewhoseskinbarrierwasdisrupted downregulated NEFs(NGFand ARTN) mRNA innor with AD (97). We patients recentlydemonstratedthatbepotastine in pruritus for beneficial be to reported were Theme issue: Itch and pruritic disorders Table I.Therapiesfordryskin-induceditch of gel-like moisturizing lotion (TSG), which contained levels inthemouseskin(33).Inaddition,application NGF and fibres nerve intraepidermal penetrated of ber H of application topical that found nerve density indryskinconditions (98). Another report fective forcontrollingitchassociatedwithepidermal H histamine the via mechanisms NF-kB-dependent mediated by the transcription activity of AP-1- and/or mal humanepidermalkeratinocytes. The alterationwas H Second-generation Antihistamines Table I). the managementofdryskin-induceditch(Fig.2and models werereported,therehavebeenmanystudieson Since themechanismsofdryskin-induceditchinanimal MANAGEMENT OFDRY SKIN-INDUCED ITCH tions duetodryskin. behaviour, which may also apply to chronic itch condi neurones in the regulation ofitch-related effects and 16 that second-generation H second-generation that receptor. These results provide therapeutic evidence Second generation of H1-antihistamines, e.g. bepotastine Adjunctive treatment Fish oil Antioxidants Collagen tripeptide μ-receptor antagonist& κ-opioidagonist Neurotropin Systemic treatment • Excimer lamp • • Phototherapy Film dressings • hydrophilic petrolatum, heparinoid cream, gel-like moisturizing lotion Emollients Topical treatment Therapeutic method Narrowband ultraviolet B Psoralen ultraviolet A 2 (famotidine)-antihistamines prevented epidermal prevented epidermal (famotidine)-antihistamines C. S.Moniagaetal. 1 -antihistamines (e.g.bepotastine) 1 -antihistamines maybeef 1 (diphenhydramine) • Reduction in nerve elongation factors and epidermal hyperplasia • Improvement of skin barrier function • Inhibitionof oxidative stress in theperiphery • Reduction in epidermal nerve density, normalization of axon-guidance factors • μ-receptorantagonist and κ-opioid agonist in the central nervous system • Reduction in epidermal nerve density • Induction of cutaneousnerve degeneration  • Normalization of expression levels of nerve elongationfactors and nerve repulsion factors • Prevention of mechanical stimulus • Reduction in epidermal nerve density • Reduction in epidermal nerve density Mechanisms ofantipruriticeffects Reduction in epidermal nerve density ­ - - - - 1

epidermis (104). the abnormal expression ofNGFand Sema3A in the in thismodel.PUVA+BV and NB-UVBalsonormalized cantly reducedtheintraepidermalnervegrowthinduced signifi treatments lamp excimer and NB-UVB, (BV), model, PUVA, PUVA+betamethasone valerate ointment (103). Furthermore, in the acetone induced-dry skin mice reduces epidermalhyperinnervationinpatientswith AD psoriasis (102). In ourprevious study, PUVAtherapy ment ofchronicpruritusinpatientswith AD (101)and skin-related cutaneous or systemic diseases (106, 107). skin-related cutaneousorsystemicdiseases(106,107). κ-opioid receptor agonists were found to inhibit itch in dry agonists (85). Clinically, μ-opioid receptor antagonists and μ-opioid receptor antagonists (26) and κ-opioid receptor Dry skin-relateditchinanimalmodelswassuppressedby Opioids degeneration andreducedDNA damage(105). with COFareduetothe induction of epidermal nerve that theantipruriticeffects ofexcimerlampirradiation acetone-induced dryskinmousemodel. This suggests butane pyrimidine dimer, a DNA damage marker, in the reduced hyperinnervationandtheproductionofcyclo to thelamp,thusdecreasingcytotoxicwavelengths, monstrated that attaching a cut-off excimer these in changes degenerative induced nerve of tion ultraviolet B (NB-UVB), are efficacious in the treat the in efficacious are (NB-UVB), B ultraviolet UV-based therapies,suchasPUVA andnarrowband- Phototherapy inhibition ofepidermalhyperinnervation(100). by chronicdryskinthroughamechanisminvolvingthe that topicalapplicationof TSG attenuatesitchinduced in theepidermisof AEW-treated mice. This suggests nerve fibres, and induced higher expression of Sema3A and agar, reduced the number of infiltrated intraepidermal water, glycerin,urea,methylparaben,propyl In addition, we reported that excimer lamp irradia bres formed by cultured DRG neurones DRG cultured by formed fibres bres. We de We fibres. filter (COF) - - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV in acetone-treatedmicewasreducedbytheintraperito vitro (111). Moreover, theintraepidermalnervedensity NGF-induced neuriteoutgrowthofDRGneuronesin sample study(110). We foundthatneurotropininhibits inamulticentre,open-label,small pruritus resistant was reportedasaneffective treatment for antihistamine- virus, vaccinia with inoculated rabbits of skin inflamed Neurotropin, anon-proteinextractisolatedfromthe Neurotropin receptors (109). μ-opioid the to affinity high effectsand antagonistic its treatment optionforopioid-inducedpruritusbecauseof systematic review suggested that nalbuphine is asuperior clinically indicatedformoderatetoseverepain(108). A κ-opioid receptors agonist-μ-opioid receptors antagonist, in theepidermis,addition toreducingpruritus(120). improves dryskinandnormalizes axon-guidancefactors lagen tripeptide to acetone-induced dryskin model mice in murineskinvivo(119). Oraladministration ofcol acid production in human dermal fibroblasts many biologicaleffects, such asenhancinghyaluronic low allergenic collagenfractionthatisknowntohave non-antigenic, purified, highly a is tripeptide Collagen Collagen tripeptide itch by reducing intraepidermal nerve fibre density (118). for thepreventionand/oralleviationofdryskin-induced dry skin. Thus, dietary MPLs may have beneficial effects the Sema3A levelinamousemodelofacetone-induced dermis byreducingepidermalNGFlevelsandincreasing MPLs attenuate the penetration of nerve fibres into the epi mouse model(117). Recently, wereportedthatdietary HR-AD the in function barrier skin (116),improved and mice HR-1 hairless normal in hydration SC increased as beneficial effects on epidermal functions (116, 117), such milk-derived sphingomyelinhavebeenreportedto improved scratchingbehaviour(115). dry skin rat model restored the skin barrier defects and a well-known sourceofn-3PUFA, inan acetone-induced barrier function (113, 114). Supplementation of fish oil, because theircontentwithintheskinregulates metabolites playanessentialroleinskinhomoeostasis dies suggestedthatn-3PUFA andrelatedmonohydroxy (n-3) polyunsaturatedfattyacids(PUFA). Previousstu 3 omega representative are 6n-3) 22: (DHA, acid enoic Eicosapentaenoic acid(EPA, 20:5n-3)anddocosahexa Phospholipids expression ofSema3A intheepidermis(112). neal administration of neurotropin, probably through the Nalbuphine is a synthetic opioid analgesic, a mix of Dietary milk-derivedphospholipids(MPLs)and in vitro and - - - - - found thatthelevelofNGFinmouseepidermissig of theskin(124).Consistentwiththis,weandothers mice. Filmdressingsmayreduceitchhypersensitivity tion andalloknesisinthe AEW-induced dryskinmodel to contamination,alleviatedtheepidermalhyperinnerva an appropriatelymoistenvironmentandactasabarrier dressings, which are usedforwoundtreatment toprovide film of application the that reported recently,we More Film dressings on dryskin-induceditch. tert-butyl-a-phenylnitrone, may have therapeutic effects Thus, antioxidants,suchasN-acetyl-L-cysteineandN- and suppressionofp-ERKactivationinthespinalcord. tion ofoxidativestressintheperiphery(affected skin) The authorshavenoconflicts of interest todeclare. from MEXT (S1311011), andKAKENHI(18K07396). FoundationGrant-aidedProjectforPrivateUniversities Research Japan SocietyforthePromotion ofScience(18F18410),Strategic This workwaspartlysupportedbyResearchFellowshipfromthe ACKNOWLEDGEMENTS improve thequalityoflifepatients. complex interactions andto develop antipruritic drugsto Continued studies are required to better understand these including Mrgprs, TLR, cytokines,and TRP channels. nervous system,skincells,andcentralsystems, channels areinvolvedinitchsignallingamongtheskin of dryskin.Manykindsmediators,receptors,and in the AEW model,themostwell-knownmousemodel the primarycauseofdryskin-induceditch,asobserved ment. A declineinskinbarrierfunctionisthoughttobe mechanisms ofdryskin-induceditchanditsmanage This reviewpresentedrecentknowledgeregardingthe CONCLUSION the skin. induced bybarrierdisruptionandmechanicalstimulito skin moisturization prevents epidermal hyper­ disruption bytape-strippingoracetone. This suggeststhat a vapour-impermeable membrane (24) after skin barrier nificantly decreased by occlusion with emollients (33) or bouts of AEW-treated mice, possibly through the inhibi were systematicallyeffective inreducingthescratching in mice(122).Zhouetal.(123)reportedthatantioxidants histamine-independent itchviatheactivationof TRPA1 failure (121).Oxidantsweredemonstratedtoinduce including diseases, psoriasis,andchronicrenalAD, ofitch-relatedskinandsystemicin thepathogenesis Oxidative stresshaslongbeenproposedtoplayarole Antioxidants Mechanisms andmanagementofitchindryskin Theme issue: Itch and pruritic disorders innervation innervation 17 - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue: Itch and pruritic disorders REFERENCES 18 23. 22. 21. 20. 19. 18. 17. 16. 15. 14. 13. 12. 11. 10. 4. 3. 2. 1. 9. 8. 7. 6. 5. agents and itch mechanisms independent of mast-cell his Kuraishi Y. assessmentofantipruritic Methodsforpreclinical treated mice. J Dermatol Sci2007; 48: 103–111. Intraepidermal nerve fibers increase in dry skin of acetone- Tominaga M, Ozawa S, Tengara S, Ogawa H, Takamori K. Dermatol 2017;1. and treatments of dry skin induced itch. J Clin Cosmetic Kamo A,Tominaga M,Kamata Y, Takamori K.Mechanisms 2018; 36: 109–115. Dermatol Clin patient. mature the in skin dry and Toncic RJ, Kezic S, Hadzavdic SL,Marinovic B. Skinbarrier glucose isassociated with generalized pruritusinpatients Ko MJ, ChiuHC,JeeSH,HuFC,Tseng CH.Postprandial blood Diabetol MetabSyndr 2016;8: 63. tes mellitus: an epidemiology and physiopathology review. de MacedoGM,NunesS, Barreto T. Skindisordersindiabe Dartmouth (MA)2000. G, Dungan K,GrossmanA, etal., editors.Endotext.South mellitus. In: Feingold KR, Anawalt B, Boyce A, Chrousos Rosen J, Yosipovitch G. Skin manifestations of diabetes report. Acta Derm Venereol 2019; 99:442–443. the degree of pruritus in chronic liver disease: a preliminary N, Kina K, et al. Plasma dynorphin A concentration reflects Moniaga CS, Iwamoto S, Kitamura T, Fujishiro M, Takahashi theses 2018; 110: 86–89. opiate agonists: relevant after all these years. Med Hypo Bergasa NV. Thepruritusofcholestasis:Frombileacidsto E252–E262. 48: 2018; Res study.Hepatol multicenter a disease: liver M, et al. Prevalence of pruritus in patients with chronic Oeda S, Takahashi H,Yoshida H, Ogawa Y, Imajo K,Yoneda Nephrol Dial Transplant 2007; 22: 3268–3272. and their relationship to pruritus in end-stage renal disease. chez DA, Dawn AG, et al. Skin barrier structure and function Yosipovitch G, Duque MI, Patel TS, Ishiuji Y, Guzman-San sweat gland. Nephrol Dial Transplant 1995; 10: 2269–2273. modialysis: the role of decreased sweating of the eccrine Dry skin (xerosis) in patients undergoing maintenance hae Park TH, Park CH, Ha SK, Lee SH, Song KS, Lee HY, et al. study. IntJDermatol 2010;49: 1024–1030. mic patientsonhemodialysis:anEgyptiancase-controlled Attia SI,Youssef EA,Hassan ure NM.Cutaneousdisordersin 2019 Jul2. [Epub ahead ofprint]. inhibition isahallmarkofchronicpruritus.JInvest Dermatol Riepe C, et al. Peripheral sensitisation and loss of descending Pogatzki-Zahn EM, Pereira MP, Cremer A, Zeidler C, Dreyer T, Dermatol 2014;41: 205–212. reference to atopic dermatitis: therapeutic implications. J Tominaga M, Takamori K. Itch and nerve fibers with special The neurobiology of itch. Nat Rev Neurosci 2006; 7: 535–547. Ikoma A, SteinhoffM,StanderS, Yosipovitch G,SchmelzM. Dermatol Venereol 2019;33: 147–150. morbidity ofdryskininthe general population.JEurAcad G, Staubach-Renz P, et al. Prevalence, predictors and co Augustin M, Kirsten N, Korber A, Wilsmann-Theis D, Itschert Drugs Aging2015;32: 201–215. pathophysiology, theelderly: in andmanagement. diagnosis Valdes-Rodriguez R, Stull C, Yosipovitch G. Chronic pruritus a clinicalreview. JAMA 2013;310:2443–2450. Berger TG, Shive patient: theolder in Pruritus GM. M,Harper age. Maturitas 2014; 79:256–264. older in health Skin CE. Y,Griffiths Al-Nuaimi MJ, Sherratt pilot study. Acta Derm Venereol 2016; 96: 331–335. in dermatologicalpatientsexperiencingchronicitching:a Quality of life, emotional wellbeingand family repercussions Marron SE, Tomas-Aragones L, Boira S, Campos-Rodenas R. Allergy Clin Immunol2012;129:1153–1155. sistent dry skin andeczema independent of sensitization. J Wahlgren CF. Filaggrinmutationsincreasetheriskfor per Bohme M, Soderhall C, Kull I, Bergstrom A, van Hage M, dermatitis. AllergolInt2017; 66: 8–13. Murota H,Katayama I.Exacerbating factors of itchinatopic tamine. Biol PharmBull2015; 38: 635–644. C. S.Moniagaetal. ------24. 33. 32. 31. 30. 29. 28. 27. 26. 25. 45. 44. 43. 42. 41. 40. 39. 38. 37. 36. 35. 34. Liou A,EliasPM,GrunfeldC,Feingold KR,Wood LC. Amphi with type 2diabetes. Eur J Dermatol 2013; 23: 688–693. Kamo A, Tominaga M, Negi O, Tengara S, Ogawa H, Taka 23: 756–758. Elias PM. The stratum corneum revisited. J Dermatol 1996; deteriotes skinbarrier. Osaka City Med J 2008;54: 63–74. Ishii M. Latent essential fatty acid deficiency in a special diet Ishina K, Kobayashi H, Tsuruta D, Wakamatsu K, Hasegawa J, 2005; 14: 460–468. feeding a special diet to HR-1 hairless mice. Exp Dermatol by caused inflammation skin pruritic dermatitis-like Atopic Fujii M, Tomozawa J, Mizutani N, Nabe T, Danno K, Kohno S. J Invest Dermatol 2012; 132: 1886–1891. Carstens E. Mouse model of touch-evoked itch (alloknesis). Akiyama T, CarstensMI,Ikoma A,CevikbasF, SteinhoffM, 2016; 12: 1–9. itch elicited by capsaicin in a chronic itch model. Mol Pain Yu G, Yang N, Li F, Chen M, Guo CJ, Wang C, et al. Enhanced 378–383. a mouse model of chronic dry skin itch. Pain 2010; 151: evoked by PAR-2 agonist and 5-HT but not histamine in Akiyama T, Carstens MI, Carstens E. Enhanced scratching in mice. Jpn J Pharmacol 2002; 88: 285–292. Itch-associated response induced by experimental dry skin Miyamoto T, Nojima H, Shinkado T, Nakahashi T, Kuraishi Y. Invest Dermatol 1998;111:873–878. J dermatoses. inflammatory of exacerbations seasonal for hyperproliferative responsetobarrierdisruption:implication midity stimulates epidermal DNA synthesis and amplifies the Denda M, Sato J, Tsuchiya T, Elias PM, Feingold KR. Low hu 1997; 108:73–77. by barrierstatusinmurineepidermis.JInvest Dermatol regulin andnerve growthfactorexpressionareregulated Valtcheva MV, Samineni VK, Golden JP, GereauRWt,Da 2008; 99: 1581–1589. tracellular ATP and are putative nociceptors. J Neurophysiol sensory neuronsexpressingthe Mrgprdreceptorsenseex Dussor G, Zylka MJ, Anderson DJ, McCleskey EW. Cutaneous Mol Neurosci2017; 10: 205. root ganglionispivotal toitchand painsensations.Front Huang C, Lu F, Li P, Cao C, Liu Z. Tlx3 function in the dorsal matic sensory modalities. J Neurosci 2013; 33: 14738–14748. Ontogeny of excitatory spinalneuronsprocessingdistinctso Xu Y, LopesC,Wende H,GuoZ,ChengL,BirchmeierC,etal. 448: 700–703. mediates the itch sensation in the cord. spinal Nature 2007; Sun YG, Chen ZF. A gastrin-releasing peptide receptor dry skinwithitch. Neurosci Lett 2018;672:84–89. but not myelinated A-fibers, elongate into the epidermis in C-fibers, Y.Y,Non-myelinated KuraishiT, Asakawa Andoh 135: 2049–2057. tion, dry skin itch, and dermatitis. J Invest Dermatol 2015; non-peptidergic skin innervation in rat models for inflamma Holstege JC.Differential changes inthepeptidergicand Schuttenhelm BN, Duraku LS, Dijkstra JF, Walbeehm ET, 2008; 33: 161–170. progress made and promises ahead. Trends Biochem Sci Zhou Y, Gunput RA, Pasterkamp RJ. Semaphorin signaling: nervous system. Dev Neurobiol 2011; 71: 1054–1072. mediators ofdevelopment andregeneration ofthesensory NJ.Gardiner andtheextracellular Integrins key matrix: models. J Invest Dermatol 2011;131:2105–2112. implications for possible application to pruritus from in vitro trix metalloproteinase-8 is involved in dermal nerve growth: Tominaga M,Tengara S, Kamo A,Ogawa Takamori H, K.Ma intractable pruritus.Br J Dermatol 2009; 161: 1028–1037. basement membrane: implications for possible application to tro model for penetration of sensory nerve fibres on a Matrigel Tominaga M, Kamo A, Tengara S, Ogawa H, Takamori K. In vi 1241–1247. nisms andtreatmentsofitch.Biol PharmBull2013;36: Tominaga M, Takamori K. An updateonperipheral mecha mice. J Dermatol Sci2011;62:64–66. inducible intraepidermal nerve growth in acetone-treated mori K. Topical application of emollients prevents dry skin------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV 64. 63. 62. 61. 60. 59. 58. 57. 56. 55. 54. 53. 52. 51. 50. 49. 48. 47. 46. response. J Invest Dermatol 2019;139:81–90. duction in human keratinocytes – an epidermal homeostatic TE, HolFosse J, et al.Hypo-osmoticstressdrives IL-33 pro Pietka W, Khnykin D, Bertelsen V, Lossius AH, Stav-Noraas allergy. Proc Natl Acad Sci U S A 2016; 113: E7572–E7579. ates itch response in a mouse model of poison ivy contact et al. IL-33/ST2 signaling excites sensory neurons and medi Liu B, Tai Y, AchantaS, Kaelberer MM,CaceresAI,ShaoX, 155: 285–295. cytokine TSLP activates neurons to induce itch. Cell 2013; Clain SP, etal.Theepithelial cell-derived atopic dermatitis K,Katibah LM,Beattie TheL,Batia SR, Wilson Mc GE, flaky tailmice. Am J Pathol 2013;182:841–851. thymic stromal lymphopoietin and basophil accumulation in M, Jeon JE, et al. Protease activity enhances production of Moniaga CS, Jeong SK, Egawa G,Nakajima S, Hara-Chikuma 608–619 e7. nonallergic chronic itch. J Allergy Clin Immunol 2018; 141: and keratinocytes contribute differentially toallergicand receptor potential vanilloid 4-expressing macrophages Luo J, Feng J, Yu G, Yang P, Mack MR, Du J, et al. Transient histaminergic itch.JBiol Chem2016; 291: 10252–10262. ctions as a pruriceptor in epidermal keratinocytes to evoke al. Transient receptorpotentialvanilloid 4ionchannelfun Chen Y, Fang Q, Wang Z,ZhangJY, MacLeodAS, HallRP, et scratching. J Invest Dermatol 2016; 136:154–160. Ikoma A,etal.Involvement ofTRPV4inserotonin-evoked Akiyama T, Ivanov M, Nagamine M, Davoodi A, Carstens MI, 18: 145–153. large-scale single-cell RNA sequencing. Nat Neurosci 2015; D, et al. Unbiased classification of sensory neuron types by Usoskin D, Furlan A, Islam S, Abdo H, Lonnerberg P, Lou cilitation modulates chronic pain. Neuron 2014; 81: 873–887. terminal sensitization of TRPV1 by descending serotonergic fa Kim YS, Chu Y, Han L, Li M, Li Z, LaVinka PC, et al. Central J Neurosci 2013; 33:9283–9294. TRPA1 channel The ion DM, etal. itch. requiredforchronic is Wilson SR, Nelson AM, Batia L, Morita T, Estandian D, Owens Neurosci 2011; 14: 595–602. Mas-related Gprotein-coupledreceptor-mediated itch.Nat Dong X, et al. TRPA1 is required for histamine-independent, Wilson SR,GerholdKA,Bifolck-Fisher A,LiuQ, Patel KN, 2013; 16: 174–182. lation of nociceptors specifically linked to itch. Nat Neurosci Han L, Ma C, Liu Q, Weng HJ, Y,Cui Tang Z, et al. A subpopu 13: 387–398. stimulation by acid and nonproton ligand. Cell Rep 2015; ASIC3 mediates itch sensation in response to coincident Peng Z,LiWG,HuangC,JiangYM,Wang X,ZhuMX,etal. mun 2015; 6: 7864. cathepsin Sevokes itchviaactivation of Mrgprs.NatCom receptors: ofprotease-activated concept the Redefining Reddy VB, SunS, AzimiE,Elmariah SB, Dong X,LernerEA. 622–633 e9. severe chronicurticaria.JAllergyClinImmunol2014;134: X2 onmastcellsisupregulatedintheskinofpatientswith Sasaki-Sakamoto T, et al. Expression of Mas-related gene Fujisawa D, Kashiwakura J, Kita H, Kikukawa Y, Fujitani Y, 1353–1365. mediating chloroquine-induced pruritus. Cell 2009; 139: al. Sensory neuron-specific GPCR Mrgprs are itch receptors Liu Q, Tang Z,Surdenikova L,KimS, Patel KN,KimA,et sensory neurons.Cell2001; 106: 619–632. family of GPCRs expressed in specific subsets of nociceptive Dong X,HanS, Zylka MJ, Simon MI,AndersonDJ. Adiverse tors anditch.HandbExp Pharmacol 2015;226:219–235. Akiyama T, LernerEA, CarstensE.Protease-activated recep a mousemodel of psoriasis.Pain 2017; 158: 2196–2202. and increased nonpeptidergic intraepidermal fiber density in LE, Yosipovitch G,etal. Role of neurturininspontaneousitch Sakai K,Sanders KM,Youssef MR,Yanushefski KM,Jensen 2015; 16: 346–356. trigeminal neuronsinamousemodelofdryskinitch.JPain density and an expanded subset of chloroquine-responsive fiber intraepidermal nonpeptidergic Enhanced S. vidson ------76. 75. 74. 73. 72. 71. 70. 69. 68. 67. 66. 86. 85. 84. 83. 82. 81. 80. 79. 78. 77. 65. contributes to spinal cord synaptic plasticity and inflamma Zhang L, Berta T, Xu ZZ, Liu T, Park JY, Ji RR. TNF-alpha 2015; 226:163–176. of cytokinesandchemokinesinitch.HandbExpPharmacol Storan ER, O’Gorman SM, McDonald ID, Steinhoff M. Role astrocyte activation in male mice. Pain 2016; 157: 806–817. receptor 4contributestochronicitch,alloknesis, andspinal Liu T, Han Q, ChenG,Huang Y, Zhao LX, Berta T, etal. Toll-like 2011; 19: 44–53. microglia in a rat model of neuropathic pain. Neurosignals Ketamine depressestoll-like receptor 3signalinginspinal Mei XP, Zhou Y, Wang W, Tang J, Wang W, Zhang H, et al. neuropathy. Proc Natl Acad Sci U S A 2005; 102: 5856–5861. Toll-like neuroimmunity innate receptor 4 in and painful Tanga FY, Nutile-McMenemy N, DeLeo JA. The CNS role of 27: 13033–13041. regulator ofaxonal growthinmammals. JNeurosci 2007; Y, Kosaras B, et al. Toll-like receptor 3 is a potent negative Cameron JS, Alexopoulou L,SloaneJA, DiBernardo AB, Ma sensory neurons.JDent Res 2011;90:759–764. KM. LPS sensitizes via activationTRPV1 of in trigeminal TLR4 Diogenes A,Ferraz CC,Akopian AN,HenryMA,Hargreaves itch inmice.NeurosciBull 2018; 34:54–63. kine receptorCXCR3 inthespinalcordcontributestochronic Jing PB, Cao DL, Li SS, Zhu M, Bai XQ, Wu XB, et al. Chemo allergic contact dermatitis.Pain 2015; 156:1737–1746. mokine receptor signaling mediates itch in experimental Qu L, Fu K, Yang J, Shimada SG, LaMotte RH. CXCR3 che reduce? Neurotherapeutics 2007; 4: 590–601. mokine receptors in neurological disease: raise, retain, or Savarin-Vuaillat C, Ransohoff RM. Chemokines and che transmission of itch. J Neurosci 2015; 35: 16272–16281. VB, Pereira TC, etal. GRPR/PI3Kgamma: partners incentral Pereira PJ, Machado GD, Danesi GM, Canevese FF, Reddy mins’. Contact Dermatitis 2010; 63: 215–222. Brull SJ, Atanassoff PG,Silverman DG, Zhang J, Lamotte Acta Derm Venereol 2015; 95: 147–150. ching behavior inmodelsofacuteandchronicitchmice. Nalfurafine suppresses pruritogen- and touch-evoked scrat Akiyama T, Carstens MI, Piecha D, Steppan S, Carstens E. Dermatol 2007;127:2228–2235. mal opioidsystemsinpruritusofatopicdermatitis.JInvest Tominaga M,Ogawa H,Takamori K.Possible rolesof epider 12: e0178991. Patient-reported outcomebasedanalyses.PLoSOne 2017; hydrochloride onpruritusinchronicliver diseasepatients: Tsuchiya A, et al. Long-term efficacy and safety of nalfurafine Kamimura K,Yokoo T, Kamimura H,SakamakiA,AbeS, 2195–2207. sensitization, and pruritus in mice. J Clin Invest 2012; 122: deficiency impairs spinal cord synaptic transmission, central Liu T, Berta T, Xu ZZ, Park CK, Zhang L, Lu N, et al. TLR3 Invest Dermatol 2019May 24. [Epub ahead of print] associated mechanism of peripheral itch sensitization. J E, Steinhoff M. TLR3inchronichuman itch:a keratinocyte- Szollosi AG, McDonald I, Szabo IL, Meng J, van den Bogaard Biomed Res Int2016; 2016: 6029538. creased ZAP70isinvolved indryskinpruritusagedmice. Zhao N, Gu M,Yang W, Zhang M, Tian Q, Ru L, et al. In Immunopathol 2010; 32:107–116. C. ZAP70:amasterregulatorofadaptive immunity. Semin A,Picard C,CheminK,DogniauxS,Fischer leDeistF, Hivroz xiv–xv. improvements to be made. J Invest Dermatol 2003; 121: Yosipovitch G.Assessmentofitch:moretobelearnedand mechanisms. Neurosci Bull 2018; 34: 42–53. of acute and chronic itch in mice via peripheral and central TNF-alpha/TNFR1 signaling isrequiredfor the full expression Miao X,HuangY, LiuTT, GuoR,Wang B, Wang XL,etal. Pain 2011;152:419–427. tory pain: distinct role of TNF receptor subtypes 1 and 2. CXCL8 mRNA: new insights into the involvement of ‘alar of involvement the into insights new mRNA: CXCL8 IL-8/and IL-33,TNF-alpha Hsp70, Hsp90, of upregulation M. Standardized tape strippingprior to patch testinginduces Dickel H, Gambichler T, Kamphowe J, Altmeyer P, Skrygan Mechanisms andmanagementofitchindryskin Theme issue: Itch and pruritic disorders 19 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV 106. 105. 104. 103. 102. 101. 100. Theme issue: Itch and pruritic disorders 20 99. 98. 97. 96. 95. 94. 93. 92. 91. 90. 89. 88. 87. gic conditions:asystematicreview. JAMA Dermatol2019; dermatolo inflammatory chronic for treatment naltrexone Ekelem C, Juhasz M, Khera P, Mesinkovska NA. Utility of J Invest Dermatol 2014; 134: 2977–2984. neration and reduces scratching in a dry-skin mouse model. H, et al. The excimer lamp induces cutaneous nerve dege Kamo A, Tominaga M, Kamata Y, Kaneda K, Ko KC, Matsuda 62: 91–97. nerve growth in acetone-treated mice. J Dermatol Sci 2011; Inhibitory effects ofUV-based therapy ondryskin-inducible Kamo A,Tominaga M,Tengara S, Ogawa H,Takamori K. dermatitis. J Dermatol Sci 2009;55: 40–46. NGF levels and modulates epidermal innervation in atopic Psoralen-ultraviolet A therapy alters epidermal Sema3A and Tominaga M,Tengara S, Kamo A,Ogawa H,Takamori K. ultraviolet B therapy. BrJDermatol 2009; 161: 542–546. predictors of time to clearance of psoriasis with narrow-band Kerkhof PC,Kraaimaat FW, Itchandscratching etal. as Evers AW, Kleinpenning MM, Smits T, Boezeman J, van de 106–112. review. Photodermatol Photoimmunol Photomed 2007; 23: erapy in the management of atopic dermatitis: a systematic Meduri NB, Vandergriff T, Rasmussen H,JacobeH.Phototh mouse. J Cosmetics Dermatol Sci Applic 2015; 5: model 254–261. skin dry chronic a in density fiber nerve epidermal H, etal.Topical application of tenshino-softgeltmreduces Noguchi A, Tominaga M, Ko KC, Matsuda H, Suga Y, Ogawa environment. J Invest Dermatol 2001; 116: 261–265. dermal hyperplasia induced by barrier disruption in a dry antagonists accelerate skin barrier repair and prevent epi Ashida Y, Denda M,Hirao T. HistamineH1andH2receptor epidermal keratinocytes. J Dermatol Sci 2018; 91: 219–222. expression of nerve elongation factors in normal human Tominaga M, et al. Bepotastine besilate downregulates the Kamata Y, Sakaguchi A, Umehara Y, Suga Y, Ogawa H, dermatitis. ExpDermatol 2015; 24: 332–333. Church MK, Maurer M. H1-antihistamines and itch in atopic component of itch. J Neurosci 2019; 39: 3345–3356. subpopulation ofamygdala neuronsmediatestheaffective Sanders KM,SakaiK,HenryTD, HashimotoT, Akiyama T. A 2015; 95: 645–652. induced by histamine and capsaicin. Acta Derm Venereol HO. Cerebral networks linked to itch-related sensations Handwerker A, Dorfler R, VogelgsangV, C, Vierow Forster by CRFR1antagonist.Pain 2018; 159: 2201–2213. itch impairsmoodandHPA axisfunctioninmice:modulation Zhao X,Yu C,Ye F, Wang YG,MeiQY, Ma Q, etal.Chronic Derm Venereol 2012;92: 543–546. ideation: a population-based cross-sectional study. Acta Itch and paininadolescentsare associatedwithsuicidal Halvorsen JA, Dalgard F, ThoresenM,BjertnessE,LienL. itch. Science 2018;360:530–533. Merkel cell signaling modulates the conversion of touch to Feng J, Luo J, Yang P, Du J, KimBS, Hu H. Piezo2 channel- Nature 2014;509:622–626. al. Piezo2 isrequiredfor Merkel-cell mechanotransduction. Woo SH,Ranade S, Weyer AD, Dubin AE,BabaY, QiuZ,et alloknesis. Pain 1997; 73: 239–243. effects antagonist H1 pruritus induced on andhistamine Heyer G, Dotzer M, Diepgen TL, Handwerker HO. Opiate and model. JNeurophysiol 2011;105:2811–2817. agonist but not histamine in a mouse hindpaw dry skin itch lumbar superficial dorsal horn neurons to intradermal PAR-2 Akiyama T, Carstens MI, Carstens E. Enhanced responses of cations ofitchsensitization.Pain 2018; 159: 1185–1197. mechanisms, assessmentmethodology, andclinicalimpli Elberling J, Yosipovitch G,et al. Alloknesis and hyperknesis- Andersen HH, Akiyama T, Nattkemper LA, van Laarhoven A, evoked itch inhumans. Pain 2005; 113: 148–154. Ikoma A, Handwerker H, Miyachi Y, Schmelz M. Electrically Somatosens MotRes 1999; 16: 299–303. evoked anareaofcutaneousallodynia. in dysesthesiae RH. Attenuation of experimental pruritus and mechanically C. S.Moniagaetal. - - - - - 110. 109. 108. 107. 115. 114. 113. 112. 111. 124. 123. 122. 121. 120. 119. 118. 117. 116. a multicenter, open-label, small sample study. J Cutan Im and antihistamine-resistant itch in patients with pruritus: onmoisturizer- effectofNeurotropin injection Antipruritic al. Kaneko S, Kohno K, Honda S, Tohgi K, Niihara H, Chinuki Y, et 32: 87–93. pruritus: a systematic review of literature. Clin J Pain 2016; Jannuzzi RG.Nalbuphinefor treatmentofopioid-induced effect onpruritus.BMCNephrol2015; 16: 47. release tablets in hemodialysis patients with exploratory Pharmacokinetics of nalbuphine hydrochloride extended Hawi A, Alcorn H, Jr., Berg J, Hines C, Hait H, Sciascia T. double-blind trial. Hepatol Res 2017; 47: 972–982. chronic liver disease with refractory pruritus: a randomized, K, et al. Efficacy of nalfurafine hydrochloride in patients with Kumada Miyakawa H, H,Muramatsu T, AndoN,OhT, Takamori 155: 229–236. Silva H, Veit JC, et al. Oral supplementation with fish oil re Barcelos RC,deMello-Sampayo C,AntoniazziCT, SegatHJ, omega-3 fatty acids. Clin Dermatol 2010;28: 440–451. the structural andimmunologicrolesof theomega-6and McCusker MM, Grant-Kels JM. Healing fats of the skin: fatty acids in the skin. Arch Pharm Res 2002; 25: 747–758. al fatty acids/prostanoids/lipoxygenase-derived monohydroxy Ziboh VA, Cho Y, Mani I, Xi S. Biological significance of essenti Exp Dermatol 2013; 38: 665–668. density intheacetone-treated dry-skin mousemodel.Clin Neurotropin inhibitstheincreaseinintraepidermal nerve Kamo A, Tominaga M, Taneda K, Ogawa H, Takamori K. matol 2010; 35:73–77. in cultured rat dorsal root ganglion neurones. Clin Exp Der release andnerve growthfactor-induced neuriteoutgrowth Neurotropin inhibits both capsaicin-induced substance P Taneda K,Tominaga M,Tengara S, Ogawa H,Takamori K. munol Allergy 2018;1: 109–116. 2018; 98: 902–903. sitivity using murine dry skin models. Acta Derm Venereol skin model. J Dermatol Sci2012; 66: 136–143. improves dryness and pruritusintheacetone-induceddry kamura F, etal.Oral administration ofcollagentripeptide teoarthritis. Biosci Biotechnol Biochem 2010; 74: 2096–2099. rat model.JDermatol Sci2015; 79: 298–304. duces drynessandpruritusintheacetone-induceddryskin Ogawa H, et al. Effects of film dressings on itch hypersen itch on dressings film of Effects al. et H, Ogawa Iwanaga T, Tominaga M,Hirata Y, MatsudaH,ShimanukiT, Bull 2017; 33: 423–435. central mechanisms of oxidative stress in pruritus. Neurosci Antioxidants attenuate acute and chronic itch: peripheral and Zhou FM, Cheng RX, Wang S, Huang Y, Gao YJ, Zhou Y, et al. Neurosci Bull 2012;28:145–154. of transient receptor potential subtype ankyrin 1 in mice. T,Liu RR. OxidativeJi activation stress via itch induces of skindisease.JInvest Dermatol 2006; 126: 2565–2575. Bickers DR,Athar M.Oxidative stressin the pathogenesis Okawa T, Yamaguchi Y, Takada S, Sakai Y, Numata N, Na ingestion of collagen hydrolysates in a guinea pig model of os acid synthesisusinginvitroculturedsynovium cellsandoral Hyp, a collagen hydrolysate-derived peptide, on hyaluronic Ohara H, Iida H, Ito K, Takeuchi Y, Nomura Y. Effects of Pro- Dermatol 2017;42: 890–894. into epidermis in a mouse model of acute dry skin. Clin Exp phospholipids inhibits penetration of cutaneous nerve fibres R, Umehara Y, et al. Oral administration of milk-derived Sakaguchi A, Kamata Y, Takahashi N, Matsuda H, Kosaka Dermatol Sci2015;78: 224–231. J mice. hairless in inflammation skin ceramidesand bound dietary milk phospholipids: effect on epidermal covalently et al. A novel mechanism for improvement of dry skin by Morifuji M, Oba C, Ichikawa S, Ito K, Kawahata K, Asami Y, Sci 2012; 68: 56–62. in thewater-holding capacity of hairless mice. J Dermatol milk is incorporated into skin sphingolipids and is involved Kato K, et al. Orally administered sphingomyelin in bovine Haruta-Ono Y, SetoguchiS, UenoHM,Higurashi S, UedaN, ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV This isan open access article under the CC BY-NC license.www.medicaljournals.se/acta Wiesbaden, and The underlyingmechanisms ofdrugscausingpruritus intake and, inparticular, polypharmacy contributes toCI. (Table I). To date,itisnowknowntowhatextentdrug drug-induceditch so-called as well as endocrine diseases, disease, avarietyofhepatobiliary, haematological, and of otherdiseases/origins. This compriseschronickidney dermatological disorders,can alsobe causedbyanumber some timetorealizethatchronicitch(CI),asidefrom skin infestations.Ittookmedicaldoctorsandresearchers in whichscratchingaimedatextractingmitesorother skin disease. This may result from previous conditions, that itchingandscratchingmustbeassociatedwith a prurigo (CPG;Fig.1).Foralongtimeitwasassumed variable degree,includingtheclinicalpictureofchronic with normal-lookingskinorchronicscratchlesionsof rently haveaskindisease. These patientsusuallypresent P many. E-mail:[email protected] Ger Erlangen, DE-91054 18, Ulmenweg Erlangen-Nürnberg, University Corr: Acta DermVenereol 2020;100:adv00025. Accepted Oct15,2019;PublishedJan9,2020 systemic disease;uraemic itch. Key words: cholestasis; chronic kidney disease; liver; pruritus; creasing medicalchallengeinthe future. ofnon-dermatologicalitch origin will anin represent zed byincreasinglifeexpectancyandpolypharmacy, demographic situation of the population, characteri intake, quality and intensity of With itch. regard to the modal, considering age, comorbidities, current drug dermatological origin. Treatment is frequently multi frequent cofactor contributing to of itch chronic non- is often of systemicor mixed origin. Xerosisis cutis a itch relevanceinelderlypeoplewhomchronic cular 1 Andreas E.KREMER Non-dermatological ChallengesofChronicItch and to improvepatients’quality of life.Thisisof parti available, treatment best the of identification enable toare necessary evaluate the underlying aetiology, to prurigo.lesions chronic Precisediagnostics including withpresent unaltered skinorwith scratch chronic itch is categorized as “mixed origin”. Thesepatients co-exist, chronic or causes When severaldiseases disorders,or iscausedbydrugintake. psychosomatic a variety of systemic,neurological, and psychogenic/ but alsoin inmanyskindiseases, Chronic occurs itch Journal Compilation ©2020ActaDermato-Venereologica. Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Erlangen-Nürnberg, Friedrich-Alexander-University 1, Medicine of Department evoke scratchingeveninpatientswhodonotcur ruritus oritchisanunpleasantsensationthatcan Andreas Kremer, Department of Medicine 1, Friedrich-Alexander- 3 Occupational Dermatology,Departmentof Dermatology, Ruprecht-Karls University Heidelberg,Germany 1 , Thomas METTANG Centenary theme section:ITCHANDPRURITIC DISORDERS 2 andElke WEISSHAAR REVIEW ARTICLE ------haemochromatosis. with apatient legin upper the on prurigo 1.Chronic Fig. nerve damage,asseeninbrachioradialitchandnotalgia condary tobrainandspinalcordinjuriesorperipheral aetiologies ofCI.Italsodescribesneuropathicitchse for patients with CI with no underlying skin disease (3). itch research,withtheaimofimprovingmedicalcare observations representanimportantincentivetoincrease reduces thequalityoflifeinchronicallyillpatients. These tological pruritus. Chronic pruritus further significantly increased numberofpatientsexperiencingnon-derma ill patientsprolongstheirlifeexpectancy, albeitwithan possible mechanisms(1,2). from mainlytype-Iandtype-IV allergy toseveralother as adverseeventsareonlypartiallyunderstood,ranging systemic causes are summarized. effective, multimodal treatment options for the different use. Furthermore, a diagnostic approachispresented, and re, haematological disorders and adverse reactions of drug chronic itch, in particular liver disease, chronic renal failu prurigo. This review focusses on the systemic causes of of variable degree, including theclinicalpicture of chronic present withnormal-lookingskinorchronicscratch lesions sorders, or is caused by drug intake. These patients usually systemic, neurological, and psychogenic/psychosomatic di occurring in many skin diseases, but also in a variety of sensation unpleasant an is pruritus) term: (medical Itch SIGNIFICANCE 3 This review summarizes majornon-dermatological summarizes review This Advanced technicalandmedicalcareforchronically 2 Department ofNephrology,DKDHeliosClinic, Acta DermVenereol 2020;100: adv00025 doi: 10.2340/00015555-3345 - -

- - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue: Itch and pruritic disorders unknown origin(PUO)the diagnosticapproachshould and bile duct malignancies (11, 12). In case of CIof unravelled solely increased rates forhaematological with CIwithoutprimary skin changes,respectively, I). Two large cohortstudiesof8,744 and12,813patients themia vera(10). to several years prior to diagnosis, as seen in polycy­ disease. This so-calledpremonitoryitchmaypresentup nifestation and/orclinicaldiagnosisoftheunderlying diagnostics (6). diagnosis isrecommended,includingvariouslaboratory examination areinconclusiveastep-wiseapproachfor drug intake(8,9).Ifmedicalhistorytakingandclinical neurological orpsychiatric/somatoform disordersor on primarilyunaffected skinisoftencausedbysystemic, further helptoestablishaclinicaldiagnosis(6).Pruritus gical analysesshouldbeperformed.Skinbiopsymight bacterial, mycological,allergic andautoimmune-serolo logical disease.Inadditiontoclinicalskininvestigations, been developed(7). For thispurposeastructuredpruritusquestionnairehas radiological diagnostics are of significant importance (6). clinical examinationandinterdisciplinary, laboratoryand (5). Thus, carefulanddetailedmedicalhistorytaking, often from systemic asfrom dermatological disorders Patients with generalized pruritus suffer comparably pruritus andasystemicdiseaseasunderlyingcause. doctrines, thereisnocorrelationbetweengeneralized those with many comorbidities (4).Incontrasttoprevious CI illustrated thatitoccursmainlyinolderpatientsand in recent cohortanalysisofmorethan3,000patientswith physician, butisamajorneedfortheaffected patient. A often represents a clinical challenge forthe treating Identifying theunderlyingdiseaseoritch-causingdrug DIAGNOSING NON-DERMATOLOGICAL ITCH the occurrenceofCInon-dermatologicalorigin. by thefactthatseveraloriginsfrequentlycontributeto nosis and treatment is challenged in daily clinical routine paraesthetica. Finally, thisreviewemphasizesthatdiag Table I.Systemicdiseasesassociatedwithchronicpruritus 22 Rare Common Frequency In rare cases malignancy is responsible for CI (Table It shouldbenotedthatCImayoccurpriortoma Pruritus onprimarilyaffected skinhintsatadermato A. E.Kremeretal. Solid tumours Infectious diseases Malassimilation syndromes Endocrine diseases Haematopoietic diseases Hepatobiliary disorders Renal disorders Organ system sarcoma Carcinoma of the thyroid gland,ears, nose and throat,breast, lungs,stomach, pancreas, colon, prostate, uterus and Chronic HBV-/ HCV-/ HIV-/ HSV-infection, H.p. infection,VZV-reactivation (post-herpetic), parasitoses Lactose intolerance, coeliac disease, anorexianervosa, iron deficiency, vitamin B/D deficiency Hyperthyreoidism, hypothyreoidism, hyperparathyreoidism, carcinoid syndrome, diabetes mellitus mastocytosis Polycythaemia vera, essential thrombocytosis, Hodgkin and non-Hodgkin lymphoma, hypereosinophilic syndrome, cholestasis, liver cirrhosis, benign or malignant obstructive cholestasis Primary biliary cholangitis,primary / secondary sclerosing cholangitis, IgG4-related cholangitis, drug-inducedtoxic Chronic kidneyfailure Diseases - - - - severity ofcholestasisorliverfunction. of pregnancy. Hepatic itch presents independently of the during hormonereplacement,andinthelasttrimester patients pruritus typically worsens premenstrually, feet, albeitCImayoftenbegeneralized(14).Infemale in particularthepalmsofhandsandsoles patients often reportthehighestintensityontheirlimbs, in chronicviralhepatitisCinfections(13). Affected in benignandmalignantbiliarydisorders,5–15% primary andsecondarysclerosingcholangitis,15–45% of pregnancy, upto70%inprimarybiliarycholangitis, cholestasis intrahepatic in symptom defining as 100% derably betweenthedifferent underlyingdiseases,with lestatic features.Prevalenceofhepaticitchvariesconsi with hepatobiliarydiseases,inparticularthosecho Chronic pruritus is commonly reported by many patients HEPATOBILIARY DISEASES may beperformed. nosis couldbeestablishedanannualrepetitivework-up for theunderlyinghepatobiliary disease,whichmay this pathophysiologicalconcept. have notyetbeeninvestigated inhepaticitchtoprove the However,inhibiting (19). drugs ATX-LPAitch axis hepatic of mediators potential as identified been have acid (LPA) forming enzymeautotaxin(ATX) andits are largely ineffective (18).Recently, lysophosphatidic such aserythema,urticaria orwheals, andantihistamines do notpresentwithhistamine-inducedskinalternations, this observationislacking(16,17).Cholestaticpatients receptor X4(MRGX4),albeithumandatasupporting cholestatic itchviathemas-relatedGprotein-coupled have suggestedthatbilirubinandbilesaltsmaymediate (PBC) dose-dependentlyworsenspruritus.Recentdata licensed forthetreatmentofprimarybiliarycholangitis synthetic bilesaltobeticholicacid,whichhasbeen could notbeestablished (15). Interestingly, the semi- sed as culprits, albeit a correlation with itch intensity metabolites andendogenousopioidshavebeendiscus derstood. Inthepast,bilesalts,histamine,progesterone focus onthese2cancerentities.Ifnounderlyingdiag The pathogenesis of hepatic itch is not yet fully un Treatment should focusprimarilyonadequatetherapy - - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV a Table II.Therapeuticrecommendationsforhepaticpruritus been suggestedtoplayaroleinthepathophysiology. have inflammation skin subclinical and xerosis as well Increased levelsofuraemictoxinsandparathormone,as underlying pathologicalmechanismremainselusive. depending ontheinvestigatedcountry(25,26). The haemodialysis have CKD-associated pruritus (CKD-aP) miological studiesindicatethatupto50%ofpatientson metheus as plasmapheresis,albumindialysis(e.g.MARS trials (24).Inrefractorycasesinvasiveprocedures,such which arecurrentlyinvestigatedinplacebo-controlled ileal bileacidtransporter(IBAT) in the terminal ileum, 23). Futuretherapiescouldbebasedoninhibitorsofthe (22, approaches alternative as used be may fenofibrate or Bezafibrate current guidelines(13,20)(Table II). day) and sertraline(75–100 mg/day)according to the by rifampicin(150–600 mg/day),naltrexone(25–50mg/ (4–16 lestyramine cholestatic itchisrecommendedtobetreatedwithcho intensity.in insufficient, mild If if itch hepatic mitigate and cooling(e.g.menthol-containing)ointmentsmay improve itch intensity. Topical treatment with rehydrating significantly not did UDCA trials placebo-controlled cholestasis of pregnancy (21). However, in randomized fective anti-pruritictherapyinwomenwithintrahepatic cholestasis ofpregnancy(20).UDCA isasafeandef primary sclerosingcholangitis,andintrahepatic as PBC, tic baselinetreatmentinmanycholestaticdisorders,such clinical challenge. due to intrahepatic cholestasis may represent a significant transcutaneous ornasobiliarydrainage.Incontrast,itch stenting, biliary endoscopic by ameliorated efficiently to obstructionoftheextrahepaticbiliarytreeisoften result inreliefofhepaticitch.Inthisregard,itchdue po: per os. drugs areoff-label use. kidney disease(CKD),mostlythoseondialysis.Epide (UP), affects patients with advanced stages of chronic Itch inrenaldisease,alsoreferredtouraemicpruritus RENAL DISEASES experience reliefofCI. be performed. After livertransplantationmostpatients 4 6 5 3 2 1 Approach Solely colestyramine islicensedfor thetreatmentof hepatic pruritus;allother th th th rd nd st line line line line line Ursodeoxycholic acid (UDCA)isusedas anticholesta line ® ), transcutaneousornasobiliarydrainage,may Bezafibrate Drug UVB light Gabapentin Experimental approaches, e.g. Sertraline Naltrexone Rifampicin Colestyramine a g/day) as first-line therapy,first-line as g/day) followed 400 mg/day (po) 1–2×/week 300–3,600 mg/day 100 mg/day (po) 25–50 mg/day (po) 150–600 mg/day (po) 4–16 g/day (po) Dose ® , Pro - - - - - peripheral neurones,eitherlocalized(e.g.nervecompres Neuropathic itch is caused by neuronal or glial damage to NEUROPATHIC DISEASES and dosagesisgiveninTable III. uraemic patients(31).Detailedinformationaboutdrugs phototherapymayameliorateitchin(30). Ultraviolet although notlicensedforthisindication,maybehelpful essential. In early stages gabapentin and pregabalin, challenge. Emollients forskin care and hydration are (Fig. 1).MedicaltherapyforCKD-aP remainsaclinical in some patients and, in some cases, chronic prurigo excoriations with or without impetigo, may be observed a frequentlyobservedxerosis.Scratchlesions,suchas patients, exceptforcommonchangesinskincolourand uraemic itchoccurs,skinappearanceisnormalinmost higher serumcalcium/phosphoruslevels(29). When C virusinfection,neurologicaldiseases,depressionand dities, suchascongestiveheartfailure,chronichepatitis has begun. These include male sex and certain comorbi factors forUP indialysispatientsevenbefore risk identified analyses Retrospective (25). patients ted blockers inthesepatients(28). may explainthegoodresponsetocalcium-channel- and neuroplasticchangesinpatientswithCKD-aP, which Recent experimentaldatasuggestedcentralneuropathic CKDaP.of treatment the in agonists κ-opioid and nists a associated pruritus kidney disease Table III.Therapeuticrecommendationsforchronic itch havelocalizedwithinthedorsolateralpartsof brachioradial with Patients fibres. nerve thoracic ting but NP ispresumedtobeamononeuritic diseaseaffec character. The pathophysiology ofthisentityisunclear, region, associatedwithaslightlypainfulorburning gia paraesthetica(NP)perceiveitchinthesubscapular brain orinthespinalcord,rarelycausespruritus. to thecentralnervoussystem,suchasbytumoursof sion) orgeneralized(e.g.nervedegeneration).Damage po: per os; iv: intravenous. least partially, explain the efficacy of μ-opioid antago μ-opioid of efficacy the partially,explain least at may, This (27). activity κ-opioid of downregulation role, possiblythroughupregulationofµ-opioidand/or Furthermore, theendogenousopioidsystemmayplaya 4 5 3 2 1 Approach All drugsare off-label-use. th th rd nd st line line line line CKD-aP greatlyimpactsthequalityoflifeaffec Several entities can be discerned. Patients with notal line Drug UVB light Curcuma Tacrolimus Nalfurafine Experimental approaches, e.g. Capsaicin Pregabalin Gabapentin Chronic itchinnon-dermatologicaldiseases a Theme issue: Itch and pruritic disorders 1–3×/week 500 mg 3×/day 2×/day (topical) after dialysis 2.5–5 μg/day (po) or 5 μg (iv) 3–5×/day (topical) 75 mg 2×/week–75 mg/day (po) 2×/week (po) or 300 mg 3×/week or 400 mg After dialysis: 100 mg 3×/week Dose 23 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue: Itch and pruritic disorders by 15–50%ofpatients(40). Severeitchmayprecede lymphoma. CIonprimarily unaffected skinisreported primary myelofibrosisoften reportaquagenicitch. Similarly, patients with essential thrombocytosis and in additiontoimprovingtheunderlyingdisease(38,39). pathway, suchasruxolitinib,stronglyattenuatedpruritus JAK2 617V mutation (37). Inhibitorsof the JAK-STAT most commonlyobservedinpatientswithahomozygous patients report itch in 30–65% of cases. Aquagenic itch is dysfunction ofpluripotenthematopoieticcells. Affected vera isararemyeloproliferativediseasewithclonal ter aftercontactoftheskinwithwater. Polycythaemia in manyofthesepatients,withapungentitchycharac logical diseases. Aquagenic pruritusisatypicalfeature Itching iscommonlyreportedinpatientswithhaemato AQUAGENIC ITCH HAEMATOLOGICAL DISEASES INCLUDING and multipleendocrineneoplasiatypeII. ciated withtheoccurrenceofCIincludeGrave’s disease without diabetes (36). Further endocrine diseases asso was presentinonly2.9%of499age-matchedpatients reported itch locatedonthetrunk, whereasthissymptom patients. Of2,656patientswithdiabetesmellitus,11.3% another studytruncalitchwasmostprominentindiabetic 27.5%reportedongeneralizeditch(35).In with diabetes of debate.Inonestudyinvestigating almost 400patients frequently afflicted than those without remains a matter seases. Whether patients with diabetes mellitus are more CI mayoccurinassociationwithseveralendocrinedi ENDOCRINE DISEASES alleviate pruritus(3,34). channel-blockers, such as gabapentin or pregabalin, may ment with capsaicin orsystemic treatment with calcium- by traumaorburns. post-herpetic itch,polyneuropathiesandscarsinduced in the course of herpes zoster infections as so-called skin biopsywithreducedsmallfibredensity(33). establish, requiringthermoregulatorysweattestingand and orthostatic hypotension. The diagnosis is difficult to mic nervous system, such as gastrointestinal dysmotility thermoregulation and signs ofmalfunction ofthe autono symptoms, includingpain,tingling,numbness,deranged some patients. This sensorydisorderleadstoavarietyof of peripheralnervesaccompaniedbyseverepruritusin observed inthesepatients(32). Cervical cordcompressionorradiculopathieshavebeen As inNP, patients reportmixeditchandpainsensations. the forearmsand,lessfrequently, aroundtheshoulders. 24 Hodgkin’s disease belongs to the class of B-cell of class the to belongs disease Hodgkin’s Treatment of neuropathic itch is difficult. Local treat Apart fromtheseentities,neuropathicitchmayoccur neuropathy systemic a is neuropathy fibre small The A. E.Kremeretal. ------CI furtherimpairsqualityoflifeinpatientswithmalig According totheliteratureandourownclinicalstudies important incancerpatientswithparaneoplasticdiseases. receiving moreattentionandbeingregardedas is limited. This maymainlybeduetoothersymptoms frequency remainsunknown,asepidemiologicaldata rarely reportedinpatientswithsolidtumours.Itstrue commonly in lymphoreticular malignancies, while being general, PIisconsideredasararedisorder. Itoccursmost caused byhaematologicaldiseasesisdescribedabove.In (PI) isusedtodescribeitchinpatientswithcancer. Itch itch” “paraneoplastic term the practice clinical daily In PARANEOPLASTIC DISEASES ANDCANCER mirtazapine (7.5–30 mg/day)(Table IV)(6). (75–600 mg/day), acetylsalicylicacid(300mg/day)and blockers gabapentin (300–2,400 mg/day) and pregabalin Recommended therapyconsistsofthecalciumchannel leukaemia andinchroniccomparedwithacuteforms. monly observedinlymphaticcomparedwithmyelocytic 30% ofpatients.InleukaemiapatientsCI is morecom affectto may up pruritus lymphoma non-Hodgkin with also indicate a relapse of Hodgkin’s disease. In patients ralize. After successfulanti-tumourtherapy, CImay a origin hematopoietic of forpruritus recommendations Table IV.Therapeutic ill patients,aswelladversedrugreactions. The me or non-dermatological diseases occurring in chronically asons forCI,suchasparaneoplasticskindiseases, re and aetiologies other exclude to difficult remains may returnwithitsrelapse(40). PI usuallydisappearswithremissionofthetumourand vasive growthofcancercellsorbyanti-tumourtherapy. This termexcludesitchinducedeitherbythelocalin presence ofasolidtumourorhaematologicalmalignancy. itching occursasasystemic,butnot local, reactionin the that thetermparaneoplasticitchshouldbeusedincase the different typesofparaneoplasticitch. The SIGstates with theaimofgeneratingacleardefinitionPI(40). group (SIG)ofphysiciansandresearcherswasfounded, nant diseases.In2012,aninterdisciplinarystudyinterest po: per os. at night,oftenstartsthelowerlimbs,andmaygene the outbreakofdiseasebymanyyears.CIworsens 4 5 3 2 1 Approach All drugsare off-label use. th th rd nd st line line line line Diagnosing PIrepresentsaclinicalchallenge,asit Previously, severaltermshavebeenusedtodescribe line Acetylsalicylic acid Drug Nalfuraphine Naltrexone Aprepitant Experimental approaches, e.g. Mirtazapine Pregabalin Gabapentin a 300 mg/day (po) 2.5–5 μg/day (po) 50–150 mg/day 125-80–80 mg/week or 80mg/day 7.5–30 mg/day (po) 75–600 mg/day (po) 300–2,400 mg/day (po) Dose ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV µ-receptor-antagonists, such asnaloxone. by effectively treated be can It (47). receptor μ-opioid may bemediatedbyactivation oftheisoformD when appliedepidurallyor intrathecally(46)which mostly frustrating(45). peripheral nerves(44). Treatment iscumbersomeand in depositions HES by caused be to thought is infusion (43). in Africans to melanin with significantly higher skin concentrations monly affected potentiallyby astrongbindingcapacity mainly inblack Africans, while Caucasians arelesscom prX1-receptor. Interestingly, chloroquine provokes itch drug, caninduceitch,probablybyactivatingtheMrg the developmentofitch. considerable delaybetweenthestartofdrugintakeand patients are takingmultipledrugsand there mightbea remains, for many cases, a clinical challenge, as many compound (42).Identifyingtheresponsible reactions nic compounds than in IgE-mediated hypersensitivity is activated,resultinginadifferent releaseofpruritoge evidence that,withsomedrugs,theMRGX2-receptor mostly unknown,pathophysiologicalprocess. There is towards thedrugor, asinmanycases,duetoanother, induced itchmayemerge asahypersensitivityreaction drug may cause localized or generalized itch. Drug- drugs isacommonphenomenon(41). Almost every Itch associatedwithsystemicallyorlocallyapplied DRUG-INDUCED ITCH may induceCIasaside-effect. patients withcancerfrequentlyreceiveanalgeticsthat gical cancertreatment(40).Itshouldbeconsideredthat T-cell lymphoma, solid tumours and itch-related biolo e.g. aprepitant,havebeenusedforitch,examplein day orally)orneurokinin(NK)-1-receptor-antagonists, naloxone (0.8–2mgi.v./day), naltrexone(50–100 mg/ 50–200 mg daily. Opioid receptor antagonist, such as balin, canbeusedfortreatingPIaswellthalidomide prega and gabapentin as such blockers, (2)-γ-channel such asparoxetine,upto20mgdaily, calciumalpha sidered inPI(3).Serotoninreuptakeinhibitors(SSRI), longer systemic treatment with prednisone may be con nisone (seeabove)actingviadifferent mechanisms,and ineffective. PIinlymphomacanimprovewithoralpred mostly are H1-antihistamines relief. symptomatic to Topical therapies,includingcoolingagents,maylead be explained largely by the rarity and diversityofPI. trolled trials(RCTs) forthetreatmentofPI,whichmay therapies are effective. There arenorandomizedcon underlying malignancy. Inmanycases,cytoreductive chanisms ofPIarestillnotunderstood. Opioidergic drugsmaycause strongitch,especially (HES) starch hydroxylethyl by provoked Itching Chloroquine, whichismainlyusedasanantimalarial Baseline therapyofPIcomprisesthetreatment ------18. targeted tumourtherapies,numerousreportshaveemer 17. 14. 11. 20. 19. 16. 15. 13. 12. 10. REFERENCES The authorshavenoconflictsofinterest todeclare. antipruritic potentialinsuchcases(53). The neurokinin-1-antagonistaprepitantseemstohave ged abouttherapy-associatedchronicpruritus(48–52). 3. 7. 9. 2. 6. 5. 4. 8. 1. Along withtheexpansivedevelopmentanduseof Jones EA, Bergasa NV. Evolving concepts of the pathogenesis Weisshaar E, Szepietowski JC, Dalgard FJ, Garcovich S, Gie Weisshaar E, Ständer S, U, Gieler Matterne U, Darsow U. Ent Meixiong J, Vasavda C,Snyder SH,Dong X.MRGPRX4isa Bergasa NV, Mehlman JK, Jones EA. Pruritus and fatigue in Fett N, Haynes K, Propert KJ, Margolis DJ. Five-year ma Weisshaar E, Szepietowski JC, Darsow U, Misery L, Wal Ebata T. Drug-induceditchmanagement.CurrProblDermatol Ständer S, Zeidler C, Augustin M, Bayer G, Kremer AE, Legat Weisshaar E, Apfelbacher C, Jager G, Zimmermann E, Bruck Ständer S, Pogatzki-Zahn E, Stumpf A, Fritz F, Pfleiderer B, EASL Clinical practice guidelines: the diagnosis and manage Kremer AE, Martens JJ, Kulik W, Rueff F, Kuiper EM, van Meixiong J, Vasavda C, Green D, Zheng Q, Qi L, Kwatra SG, Beuers U, KremerAE,Bolier R,Elferink RP. Pruritusincho Dull MM, Kremer AE. Management of chronic hepatic itch. Johannesdottir SA, Farkas DK, Vinding GR, Pedersen L, Lam Siegel FP, Tauscher J, Petrides PE. Aquagenic pruritus in Pereira MP, Agelopoulos K, Kremer AE, Schmelz M. Aktuelles McNeil BD, PundirP, Meeker S, HanL,UndemBJ, Kulka M, and treatment of the pruritus of cholestasis. Can J Gastro 2019. 116: 10525–10530. contribute tocholestaticpruritus.ProcNatlAcadSciUSA G protein-coupled receptor activated by bile acids that may primary biliary cirrhosis. Baillieres Best Pract Res Clin Gast 2016; 50: 155–163. Ges 2017; 15: 860–872. chronic pruritus – update – short version. J Dtsch Dermatol FJ, et al. S2k guidelines for the diagnosis and treatment of report from amulti-disciplinary medicalitchcentreinGer Ritzkat A,etal.Facing thechallengesof chronicpruritus:a Buuren HR, et al. Lysophosphatidic acid is a potential medi a componentof cholestatic itch. Elife2019; 8 pii: e44116. et al. Identification of a bilirubin receptor that may mediate Dermatol Clin2018; 36: 293–300. of life in 441 patients.Am J Hematol2013; 88: 665–669. quality on influence vera:polycythemiacharacteristicsand zur Neurobiologie von Pruritus. Hautarzt 2018; 69: 620–625. pseudo-allergic drug reactions. Nature 2015; 519: 237–241. et al. Identification of a mast-cell-specific receptor crucial for patients. Br JDermatol 2006; 155: 957–964. cal characteristics and quality of life in German and Ugandan ner T, DiepgenTL,etal.Pruritusasaleadingsymptom:clini many. ActaDerm Venereol 2015;95: 266–271. chronic pruritus. Acta Derm Venereol 2019; 99: 469–506. ler U, Gimenez-Arnau AM, etal.European S2kguidelineon 1008–1018. ator of cholestaticpruritus.Gastroenterology 2010;139: enterol 2000; 14: 33–40. lestasis: facts and fiction. Hepatology 2014;60:399–407. roenterol 2000; 14: 643–655. cohort study. Br J Dermatol 2014;171:839–846. with a hospital diagnosis of pruritus: a nationwide Danish berg A,SorensenHT, etal.Cancerincidenceamong patients screening practices. J Am Acad Dermatol 2014; 70: 651–658. unnecessary atlimiting cohortstudyaimed population-based patients incidence in lignancy with chronic apruritus: pruritus. Acta Derm Venereol 2012; 92:563–581. lengren J, MettangT, etal. Europeanguidelineonchronic und erste Ergebnisse. Hautarzt 2011; 62:914–927. Hintergrund (AGP-Fragebogen). Pruritus chronischem von wicklung eines deutschsprachigen Fragebogens zur Erfassung Chronic itchinnon-dermatologicaldiseases Theme issue: Itch and pruritic disorders 25 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV 36. 35. 34. 33. 32. 31. 24. 30. 28. 23. 37. 29. 27. 26. 25. 22. 21. Theme issue: Itch and pruritic disorders 26 Yamaoka H, Sasaki H, Yamasaki H, Ogawa K, Ohta T, Fu Ko MJ, FC,Tseng Hu JeeSH, HC, Chiu Postprandial CH. blood Savk E. Neurologic itch management. Curr Probl Dermatol Lauria Lauria G, Bakkers M, C, Lombardi R, PenzaSchmitz P, Devigili Marziniak M,PhanNQ, Raap U, SiepmannD, Schurmeyer- Tan JK, Haberman HF, Coldman AJ. Identifying effective Hegade VS, Kendrick SF, Dobbins RL,MillerSR,Thompson Nofal E,Farag F, NofalA,EldesoukyF, Alkot R,Abdelkhalik Papoiu AD, Emerson NM,Patel TS, Kraft RA, Valdes-Rodriguez Corpechot C, Chazouilleres O, Rousseau A, Le Gruyer A, Vannucchi AM, Antonioli E, Guglielmelli P, Rambaldi A, Khanna D, Singal A, Kalra OP. Comparison of cutaneous Mettang T, Kremer AE. Uremic pruritus.Kidney Int 2015; Rayner HC,LarkinaM,Wang M,Graham-Brown M,van der Weiss M, Mettang T, Tschulena U, Passlick-Deetjen J, Weiss outcome on bezafibrate of Effects P,A. Sese Pares A, Reig Williamson C, Geenes V. Intrahepatic cholestasis of preg with type 2 diabetes. Eur J Dermatol 2013;23:688–693. glucose is associated with generalized pruritus in patients 2016; 50: 116–123. 2010; 15: 202–207. a worldwide normative reference study. J Peripher Nerv Syst G, et al. Intraepidermal nerve fiber density at the distal leg: 65: 756–762. resonance tomography study. J Am Acad Dermatol 2011; result of cervical spine pathology: the results of a magnetic Horst F, Pogatzki-Zahn E, et al. Brachioradial pruritus as a 25: 811–818. treatments for uremic pruritus. J Am Acad Dermatol 1991; D, RichardsD, etal.Effect ofileal bileacidtransporter inhi review of literature. J Dermatolog Treat 2016; 27: 515–519. hemodialysis patients: a randomized-controlled trial and Z. Gabapentin: a promising therapy for uremic pruritus in arterial spin labeling fMRI reveal neuropathic and neuro R, Nattkemper LA, et al. Voxel-based morphometry and 2018; 378:2171–2181. Med J Engl N cholangitis. biliary primary in bezafibrate of Habersetzer F, Mathurin P, et al. A placebo-controlled trial dialysis. Postgrad MedJ2010; 86: 641–647. manifestations in chronic kidney disease with or without 87: 685–691. Veer SN, Ecder T, et al. International comparisons of pre 113: 49–55. 2018; Gastroenterol J Am response. acid ursodeoxycholic and pruritusinprimary biliary cholangitiswithsuboptimal 33: 150–155. symptom of diabeticpolyneuropathy. Diabetes Care2010; ruta H,etal.Truncal pruritusof unknownoriginmay bea disease. JNeurophysiol 2014; 112:1729–1738. plastic features of brain processingof itch in end-stage renal hemodialysis. Clin J Am Soc Nephrol 2017; 12: 2000–2007. valence, awareness, and treatment of pruritusin people on study. ActaDerm Venereol 2015;95: 816–821. in haemodialysispatients:arepresentative cross-sectional haar E. Prevalence of chronic itch and associated factors phase 2a study. Lancet 2017;389:1114–1123. a double-blind, randomised, placebo-controlled, crossover, bitor GSK2330672onpruritusinprimarybiliarycholangitis: nancy. Obstet Gynecol 2014; 124: 120–133. 2017. 67: 145–172. ment ofpatientswithprimarybiliarycholangitis.JHepatol A. E.Kremeretal. ------43. 42. 41. 45. 40. 52. 49. 38. 44. 39. 53. 51. 50. 48. 47. 46. Bussaratid V, Walsh DS, Wilairatana P, Krudsood S, Si Meixiong J, Anderson M, Limjunyawong N, Sabbagh MF, Hu Maleki K, Weisshaar E. Arzneimittelinduzierter Pruritus. Bork K.Pruritusprecipitatedby hydroxyethyl starch:are Weisshaar E, Weiss M, Mettang T, Yosipovitch G, Zylicz Z. Phillips GS, Freites-Martinez A, Wu J, Chan D, Fabbrocini G, Clabbers JMK, Boers-Doets CB, Gelderblom H, Stijnen T, La Kirito K,SuzukiMiyamura K,Takeuchi M,HandaH,Oka Metze D, Reimann S, Szepfalusi Z,BohleB, Kraft D, Luger Verstovsek S, Passamonti F, Rambaldi A,BarosiG,Rosen PJ, Santini D, Vincenzi B, Guida FM, Imperatori M, Schiavon G, Phillips GS, Wu J, Hellmann MD, Postow MA, Rizvi NA, Freites- Wu J, LacoutureME.Pruritusassociatedwithtargetedan CJ,Ensslin Rosen AC,Wu S, patients in LacoutureME.Pruritus Liu XY, LiuZC, SunYG,Ross M,KimS, Tsai FF, etal.Unidi Jacobson L,ChabalC,BrodyMC,Ward RJ, Wasse L.Intrat itch. Immunity 2019; 50:1163–1171 receptorsdrives g-protein-coupled related non-histaminergic E, Mack MR, et al. Activation of mast-cell-expressed mas- Hautarzt 2014; 65: 436–442. h Suy f th IS) At Dr Vnro 21; 95: 2015; 261–265. Venereol Derm Acta (IFSI). Itch of Study the Special InterestGroup(SIG)of theInternational Forum on Paraneoplastic itch:anexpertpositionstatementfromthe Hellmann MD, etal.Clinical characterization ofimmunothe Br JDermatol 1997;136: 553–559. therapy: a result of long-term storage in cutaneous nerves. TA. Persistent after hydroxyethyl pruritus starch infusion 2014; 120:513–520. vera who are refractory or intolerant to hydroxyurea. Cancer and JAK2 Inhibitor, inpatientswithadvanced polycythemia Rumi E,etal.Aphase2studyofruxolitinib, anoral JAK1 Venditti O, et al. Aprepitant for management of severe pru cutaneous adverse events. J Clin Oncol 2019: JCO1802141. Martinez A,etal.Treatment outcomesof immune-related and meta-analysis. J Am Acad Dermatol 2013; 69: 708–720. treated with targeted cancer therapies: systematic review or essential thrombocythemia. Blood 2007;110:840–846. JAK2 617V>Fmutationinpatientswithpolycythemia vera homozygous of profile Clinical al. et R, Marchioli G, Barosi in Thailand.Trop Doct 2000;30: 211–214. Plasmodium vivax malaria patients treated with chloroquine lachamroon U, Looareesuwan S. Frequency of pruritus in 107: 173–184. polycythemiavera splenomegaly.with 2018;Hematol J Int tients with hydroxyurea-resistant or hydroxyurea-intolerant moto S, et al. Ruxolitinib is effective and safe in Japanese pa Lancet Oncol 2012; 13:1020–1024. ritus relatedtobiologicalcancertreatments:apilotstudy. tology clinics.JAMA Dermatol 2019; 155: 249–251. rapy-related pruritusamongpatientsseenin2oncoderma 2018; 36: 315–324. ticancer therapies and their management. Dermatol Clin Cancer 2016;24: 513–521. as major EGFRI-associated adverse events. Support Care couture ME, van der Hoeven KJM, et al. Xerosis and pruritus and analgesia induced by opioids. Cell 2011; 147: 447–458. rectional cross-activation of GRPR by MOR1D uncouples itch with intrathecal morphine 0.5 mg. Pain 1990; 43: 141–148. hecal methadone: a dose-response study and comparison view. Br J Dermatol 2005;152:3–12. ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV This isan open access article under the CC BY-NC license.www.medicaljournals.se/acta an affected individual. The impactisalwaysreciprocal: altering bothphysicalandpsychological homeostasisof especially acquiredduring earlychildhood,ensuein chronic skindiseaseswith theirrichsymptomatology, others mayleavetheirtrace. Itseemssubstantiatedthat which on “surface” a as and relationships, establish to order in communication” of “means or “place” specific ternal aggression.Lastly, skin may beconsideredasa world, whichservesasaprotectivebarrieragainstex outside the with “interface” an is skin Secondly, for. experienced byababyduringnursingandbeingcared “bag” or “container”, as it embraces the positive stimuli needs ofthepsyche.Firstly, skinhasthefunctionofa sesses a wide psychological meaning, reflecting various tensively reviewedbyDutray&Misery(1)),skinpos B 50-368 Wrocław, Poland. E-mail:[email protected] and Allergology, Wrocław Medical University, 1 Chałubińskiego Street, PL- Corr: Jacek C. Szepietowski, Department of Dermatology, Venereology Acta DermVenereol 2020;100:adv00026. Accepted Oct15,2019;PublishedJan9,2020 den ofdisease. Key words: itch,psyche, pathogenesis, stress, psychiatry, bur well-being. toapproach thesepatientsinorderto improvetheir ledge supports the role of a holistic, interdisciplinary associations know current stillposemanyquestions, and stigmatization. Despitethefactthat itch–psyche impairment of health-related qualitylife (HRQoL) of related to andtheburdenof itch, with itch to respect of itch, psychological and considerationspsychiatric relevant associations with stress, the contagiousness This paper reviews key aspects ofitch pathogenesis, mediators. inflammatory various as well as systems, nervous involves theperipheralandcentral which isbilateral. hasacomplex Itch psyche pathogenesis, stantiating that and itch therelationship between componentsthese impactson theother, therebysub gardless of age.Altering the homeostasis ofone of psyche arecloselyrelatedto physiologicalpsyche state re Beginning fromembryological development, skinand According tothemoi-peauconcept(2)(Fig.1)(asex normal psychosocial development ofan individual. unfold afterbirth,andconstitute a foundation for the ectodermal origins(1). These associationscontinueto Journal Compilation ©2020ActaDermato-Venereologica. Department of Dermatology, Venereology and Allergology, Wrocław MedicalUniversity,Wrocław,Poland Radomir RESZKE andJacek C. SZEPIETOWSKI Itch andPsyche:BilateralAssociations are organs thatarecloselyconnectedduetotheir eginning withhumanembryogenesis,skinandbrain Centenary theme section:ITCHANDPRURITIC DISORDERS REVIEW ARTICLE ------to (1)). (according Fig. 1.Themoi-peauconcept(The Ego-Skinconcept) tion, stress,impairmentofmood,lackconcentration, reduction inqualityoflife(QoL),feelingsstigmatiza mortality, morbidity, significant with associated is CI unknown origin(PUO)isestablished. The presenceof tric disorders.Occasionally, thediagnosisofpruritus may alsostemfromsystemic,neurological,orpsychia itch (CI)isafeatureofvariousdermatoses,althoughit less ormorethan6weeks,respectively)(3).Chronic scratching, further classified as acute or chronic (lasting signs andsymptoms“scar”thepsyche. itch, chronicscratchlesions),whereasdermatological the psyche may predispose to cutaneous complaints (e.g. tization. to impairment of health-related quality of life and stigma aspects related to itch, and the burden of itch with respect the contagiousness of itch, psychological and psychiatric covers the pathogenesis of itch, associations with stress, review This field. this in published articles clinical and tal with psyche is indicated by the abundance of experimen bilateral. Increasing interest in itchand itsassociations The relationship between itch and psyche is complex and SIGNIFICANCE Itch is defined as an unpleasant sensation leading to leading sensation unpleasant an as defined is Itch Acta DermVenereol 2020;100: adv00026 doi: 10.2340/00015555-3346 - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue: Itch and pruritic disorders rimotor cortex,prefrontal cortex, posteriorinsulaand associated withtheactivation ofcontralateralsenso motor areas were involved. Itch unpleasantness was cortex; in addition, both ipsilateral and contralateral resulted in activation of thecontralateral somatosensory flow (rCBF) revealed that a skin prick test with histamine Another study utilizing PET and regional cerebral blood supplementary motorareaandpremotorcortex(17). sensory cortex,aswelltheprimarymotor jection resultedinmajoractivationtheleftprimary (PET) studyamonghumanparticipantshistaminein behaviour (17–20).Inapositronemissiontomography need toscratch,andpreparingexecutingscratch location, associatedunpleasantfeelings,generatingthe cortical areasareincludedinprocessingitchintensity, that itches,nottheskin”(16)remainsvalid,asdifferent endings in the epidermis. The statement “it is the brain (CNS) iscrucialinelicitingCP, startingfromfreenerve role ofperipheral(PNS)andcentralnervoussystem is currentlydeemedaseparateentityfrompain. The sharp objects, irritants, and allergens (16). However, itch insects, parasites, as such stimuli, potentially dangerous as anevolutionarydefencemechanismagainstvarious it isthoughtthatthesymptommighthavedeveloped itch hasbeenperceivedasasubtypeofpain(15),and medical literature. From the historical point of view, itch, asthistopicisgainingincreasedattentioninthe There isgrowingdataconcerningthepathogenesisof ITCH PATHOGENESIS and stigmatization. and theburdenofitchwithrespecttoimpairmentQoL psychological andpsychiatricaspectsassociateditch, play betweenitchandstress,thecontagiousnessofitch, regions associatedwithpathogenesisofitch,theinter in theclinicalsetting(12–14). ciplinary approachtoitch and theassociated conditions between itchandpsychesupporttheneedformultidis causing itch(III). These complexbilateralassociations by psychosocial factors (II); and psychogenic disorders psychiatric sequelae (I); pruritic disorders aggravated the itch–psycheinteractionsaspruriticdisorderswith classified clinically have (11) al. et Teyphysiological. ating (e.g.cognitive,behaviouralandsocial)aswell as external (e.g.stressfulenvironmentalstimuli),medi of various factors: internal (associated with personality), Verhoeven et al. (10). The occurrenceofitchisaresult disorders is the Biopsychosocial Model, proposed by to explainCImechanismsinthecourseofcutaneous or exacerbationofitch.Onethemodelsthataims psychiatric alterationsmaycontributetotheoccurrence hand, cliniciansareawarethatvariouspsychologicaland to express emotions (alexithymia) (4–9). On the other reduced sexualdesireandappetite,aswellinability 28 This reviewcoversthepathogenesisofitch,cerebral R. ReszkeandJ.C.Szepietowski - - - - - lacking the sense of self-efficacy are not able to manage behaviour andsocialenvironment (29).Individuals beliefs thattheycanexertcontrol overtheirmotivation, (28). The perceived self-efficacy is a concept of people’s with low self-efficacy in individuals under higher stress Subsequently, anotherreportlinkedthepresenceofitch with thelevelofmentaldistress,regardlesssex. of itch(27).Moreover, theseverityofitchcorrelated Symptom Checklist-10) was correlated with the presence Hopkins the by (assessed distress mental adolescents pregabalin) (11, 26). may subsequently perpetuate exacerbation ofthe di atopic dermatitis)generatehugestresslevels,which chronic pruriticconditions(e.g.psoriasis,urticaria, and stress.Similarlytotheviciousitch-scratchcycle, itch of interplay the by reflected perfectly are psyche resources” (24). The bilateralassociations ofitchand and inwhichthedemandstaxorexceedavailablecoping person appraises as significant for his or her well-being it” (23) or “a relationship with the environment that the specific response of the body to any demand made upon non­ “the as e.g. ways, different in described be may it despite its widespread appearance in various situations Stress isaconceptfrequentlymentionednowadays,yet ITCH ANDSTRESS reward system. grey matter(PAG), areassociatedwiththeitch-scratch of the midbrain, as well as deactivation of periaqueductal addition, the activation of ventral tegmentum area (VTA) cortex andinsulacomparedwithpassivescratching.In higher pleasureanddeactivationofanteriorcingulate monstrated thatactivescratchingwasaccompaniedby is involvedintherewardsystem.Papoiuetal.(22)de caudate nucleus was also substantiated, as this region cortex, andmidcingulatecortex(21). The roleofthe lementary motorarea,premotorcortex,primary H first-generation towards implication therapeutic certain (26). The itch-stressassociationdoes,infact,posea and subcortical regions (corpus callosum and putamen) itch isassociatedwithactivationofthehippocampus link chronicstressanditch(25),whilestress-induced sease. Aberrant parasympatheticresponsemaypossibly itching wasassociatedwithincreasedactivityinsupp with cowhage-induceditch,asdemonstratedbyfMRI, was proportional to itching sensation.Inanexperiment more prominentinitchingthanpain.Moreover, it posterior cingulatecortexandtheinsulawas supplementary motor area (20). ­ How cortex, the anterior insula, the basal ganglia and pre- itching and pain both activated the anterior cingulate magnetic resonance imaging (fMRI) study demonstrated ipsilateral supplementarymotorarea(18). A functional 1 In a large population-based study among Norwegian -antihistamines andGABA-ergics (gabapentinand ever, the activity in - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV reducing itch-scratchbehaviour, improving skinstatus, and scratch-triggering factors. The training ensuedin long-term goals,relapse prevention, habitreversal skin care,itch-triggeringfactors, stressmanagement, itch-coping grouptraining. The programme focusedon that patients with AD may benefit from multidisciplinary (51). Subsequently, itwasprovenbyEversetal.(52) targeted catastrophizingandhelplessitch-related coping successfully itch” with “Coping programme nursing a cognitive restructuring(32). A Dutchstudyreported that enhancing coping abilities ofthe affected individual, e.g. the foundationofpsychologicalinterventionsaimedat disorder (FID;psychogenicitch). an optionalcriterionforthediagnosisoffunctionalitch riations of intensity associated with stress” (50) constitute the expectation of the acute stress test (49). Notably, “va tension andsubjectivestressthanhealthycontrols,with reported thatpatientswithgeneralizedCImore dermatoses (47)andpost-burnitch(48).Recentresearch as chronic urticaria(43,44),acne vulgaris (45, 46), hand mentioned theroleofstressinpruriticdisorders,such keratinocytes of psoriatic plaques (42). Other reports kinase A andcalcitonin gene-related peptidereceptorin expression ofsubstanceP receptor, tropomyosinreceptor in psoriaticsubjectsmayalsobeassociatedwithhigher gree of itching (41). Stress-related exacerbation of itch stress reactivitywasmoderatelycorrelatedwiththede et al.(7). Another studyrevealedthattheself-reported correlated (40).Similarresultswereobservedby Amatya severity ofstressandintensityitchbeingpositively heavy stress more commonly suffer fromitch, with the demonstrated that patients under heavy or extremely impacts ontheHPA axis(39). is evidencethatacuteorchronicstresshavedifferent are coveredindetailelsewhere(33–38),althoughthere tary-adrenal (HPA axis). The relevant aspects of this issue cutaneous system (NEICS) and the hypothalamo-pitui components oftheso-calledneuro-endocrino-immuno- of particular complexity and importance and involve the stress anditchinpatientswith AD constituteaproblem with itchofvariousorigins. The associationsbetween should beconsideredasanadjunctivetherapyinpatients interventions (reviewedindetailbySchutetal.(32)) levels under acute stress. Thereby, various psychological maintaining calmandpresentinglowersalivarycortisol strated diminishedcortisolawakeningresponse,while that individualssubjectedtotheseinterventionsdemon patients with atopic dermatitis (AD). The study revealed cognitive behaviouralstressmanagementprogrammesin properties (30).Recently, Schutetal.(31)employed cise controloverstressorsduetoitsimmunomodulating of self-efficacy in psychological interventions may exer to doandpossessingthenecessaryskills. The increase demanding situationseffectively, despiteknowingwhat Itch-stress associationsarecomplex,yettheyserveas Regarding patientswithpsoriasis,ourgrouphas - - - - - most peopleanditsdegreemaybeassociatedwithneu itch contagionisanormativeresponseexperiencedby of people scratching (57). Holle et al. (58) reported that or salineinjection,followedbywatchingashortvideo to scratchthemselvesafterbeingsubjectedhistamine when comparedwithhealthycontrols,weremoreprone Subsequent researchrevealedthatpatientswith AD, participants to feel itch and exert scratching behaviour. lecture entitled “Itching – what’s behind it?” caused the the listeners,Niemeieretal.(56)provedthatapublic that lecturesaboutpruriticdermatosesinduceitchingin investigated in different studies. Based onthe experience “itch contagion” or “contagious itch” was conceived and of psycheinelicitingitch,thenocebo-relatedconcept the literature (54, 55). Acknowledging the relevant role attributed toepidemichysteriahavebeendescribedin Interestingly, outbreaksofitchamongschoolchildren which isintendedtoinducenegativeexpectations. an inert substance or undergoes a neutral procedure, placebo effect (53).Inessence,anindividualreceives The noceboeffect thenegativecounterpartof is PHENOMENON? NOCEBO EFFECT:IS ITCHACONTAGIOUS long-term. and short-term as both regarded were benefits These catastrophizing. in decline with increased, self-efficacy ment. Copingwithitchwasimproved,astheitch-related agreeableness, conscientiousness, neuroticism and open which encompasses 5 bipolar dimensions (extraversion, cription ofpersonality structure is The Big Five model, (63). Oneofthemostpopular modelsusedforthedes sense, alsoincludingthoughts, feelingsandmotivation racteristic patternofbehavioursconsideredinthebroad The personality of an individual may be defined as a cha PSYCHOLOGY OFITCH demonstrated (62). of itchinchildrenwithautismspectrumdisorderwas bal suggestion(61).Recently, increasedcontagiousness may be minimized or reversed via conditioning with ver proved thatnoceboeffects regardingtheitchsensation on itchinhealthyindividuals(60).Itwassubsequently tion mayresultinrelevantnoceboandplaceboeffects that the combination of conditioning and verbal sugges itch inhealthyindividuals. Another studydemonstrated et al.(59)revealedthatsolitaryvisualstimulantsprovoke Lloyd cortexandBA6. 44,primarysomatosensory (BA) correlated withtheactivation of the leftBrodmann area study. The fMRIexamination revealed that itch intensity itch contagionandsexorempathywasestablishedinthis traits onitchisreviewedbelow).Noassociationbetween roticism asapersonalitytrait(theimpactof decreasing the need fordermatological visits and treat Itch andpsyche:bilateralassociations Theme issue: Itch and pruritic disorders 29 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue: Itch and pruritic disorders chronic urticaria(73). ronto Alexithymia Scale (TAS) amongindividualswith score. Another groupassessedalexithymia viathe To itch exhibitedlowerscoresonthefantasizingsubscale dialysis (9).Itwasobservedthatpatientswithuraemic with end-stage renal disease on maintenance haemo Alexithymia Questionnaire(BVALQ-40) amongpatients has investigatedalexithymiausingtheBermond-Vorst inability toidentifyandverbalizeemotions.Ourgroup the defines construct personality this general, In (72). personality onphysicalillnessandhealthisalexithymia and emotions of influence the understanding for digm entiousness) patients. and undercontrolled(highneuroticismlowconsci overcontrolled (high neuroticism and conscientiousness) higher ItchyQolsymptomscorewasobservedbothin greater mean total ItchyQoL score. On the other hand, and conscientiousness)(NEO-FFI)wasassociatedwith extraversion low as (defined style personality lethargic Patient Care Database). The authors observed that the National Administration Health VeteransUS and tion with CI(recruitedfromtheNationalEczema Associa replicated (70).Kinietal.(71)investigatedpatients subsequently were with findings subjects These AD. in SCS) were significant predictors of scratching behaviour public self-consciousness (the Self-Consciousness Scale; red with healthy controls, agreeableness (NEO-FFI) and turing crawlinginsectsandskindisorders(69).Compa with AD andhealthycontrolswereexposedtovideosfea Questionnaire; WCQ). InaGermanstudy, individuals itch morefrequently(assessedviathe Ways ofCoping common copingstrategiesamongpatientsexperiencing more were self-blame and resignation However, FFI). itch (assessedviaNEO-FiveFactorInventory;NEO- regarding psoriaticpatientswithvariousfrequencyof et al.(68)foundnodifferences inbasicpersonalitytraits aggression (assessed via SSP) (67). Conversely, Janowski trait anxiety, embitterment,mistrust,andphysicaltrait somatic with associated significantly was itch severe (EPQ-R) (66).Notably, amongsubjectswithpsoriasis, ned viatherevisedEysenckPersonalityQuestionnaire and lowerextraversiontraitsthancontrolswhenexami prurigo nodularis (PN)exhibited higher neuroticism instrumental and less emotional support. Patients with was morepersistentamongindividualswhosought Burns Questionnaire(CBQ)scoresrevealedthatitch Scales ofPersonality(SSP).Moreover, theCopingwith assertiveness, asassessedbytheSwedishUniversities persistence of post-burn itchwasassociatedwithlackof aiding affected individuals.InaSwedishstudy(65)the and supportstheroleofpsychologicalinterventionsin traits onitchsensationwasexploredinseveralreports ness to experience) (64). The impact of personality 30 Another conceptthathasevolvedasapotentialpara R. ReszkeandJ.C.Szepietowski ------patients with CI, among whom 31 (22.3%) had an under Ferm etal.(77)evaluatedthemedicalrecordsof139 psychotherapeutic or psychiatric treatment was advised. diagnoses could be established.Inover60% of patients and observedthatinover70%ofthem1–6psychiatric (76), whoexamined109dermatologyinpatientswithitch recurrent depressiveepisodes. decreased, whereas recurrent itching was associated with individuals afterthedepressivesymptomsmarkedly episode. Notably, itchingdisappearedinallaffected experienced by 17.5% of patients during the depressive who werehospitalizedwithdepression (75). Itchingwas itch. Similarly, our group enrolled inpatients (n that stresswasoneofthemajoraggravatingfactors psychiatric ward,CIaffected 32%.Ofthose,45%stated among a cohort of patients (n chiatric comorbidities. In a study by Mazeh et al. (74) (STAXI) tools,respectively).Inpatientswithchronic (SCL-90-R) andState Trait Anger eXpressionInventory and anger(assessedviathe SymptomChecklist90-R itch andseveral domains, including emotional distress sis. The investigators assessedtherelationshipbetween idiopathic urticaria(CIU)and44patientswithpsoria executed acomplexstudyof41patientswithchronic in depressionscores.Subsequently, Conradetal.(43) (81) linkedalleviationofitchinpsoriasiswithchanges with regardtopsychiatriccomorbidities.Guptaetal. evaluated also were which disorders, pruritic “classic” (79, 80). of selectiveserotoninreuptakeinhibitorsorneuroleptics origins; however, itchmayalsobeinducedbytheuse psychoactive drugsinordertoalleviateitchofdifferent lesions. Dermatologistsandpsychiatristsoftenutilize of itch,longerdurationandcoexistencechronicscratch psychosomatic comorbiditiespresentedhigherintensity and others(17%).Notably, patientswiththepsychiatric/ (11.2%), anxiety/compulsive disorder (F40–F42) (6.6%) ciative/somatoform disorder/hypochondria(F44–F45) (30.7%), adjustmentdisorder(F43.2)(17.8%),disso according to ICD-10) (74.5%), depression (F32–F34) psychological/psychosomatic cofactors in itch (F54 (78). The mostcommoncomorbiditiesencompassed had atleastonepsychosomatic/psychiatriccomorbidity a psychosomaticconsultationdemonstratedthat77.1% tients with CI who were referred by the dermatologist for lying psychiatricdisorder. A recentstudyamong 560pa of itchmayfrequentlyensueinawidespectrumpsy background ofitchincertaincases,whereasthepresence itch andpsyche,onecannot omit the obviouspsychiatric Taking intoaccountthewidespreadrelationshipbetween PSYCHIATRIC PERSPECTIVE ONITCH A different approachwaspresentedbySchneideretal. There are also reports in the literature concerning = 111) hospitalizedinthe = 40) - - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV psoriasis with severe itchpresented higherscoresforde severe psoriasis with ( several criteria. The 3compulsory criteriaencompass: pruritus” (50,86)andcan bediagnosedaccordingto triggering intensity, aggravation or persistence of the where psychologicalfactors playanevidentroleinthe where itchisatthecentreofsymptomatology, and disorder, itch “an as defined was entity This itch). nic in functionalitchdisorder(FID;alsotermedpsychoge plicated itchandpsycheinterplayiselegantlyembraced depressive symptoms(assessedbyBDI)(85). The com disease, theseverityofCI(4IIQ)wascorrelatedwith (p sive (p aggres more significantly be to tend patients German formed intermsofemotionalreactions,revealingthat and associated withunderlyingsystemicdisorders(p CI duetodermatologicaldiseasesthanthosewith sion, weremorecommoninGermanindividualswith that affective reactions,suchasdepressionandaggres controls (69). D) andhigherincreaseinitchintensitycomparedwith HADS- Scale; Depression and (Hospital Anxiety scale is aconnection between high scores onthedepression A studyamong27patientswith AD reportedthatthere pression andanxiety(asassessedviaSTAI andBDI-II). by Remröd et al. (67)(n suicidal ideation(83).Inapreviouslymentionedstudy and anxiety. Inaddition,patientswithPNmore oftenhad study concerningPNburdenwithrespecttodepression controls (82).Similarrelationswerereportedinarecent 4.64; (adjusted OR (adjusted OR2.06;p of antidepressants(adjustedOR2,6;p sion (adjustedoddsratio(OR)2.82;p extraversion. Subsequently, PNwaslinkedtodepres neuroticism, whilelowerthanthecontrolsconcerning describing howsubjectfeelingeneral),depressionand higher scoresforthe T-anxiety scale(STAI –formy-2; (STAI). It was observed that patients with PN exhibited (BDI-II) andtheState Trait Anxiety Inventory–form Y EPQ-R, theBeckDepressionInventorysecondedition compared withhealthycontrolsregardstoscoresin In astudybyDazzietal.(66)20subjectswithPMwere for thepresenceofitchaccompanyingurticarialwheals. histamine. These aspectsmight,atleast,partiallyaccount cell activationanddegranulationofmediators,suchas phin-releasing hormone,subsequentlyleadingtomast involving angerandstress,whichstimulatecorticotro­ with CIU,theauthorsdiscussedpossiblepathway severity inpatientswithpsoriasis.Regarding itch influence to seemed depression whereas severity, idiopathic urticaria(CIU)anger German andUgandanpatientswithCIwasalsoper i ) localizedorgeneralized itch withoutprimaryskin Interestingly, a study by Weisshaar et al. (84)recounted < 0.0001). Inacohortofpatientswithend-stagerenal p = < 0.03, respectively). A comparisonbetween 0.0001) andmoreoftendonothaveanydrive p < < 0.05) andtheuseofanxiolytics 0.001) compared healthywith = 101) subjects with plaque was apredictorofitch 0.001), anxiety < 0.001), < 0.001), theuse = 0.04 ------several life aspects, e.g. reactions to life occurrences, dis of goodness the of measure a as defined be may QoL IMPAIRMENT: THEBURDEN OFSCRATCHING HEALTH-RELATED QUALITYOFLIFE suicide thatthosewithoutthedisease(90). to havesuicidalideationand36%morelikelydieby considered aconstantfeature)were44%morelikely analysis, patientswith AD (inwhichitchisgenerally 8.4% amongsubjectsdenyingitching.Inalarge meta- suicidal ideationwasreportedby21.1%,incontrastto ideation (OR3.0). Among theindividualsreportingitch, tion. Severe itch wasstrongly associatedwith suicidal questionnaire focusingonitch,painandsuicidalidea toaspecial responded et al.(89),3,682adolescents Halvorsen by study a In suicide. of risk the mentioning sociations with itch are nowhere near complete without FID in particular have rarely been investigated (87, 88). associated withpsycheandwell-beingofpatients somatic origin)(3).Unfortunately, thedetailedaspects associated withthe4 is FID aetiology, its to according classification (IFSI) Regarding theInternationalForumforStudyofItch ( ritus thatcouldbe improved by psychotropic drugs, and concentrating, and23%changed theireatinghabits. more agitated,24%became depressed,30%hadtrouble bothered 84 (84%) patients, amongwhom 35% became with psoriasis. According to Yosipovitch etal.(96),itch orders. These issueswere studiedindetailsubjects both incutaneousandprimarilyextracutaneousdis validated inseverallanguages(95). been has HRQoL assessing for (ItchyQoL) instrument with a special emphasis on CI. Recently, an itch-specific stems from various disease-related signs and symptoms, HRQoL in Impairment (94). Skindex or (93) (DLQI) multiple tools,e.g.theDermatologyLifeQualityIndex HRQoL in dermatological patients can be measured with and social domains of health” (92). The impairment in and his orher perceived well-beinginphysical,mental life their in functions person a well “how encompasses which has multiple definitions. One of theHRQoL, most relevant with confused is term this infrequently, Not as satisfactionwithworkandpersonalrelationships(91). position, sense of life fulfilment and satisfaction, as well inaction, (v)associatedpsychologicaldisorder, (vi)pru nocturnal variations,(iv)predominanceduringrestor ( life eventsthatcouldhavepsychologicalrepercussions, a chronological relationship of pruritus with 1 or several the following7additionalcriteriahavetobefound:(i) and (iii)nosomaticcause.Inaddition,atleast3outof lesions, (ii ) pruritus that could be improved by psychotherapies. vii) pruritusthatcouldbeimprovedbypsychotherapies. ) variations in intensity associated with stress, (iii) stress, with inintensityassociated ii) variations Finally, considerationsconcerningpsychiatricas There is recent literature focusing on itch and HRQoL, ) chronic pruritus of at least 6 weeks’ duration, Itch andpsyche:bilateralassociations th Theme issue: Itch and pruritic disorders category(psychogenic/psycho 31 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV debilitating impactofCIon QoL hasalsobeeninvesti between thetotalSF-36score anditchintensity. The correlations negative significant found we addition, In was markedlyworseamong pruritic subjects(p Among theSF-36dimensions,generalhealthperception Theme issue: Itch and pruritic disorders gated inothersystemicconditions (chronicvenous (SF-36) (93.0 life according to the 36-item Short Form Health Survey with uraemic pruritus had significantly lower quality of disease, amongwhomCIconcerned38%(85).Patients also evaluatedCIin200patientswithend-stagerenal has group Our symptoms. and functionality efficacy, with respecttotheemotionssubscale,followedbyself- correlation withthemeanitchseveritywasobserved the total score of the ItchyQoL (106). The strongest monstrated thatthemeanseverityofCIcorrelatedwith (p CI with those among affected more significantly was HRQoL, revealing that the physical component subscale respectively. The SF-12 questionnaire was used to assess valence andlifetimeprevalencewere27.2%35.2%, associated with sexual dysfunction (assessed by the 9 gical outpatients (n mustard (103). Notably, in a large cohort of dermatolo sclerosis (102)anditchfollowingexposuretosulphur T-cell lymphoma (100),dermatomyositis (101),systemic Other researchers proved impaired HRQoL in cutaneous did. intensity its whereas scores, DLQI not correlatewith was reportedby62.1%ofpatients(99).Itspresencedid among patients with hidradenitis suppurativa (HS), itch on children’s andtheirparents’ sleep(98).Inourstudy influence detrimental its acknowledge to imperative is it 97); (35, well-documented is AD in HRQoL on itch (4IIQ) andvisualanaloguescale(VAS). The impactof itch intensityassessedviathe4-ItemItchQuestionnaire with itch (6). In addition, the DLQI score correlated with patients in decreased significantly was DLQI, the via assessed HRQoL, that found group our Subsequently, reported decreasedornon-existentsexualfunctions. decreased ornon-existentsexualdesire,whereas35% to itch. Moreover, 40%ofpruritic subjects reported due awakenings night and asleep falling difficulties by Remarkably, two-thirds ofthe patients were bothered 32 prevalence of CIwas25.2%, while the 12-month pre 860 patientsonhaemodialysis,revealingthatthepoint In astudyby Weiss etal.(105),theauthorsevaluated A prominent example is CI due to end-stage renal disease. have been associated with CI and impairment in HRQoL. organs different afflicting conditions systemic various (p HRQoL decreased with disorders causingCIweremorecommonlyassociated that, compared with dermatological disorders, systemic disorders. ItwasobservedamongGermanindividuals been investigatedinrelationtounderlyingsystemic question oftheDLQI)(104). The HRQoL issues associated with itch have also have itch with associated issues HRQoL The < 0.05). A subsequentstudyonthesamecohortde R. ReszkeandJ.C.Szepietowski

±

20.4 vs. 99.6 = 3,485), thepresenceofitchingwas = 0.003) (84).Nevertheless,

±

99 points, 19.9 0.0003). = 0.0003). p

=

0.03). th - - - -

explanation involves itch as an elicitor of scratching be strongest predictorsofstigmatization. The possible at thetimeofstudy(followedbyitching)were reported itch;itwasobservedthattheextentofbleeding and secretiveness).Ninety-threepercentofparticipants opinions ofothers,guiltandshame,positiveattitudes, the to sensitivity flawed, being of feelings rejection, ing 33questionsfocusingon6factors(anticipationof psoriatic subjects via an original questionnaire contain Link (115) inacohortof53 exploredstigmatization with higherlevelsofstress(114). In1989Ginsburg & tion inpatientswith AD orpsoriasismaybeassociated The roleofitchandfatigueinexperiencingstigmatiza sis, vitiligo,leprosyoracne,tonamejustafew(113). clinicians. Taking into account the abundance of both ex are bilateral and multidimensional, posing challenges for of itch. The knownassociations between itch andpsyche still many unresolved questions about the phenomenon Despite aconstantlyincreasing volumeofdata,thereare CONCLUSION tization levelassessedviathe6ISS(116). intensity of itching significantly correlated with stigma Feelings ofStigmatizationQuestionnaire,whereasthe in 78.7%)predictedstigmatizationaccordingtothe with psoriasis(n mostly influenced. Another study among Arabic subjects “sensitivity to other attitudes” and “secretiveness” were flawed”, being of “feeling domains the latter, the ding the FeelingsofStigmatizationQuestionnaire.Regar level of stigmatization assessed via the 6ISS, as well as (6). The intensity of itch correlated significantly with the with plaque-psoriasis,amongwhomitchaffected 89.2% our groupinvestigatedthewell-beingof102patients stigmatization ona4-pointLikertscale.Subsequently, Stigmatization Scale(6ISS)regardingtheperceived were evaluated by several tools, including the6-Item outpatients with psoriasis and 139 outpatients with AD itch tostigmatization.InastudybyLuetal.(114) 131 knowledge, this was the first experimental study relating haviour, whichmayensueinbleeding. To thebestofour context ofvariouscutaneousdisorders,suchaspsoria Unsurprisingly, stigmatizationhasbeenstudiedinthe attribute or physical mark and on social rejection (112). disapproval, discreditingordevaluation,basedonan Stigmatization may be defined as an awareness of social STIGMATIZATION THE SOCIAL WOUNDS: ITCHAND are beyondthescopeofthisreview. considerations detailed although (111)), infection HIV sclerosing cholangitis(109),polycythemiavera(110) or insufficiency (107), Sjogren’s syndrome (108), primary = 108) revealedthatitching(present ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV REFERENCES an unusualunionthatlastsalifetime. management ofbothskinandpsyche,astheyconstitute approach tothepatient. This isasurerecipeforbetter holistic the of basis the is field, the in specialists other experience and involving psychiatrists, psychologists and perimental and clinical findings, coupled with increasing 19. 18. 17. 16. 15. 14. 13. 12. 11. 10. 9. 8. 7. 6. 5. 4. 3. 2. 1. Okamura N,Yanai K.Neural correlatesof perceptualdif Mochizuki H,SadatoN,Saito DN, Toyoda H,Tashiro M, 2001; 92: 295–305. of O-15H2Opositronemission tomography studies.Pain itch: analogies to pain processing: a correlational analysis F,Munz Central etal. activation by histamine-induced Drzezga U, A,Darsow Treede RD, M, Frisch H, Siebner reactions. J Invest Dermatol 2000; 115: 1029–1033. human cerebral cortex: a correlation analysiswithdermal stein P, etal.Processingofhistamine-induceditchinthe Darsow U, Drzezga A, Frisch M, Munz F, Weilke F, Barten therapy. J ClinInvest 2006;116: 1174–1186. tus research: scratching the brain for more effective itch Paus R, Schmelz M, Bíró T, Steinhoff M. Frontiers in pruri basis of itchsensation.Science 2009; 325: 1531–1534. Sun YG, Zhao ZQ, Meng XL, Yin J, Liu XY, Chen ZF. Cellular ronic pruritus.IndianJDermatol 2015;60:218. of amultidisciplinaryitchclinicinthemanagementch Michelle LW, Yan L, Soon-Leong AT, Liang TH. Effectiveness Immunol 2013; 24: 527–539. group of dermatologists and pediatricians. Pediatr Allergy in infancy and childhood: update from an interdisciplinary U. Chronic pruritus associated with dermatologic disease Metz M,Wahn U, Gieler U, Stock P, Schmitt J, Blume-Peytavi 553–554. clinic? Apatientsurvey. ActaDermVenereol 2012;92: tients with chronic pruritus benefit from a specialized itch Weisshaar E, Büttner M, Ofenloch R, Matterne U. Do pa in pruritus. Clin Dermatol 2013;31: 31–40. Tey Wallengren HL, J, Yosipovitch G.Psychosomatic factors Derm Venereol 2008;88: 211–218. chronic itch in patients with skin diseases: a review. Acta PC, deJongEM,Evers AW. Biopsychosocial mechanismsof Verhoeven EW, deKlerkS, Kraaimaat FW, van deKerkhof pruritus. Acta Derm Venereol 2016; 96:699–700. Heisig M,Reich A,Szepietowski JC.Alexithymia inuraemic with neurodermatitis. JAndrol 2011; 32:165–169. Deveci A, Ozturk F. Sexual dysfunction in female patients Ermertcan AT, Gencoglan G, Temeltas G, Horasan GD, 822–826. 22: 2008; Venereol Dermatol Acad Eur J study. based of pruritusinchronicplaquepsoriasis:aquestionnaire- Amatya B, Wennersten G, Nordlind K. Patients’ perspective psoriatic patients. Acta Derm Venereol 2010; 90: 257–263. of well-being the influencing negatively factor important Reich Szepietowski E, A,Hrehorów an is JC.Pruritus 150: 613–620. of chronicpruritusonquality of life. JAMA Dermatol 2014; Carr CW, Veledar E,ChenSC.Factors mediatingtheimpact 3495–3505. 21: Transplant2006; Dial Nephrol (DOPPS). Study terns Outcomes and Practicefrom the results Dialysis Pat ML, etal.Pruritusinhaemodialysispatients: international Pisoni RL, Wikström B, Elder SJ, Akizawa T, Asano Y, Keen Itch. Acta Derm Venereol 2007; 87:291–294. position paper of the International Forum for the Study of Carstens E, Ikoma A, et al. Clinical classification of itch: a Ständer S, Weisshaar E, Mettang T, Szepietowski JC, Anzieu D. LeMoi-peau.Paris: Dunod; 1985. London: Springer-Verlag; 2010:p. 217–221. logical approach. In: Misery L, Ständer S (editors). Pruritus. Dutray S, Misery L. Psychosomatics and psychiatry. Psycho ------28. 27. 26. 25. 24. 23. 22. 21. 20. 39. 38. 37. 36. 35. 34. 33. 32. 31. 30. 29. population-based cross-sectionalstudy. ActaDerm Vene Norwegian a girls: and boys 18-year-old among efficacy Dalgard F, SternR,LienL,HauserS. Itch,stressandself- 89: 39–44. study among late adolescents. Acta Derm Venereol 2009; ness E,LienL.Itchandmentaldistress:across-sectional Halvorsen JA, Dalgard F, Thoresen M, Thoresen M, Bjert pruritus using fMRI. Int J Dermatol 2016; 55:434–442. a preliminarystudyof themechanismofstress-induced Kim HJ, Park JB, Lee JH, Kim IH. How stress triggers itch: Exp Dermatol 2013; 22: 239–244. sponse: anewperspective linkingchronicstressanditch. Kim HS, Yosipovitch G. An aberrant parasympathetic re 1986: p. 63–80. tors). Dynamics of stress. Springer-Verlag, New York, US; Trumbull(edi MH, RA circularity.Appley of In: issue the Lazarus RS, Folkman S. Cognitive theories of stress and US; 1976:p. 137–146. (editor). Psychopathology Springer-Verlag ofhumanadaptation. H Selye In: Distress. without Stress H. Selye One 2013; 8: e82389. doi: 10.1371/journal.pone.0082389. itch relief. a functional MRI study of active scratching. PLoS Coghill RC, Yosipovitch G. Brain’s reward circuits mediate Papoiu AD, Nattkemper LA, Sanders KM, Kraft RA, Chan YH, itch patients.J Invest Dermatol 2015; 135: 2814–2823. in motor-related regions and reward system in chronic Coghill RC, Yosipovitch G. Scratching induces overactivity Mochizuki H,Papoiu ADP, Nattkemper LA, LinAC,Kraft RA, 2017; 66: 14–21. alteration through non-invasive treatments. Allergol Int possible andits dermatitis atopic in ofitch mechanism Mochizuki H,Schut C, Nattkemper LA, Yosipovitch G. Brain Neuroimage 2007; 36: 706–717. ference between itching and pain: a human fMRI study. Lin TK, Zhong L, Santiago JL. Association between stress Dermatol 2019;180:821–827. patients with atopic dermatitis and healthy controls. Br J acute stressonitchsensationand scratching behaviour in des Rodriguez R,StullC,etal,Yosipovitch G.Impactof Mochizuki H, Lavery MJ, Nattkemper LA, Albornoz C, Val pone.0113552. study. PLoS One 2014; 9: e113552. doi: 10.1371/journal. perimental mentalstressina randomized controlledpilot fected inatopicdermatitisandresponsetoacuteex af are system cholinergic the and plasticity neuronal – S, Niemeier V, et al. Mental stress in atopic dermatitis Peters EM, Michenko A, Kupfer J, Kummer W, Wiegand Acta Derm Venereol 2010; 90: 582–588. Association of stress with symptoms of atopic dermatitis. Oh SH, Bae BG, Park CO, Noh JY, Park IH, Wu WH, Lee KH. 27: e239–e242. Venereol AcadDermatol JEur dermatitis. atopic 2013; hip between itch and psychological status of patients with Chrostowska-Plak D, Reich A, Szepietowski JC. Relations of pruritus.Int J Dermatol 2002;41: 212–216. dermatitis usinganew questionnaire forthe assessment ItchcharacteristicsCL. atopic with patients Chinese in Yosipovitch G, Goon AT, Wee J, Chan YH, Zucker I, Goh between stress and itch. Exp Dermatol 2015; 24: 334–335. Grandgeorge M, Misery L. Mediators of the relationship Acta Derm Venereol 2016; 96: 157–161. Psychological interventions inthetreatmentofchronicitch. Schut C,MollanazarNK,Kupfer J, GielerU, Yosipovitch G. Acta Derm Venereol 2013; 93: 57–61. tients with atopic dermatitis: a randomized controlled trial. Psychophysiological effects of stressmanagementinpa Schut C, Weik U, Tews N, Gieler U, Deinzer R, Kupfer J. Soc Psychol 1990;59: 1082–1094. stressors oncomponentsof theimmunesystem.JPers with coping in self-efficacy perceived of Impact K. Raska Wiedenfeld SA, O’LearyA,Bandura A,BrownS, LevineS, over AIDS infection. Eval Program Plann 1990; 13:9–17. Bandura A. Perceived self-efficacy in the exercise of control reol 2012;92: 547–552. Itch andpsyche:bilateralassociations Theme issue: Itch and pruritic disorders 33 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue: Itch and pruritic disorders 34 60. 59. 58. 57. 56. 55. 54. 53. 52. 51. 50. 49. 48. 47. 46. 45. 44. 43. 42. 41. 40. ning and verbal suggestion in placebo and nocebo effects OH, Donders AR, van Middendorp H, et al. Role of conditio Bartels DJ, van Laarhoven AI,Haverkamp EA,Wilder-Smith individuals? BrJ Dermatol 2013; 168: 106–111. visual stimuli alone provoke a scratch response in healthy Lloyd S, Hall E, DM, Hall FP. McGlone Can itch-related to it.ProcNatl Acad Sci U S A2012; 109: 19816–19821. sis of contagious itch and why some people are more prone Holle H, Warne K, Seth AK, Critchley HD, Ward J. Neural ba Dermatol 2011;164:1299–1303. sion’ of itch in atopic dermatitis and healthy subjects. Br J ‘transmis visual of study a humans: in itch Contagious Papoiu AD, Wang H, Coghill RC, Chan YH, Yosipovitch G. inducing lecture.Dermatol Psychosom 2000;1: 15–18. Niemeier V, Kupfer J, GielerU. Observations duringanitch- mentary school. Arch Intern Med 1984; 144: 1959–1962. Outbreak of itching and rash. Epidemic hysteria in an ele Robinson P, Szewczyk M, Haddy L, Jones P, Harvey W. Lancet 1974; 2: 1500–1503. break ofpsychosomatic atarural illness school. elementary Levine RJ, Sexton DJ, Romm FJ, Wood BT, Kaiser J. Out for clinical practice. Psychosom Med 2011; 73: 598–603. Colloca L, Miller FG. The nocebo effect and its relevance Acta Derm Venereol 2009; 89: 57–63. coping training programme in adults with atopic dermatitis. der Valk PG,etal.Effectiveness ofamultidisciplinaryitch- Evers AW, Duller P, deJongEM,OteroME,Verhaak CM,van skin disease. Br J Dermatol 2007; 156: 1235–1244. randomized controlledstudyinadultswithchronicpruritic a itch’: with ‘Coping programme nursing the of tiveness C, ThioBH, van derSchuur-van der Zande A, etal.Effec van Os-Medendorp H, Ros WJ, Eland-de Kok PC, Kennedy dermatology group. Acta Derm Venereol 2007; 87: 341–344. ritus: suggested diagnosis criteria from the French psycho Audra H,etal.Functionalitchdisorder orpsychogenic pru Misery L, Alexandre S, Dutray S, Chastaing M, Consoli SG, 1174–1176. 179: 2018; Dermatol study.J case-control Br perimental susceptible to social stress than healthy controls? An ex ring L,StänderS. Arepatientswithchronicpruritus more Schneider G,Stumpf A,Burgmer M,Broecker P, Volme dictors. Br J Dermatol 2008; 158:95–100. huis MK. Itching following burns: epidemiology and pre Van Loey NE, Bremer M, Faber AW, Middelkoop E, Nieuwen Dermatol 2002; 146:1031–1037. which subgroup needs additional psychological care? Br J Psychological handdermatoses: with factorsassociated Niemeier V, Nippesen M, Kupfer J, Schill WB, Gieler U. Dermatol Venereol 2008;22: 1332–1336. Acad Eur J acne. of symptom significant and common a Lim YL, Chan YH, Yosipovitch G, Greaves MW. Pruritus is suffer from itching? Acta Derm Venereol 2008; 88: 38–42. Srama M,Szepietowski JC.Acneitch:doacnepatients Reich A,Trybucka K,Tracinska D, A, Samotij B, Jasiuk 35: 156–160. chronic urticaria females. Postepy Dermatol Alergol 2018; Zalewska-Janowska AM. Stress, itchandquality of lifein Ograczyk-Piotrowska A, Gerlicz-Kowalczuk Z, Pietrzak A, Eur AcadDermatol Venereol 2008;22: 1062–1069. in patientswithchronicidiopathic urticariaandpsoriasis. J ter F. Relationship between anger and pruritus perception Conrad R, Geiser F, Haidl G, Hutmacher M, Liedtke R, Werm J Dermatol 2007; 156: 1272–1277. their receptors in psoriatic skin in relation to pruritus. Br Chang SE,HanSS, JungHJ, ChoiJH.Neuropeptidesand J Eur Acad Dermatol Venereol 2004; 18: 27–36. and psoriasis-relatedstressof Nordicpsoriasissufferers. L, MørkC,SigurgeirssonB. Self-reported stressreactivity Zachariae R,Zachariae H,Blomqvist K,Davidsson S, Molin mat 2003; 4: 151–155. influence itching in psoriatic patients? Dermatol Psychoso Reich A, Szepietowski JC, Wiśnicka B, Pacan P. Does stress 2017; 18: E2131. and theHPA Axisintheatopicdermatitis.IntJMolSci R. ReszkeandJ.C.Szepietowski ------72. 71. 70. 69. 68. 67. 66. 65. 64. 63. 62. 81. 80. 79. 78. 77. 76. 75. 74. 73. 61. A potential paradigm forpsychosomatic medicine.Psycho Taylor GJ, Bagby RM,Parker JD. Thealexithymia construct. study. Itch 2018; 3:e20. affect the reporting of chronic pruritus: a cross-sectional Kini S, Chen KH, Chen SC. Personality traits and styles may Derm Venereol 2018;98: 32–37. patients with atopicdermatitis:areplicationstudy. Acta J. as Agreeableness predictor of scratchinginduced in Schut C, Reinisch K, Classen A, Andres S, Gieler U, Kupfer Venereol 2014;94: 20–25. an experimental setting: a regression analysis. Acta Derm depression anditchinpatientswithatopic dermatitisin Schut C,BosbachS, GielerU, Kupfer J. Personality traits, 820–829. various frequenciesofpruritus.IntJDermatol 2014;53: logical characteristics of patientswithpsoriasisreporting Janowski K, Steuden S, Bogaczewicz J. Clinical and psycho Derm Venereol 2015;95: 439–443. a studyofpersonality traits, depressionandanxiety. Acta Remröd C,SjöströmK,Svensson Å.Pruritusinpsoriasis: study. J Dermatolog Treat 2011; 22: 211–214. Psychological factorsinvolved inprurigonodularis:Apilot D, C,Erma Dazzi R,Veraldi Piccinno S, M. Caccialanza Venereol 2004;84: 375–380. in long-term follow-up of burn-injured patients. Acta Derm B. L,Gerdin Ekselius personality Pruritus, traits andcoping Willebrand M, Low A, Dyster-Aas J, Kildal M, Andersson G, Oaks, CA:Sage;2018:p. 240–241. encyclopedia of lifespan human development. Thousand terberry ME, Fingerman KL, Lansford JE, editors. The SAGE Soto CJ. Big Five personality traits. In:Bornstein MH,Ar 572–573. lenges for conceptual integrations. Eur J Pers 2017;31: chal psychology: personality in definitions Basic J. Uher trincoll.edu/theses/705 Repository.Digital Available from:https://digitalrepository. lege, Hartford, CT 2018. Hartford, CT, USA: Trinity College autism spectrum disorder (ASD). Senior Theses, Trinity Col Schineller M.Increasedcontagiousitchinchildrenwith trial inhealthy humans. PLoS One 2017;12:e0182959. conditioning with verbal suggestion: a randomized clinical man KJ, Donders ART, etal.Minimizingnoceboeffects by psychiatric Arch and Dermatolcorrelates. dermatologic NJ, et al. Pruritus in psoriasis. A prospective study of some Gupta MA, Gupta AK, Kirkby S, Weiner HK, Mace TM, Schork a review. ActaDerm Venereol 2009; 89: 236–244. Reich A, Ständer S, Szepietowski JC. Drug-induced pruritus: of the literature. Pharmacotherapy 2002; 22: 516–518. nin reuptake inhibitor-induced rash: casereportandreview Sannicandro TJ, Farrar MC, Markowitz JS. Selective seroto Acad Dermatol Venereol 2019;33: e288–e291. comorbidity are highly burdened: a longitudinal study. J Eur ronic pruritus patients with psychiatric and psychosomatic Schneider G, Grebe A,Bruland P, Heuft G,StänderS. Ch Venereol 2010;90: 395–400. comorbidity in patients with chronic pruritus. Acta Derm Ferm I, Sterner M, Wallengren J. Somatic and psychiatric 762–767. patients withchronicitch.ClinExpDermatol 2006;31: S. Psychosomatic cofactors and psychiatric comorbidity in G,EversSchneider G,DrieschHeuft S, LugerTA, Ständer 2009; 89: 109–110. in depression a rare phenomenon? ActaDerm Venereol Pacan P, Grzesiak M, Reich A, Szepietowski JC. Is pruritus Derm Venereol 2008;88: 128–131. man A, Yosipovitch G. Itching in the psychiatric ward. Acta Mazeh D, Melamed Y, Cholostoy A, Aharonovitzch V, Weiz 2016; 12: 995–1004. comorbid with recurrent urticaria. Neuropsychiatr Dis Treat AR. Sense of alexithymia anxietyin patients with disorders Szromek A, AraszkiewiczMJ, Just AM, Szota EA, Ogłodek somatics 1991;32: 153–164. Bartels DJP, van Laarhoven AIM, Stroo M, Hijne K, Peerde on itch. PLoS One 2014; 9:e91727. ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV 99. 98. 97. 96. 95. 94. 93. 92. 91. 90. 89. 88. 87. 86. 85. 84. 83. 82. Matusiak Ł, Szczęch J, Kaaz K, Lelonek E, Szepietowski JC. Adolesc Med2005;159:745–750. ArchPediatr dermatitis. atopic in bance andcosleeping AJ, CellaD, ChrenMM.Thepriceofpruritus:sleepdistur Chamlin SL, Mattson CL, FriedenIJ, Williams ML, Mancini 121: 340–347. cross-sectional study. Ann Allergy Asthma Immunol 2018; of life in atopic dermatitis in US adults: a population-based Fonacier L, Grayson MH, et al. Patient burden and quality Silverberg JI, Gelfand JM, Margolis DJ, Boguniewicz M, 143: 969–973. patients with extensive psoriasis. Br J Dermatol 2000; prevalence and clinical characteristics of pruritus among Yosipovitch A, Wee G,Goon J, CL.The Goh ChanYH, 33: 391–397. pruritic dermatoses. J Eur Acad Dermatol Venereol 2019; M, et al. Cross-European validation of the ItchyQoL in Zeidler C, Steinke S, C, Bruland P,Riepe Soto-Rey I, Storck Dermatol 1996; 107:707–713. disease: reliability, validity, andresponsiveness. JInvest Skindex, a quality-of-life measure for patients with skin Chren MM,LasekRJ, QuinnLM,MostowEN,Zyzanski SJ. Exp Dermatol 1994;19:210–216. Clin use. clinical routine for measure practical simple a – Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) nomics 2016;34: 645–649. and quality of life: what is the difference? Pharmacoeco Karimi M, Brazier J. Health, health-related quality of life, J Psychol 2013;9: 150–162. Theofilu P. Quality of life: definition and measurement. Eur and meta-analysis. JAMA Dermatol 2019; 155:178–187. and ween atopic dermatitis suicidality: a systematic review Sandhu JK, Wu KK,Bui TL,Armstrong AW. Associationbet Derm Venereol 2012;92: 543–546. ideation: a population-based cross-sectional study. Acta Itch and pain in adolescents are associated with suicidal Halvorsen JA, Dalgard F, Thoresen M, Bjertness E, Lien L. (in Turkish). Turkderm – Arch Turk Dermatol Venerol 2015; 49: 28–32 pruritus withangerandassociatedpsychiatric disorders]. functional of relationship [The O. Karamustafalıoğlu R, Önem TekinA, B, GT,Bakım Demirci IK, Altunay G, Atış Clin Dermatol 2014; 15: 365–370. life: across-sectionalquestionnairestudyinTurkey. AmJ ctional prurituscomparedwithmildpsoriasisonquality of Altunay IK,Atis G,EsenK,Kucukunal A.Impactoffun Derm Venereol 2008;88: 503–504. of functional itch disorder or psychogenic pruritus. Acta Psychodermatology Group. Validation of diagnosis criteria Misery L, Wallengren J, Weisshaar E, Zalewska A, French renal disease.ActaDerm Venereol 2014;94: 276–281. sive symptoms in haemodialysis patients with end-stage mic pruritusmarkedly affects thequality oflife anddepres Suseł J, Batycka-Baran A, Reich A, Szepietowski JC. Urae 957–964. German and Ugandan patients. Br J Dermatol 2006; 155: symptom: clinical characteristics and quality of life in Bruckner T, Diepgen TL, Gollnick H. Pruritus as a leading Weisshaar E, Apfelbacher C, Jäger G, Zimmermann E, 33: 157–162. study in13countries.J EurAcadDermatol Venereol 2019; morbidities of prurigo in European patients: a multicentre Sampogna F, et al. The self-assessed psychological co Brenaut E, Halvorsen JA, Dalgard FJ, Lien L, Balieva F, e106–e107. rigo nodularis. J Eur Acad Dermatol Venereol 2017; 31: JP. Anxiety, depression and suicide in patients with pru Jørgensen KM,EgebergA,Gislason GH,Skov L,Thyssen 1988; 124:1052–1057. ------106. 105. 104. 103. 116. 115. 114. 113. 112. 111. 110. 109. 108. 107. 102. 101. 100. from chronic itch: results from GEHIS (German Epidemio related quality of life in haemodialysis patients suffering Weiss M, Mettang T, Tschulena U, Weisshaar E. Health- study. ActaDerm Venereol 2015;95: 816–821. in haemodialysis patients: a representative cross-sectional haar E. Prevalence of chronic itch and associated factors Weiss M, Mettang T, Tschulena U, Passlick-Deetjen J, Weiss countries. ActaDerm Venereol 2017; 97: 478–482. logical outpatients from a multicentre study in 13 European Titeca G, et al. Impairment of sexual life in 3,485 dermato Sampogna F, Abeni D, Gieler U, Tomas-Aragones L, Lien L, 2008; 47: 557–561. sulfur mustard-exposedIranian veterans. IntJDermatol madi-Mofrad M. Impact of pruritus on quality of life in Panahi Y, Davoudi SM, Sadr SB, Naghizadeh MM, Moham 62: 1489–1495. 2010; (Hoboken) Res Care Arthritis sclerosis. systemic sociation ofprurituswithquality of life anddisability in 10.5114/ada.2018.80271. cross sectional study. Adv Dermatol Allergol 2019; doi: a – Emirates Arab United the in patients psoriatic Arabic Dimitrov D, Matusiak Ł, Szepietowski JC. Stigmatization in with psoriasis. J Am Acad Dermatol 1989; 20:53–63. Ginsburg IH, Link BG. Feelings of stigmatization in patients 2003; 4:146–150. with psoriasis and atopic dermatitis. Dermatol Psychosom ness as predictor of perceived stigmatization in patients Lu Y, Duller P, van der Valk PGM, Evers AWM. Helpless Dosw (Online)2017;71:1115–1122. with a special focus on psoriatic patients. Postepy Hig Med Dimitrov D, Szepietowski JC. Stigmatization in dermatology 2017; 176:687–694. ved stigmatization inpatientswithpsoriasis.Br JDermatol Zeeuwen-Franssen ME,KroftEB, ofpercei Predictors etal. van Beugen S, van Middendorp H, Ferwerda M, Smit JV, quality of life.J Am Acad Dermatol 2014; 70: 659–664. southeastern United States: its prevalence and effect on YH, etal.ChronicpruritusinHIV-positive patientsinthe Kaushik SB, CerciFB, Miracle J, Pokharel A,ChenSC,Chan vera. Acta Derm Venereol 2018;98:185–190. towski JC. Burden of aquagenic pruritus in polycythaemia Szepie J, T,Kwiatkowski Wróbel Ł, Matusiak E, Lelonek Eur J Gastroenterol Hepatol 2014; 26:1374–1379. cholangitis. sclerosing primary quality with patients in oflife severely with associated is Pruritus et al. Stefan R, impaired Gotthardt DN, Rupp C,Bruhin M,Schellberg D, Weiss KH, of life. Acta Derm Venereol 2017; 97:385–386. Sjögren’s syndrome:characteristics andeffect onquality YH, Blum M, Yosipovitch G. Chronic pruritus in primary Valdes-Rodriguez R, Rowe B, Lee HG, Moldovan T, Chan on quality of life. J Am Acad Dermatol 2005; 53: impact 504–508. an with insufficiency venous chronic moderate to pain, and burning sensation are common symptoms in mild Duque MI, Yosipovitch G, Chan YH, Smith R, Levy P. Itch, 3097–3106. logy Haemodialysis ItchStudy).QualLifeRes 2016;25: Thombs BD, Canadian Scleroderma Research Group. As El-Baalbaki G, Razykov I, Hudson M, Bassel M, Baron M, 2011; 65: 1107–1116. al. Quality oflifeindermatomyositis. JAmAcadDermatol Goreshi R, Chock M, Foering K, Feng R, Okawa J, Rose M, et Symptom Manage2013; 45: 114–119. of life inpatientswithcutaneousT-cell lymphoma. JPain S, etal.Prevalence andseverity of pruritusandquality Wright A,Wijeratne A,HungT, GaoW, Whittaker S, Morris Derm Venereol 2018;98: 191–194. and pain in patients with hidradenitis suppurativa. Acta hidradenitis suppurativa. Clinical characteristics of pruritus Clinical characteristics of pruritusandpaininpatientswith Itch andpsyche:bilateralassociations Theme issue: Itch and pruritic disorders 35 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV doi: 10.2340/00015555-3347 mune system. will discusstheantipruritic therapiestargeting theim therapies workingonthenervous system,andnextwe antipruritic new discuss first will we Herein, veloped. the adventofimmunomodulatingtherapies. dermatitis (AD),havebeendramaticallyimprovedby inflammatory itch, such as psoriasis and recently atopic dial pruritus and notalgia paresthetica. Likewise, cases of only make patients drowsy, forgetting that they are itchy. antihistamines. Infact,theyarenotatalleffective, and the majorityofchronicprurituscasesdonotrespondto antihistamines as a primary treatment for itch. However, perate forrelief.Fordecades,clinicianshaveresortedto C med.miami.edu 10th Ave, RMSB 2067B, Miami, FL 33136, USA. E-mail: gyosipovitch@ taneous Surgery, University of Miami MillerSchool of Medicine, 1600 NW Corr: Acta DermVenereol 2020;100:adv00027. Accepted Oct15,2019;PublishedJan9,2020 nerve fibers. Key words: pruritus; antipruritics; cytokines; unmyelinated equipped to treat their itchy patients. antipruritic therapiesallow physiciansto bebetter tors. The promising withresults presented these new inhibi kinase janus and antagonists, interleukin veral se crisaborole, include These measures. efficacy and have becomemoretargeted, leadingto greatersafety therapies developed to work on the immune system andmanymore.receptors, Additionally, antipruritic neurokinin-1nels, sodium channels, receptors, opioid as the system, such transient receptor potential chan nervous the in receptors specific targeting developed fering fromSeveral itch. chronic treatments havebeen 1 Emilie FOWLER A NewGenerationofTreatmentsforItch Centenary theme section:ITCHANDPRURITIC DISORDERS presenting presenting more treatmentseffective for patients suf A new era of antipruritic drugs is quickly approaching, their ofby makingpatients itch. drowsyandforgetful treatment forchronic pruritus, yettheyoftenonly work antihistamines havebeenthemainstayof For decades, Acta DermVenereol 2020;100: adv00027 Miami, USA especially in cases of neuropathic itch such as brachiora as ofneuropathicitchsuch especially incases gabapentin andpregabalin,haveimprovedsymptoms, have arisen. Medications working on the nerves, such as physiology ofitch,newerandbettertargets fortreatment Dr. PhillipFrostDepartmentofDermatology and CutaneousSurgery,and New treatmentsforitchare continuouslybeingde With a more profound understanding of the patho Gil Yosipovitch, Dr. Frost Phillip Department of Dermatology and Cu- quality oflife(1),causingpatientstobecomedes hronic itchcannegativelyimpactsleep,mood,and 1,2 and GilYOSIPOVITCH 1,2 This isan open access article under the CC BY-NC license. www.medicaljournals.se/acta REVIEW ARTICLE ------­ treatment-refractory pruritus, as well as prurigo nodularis treatment-refractory pruritus, as well as prurigo nodularis to treatchemotherapy-induced nausea,iseffective for D2, andleukotrieneB4(5). histamine, tumor necrosis factor (TNF)-α, prostaglandin tion andmastcellreleaseofpruriticmediatorssuchas NK-1 by SP leads to pro-inflammatory cytokine produc hout thecentralnervoussystemandskin. Activation of (SP), aknownpruriticmediator. NK-1islocatedthroug Neurokinin-1 (NK-1)servesasareceptorforsubstance P Neurokinin-1 inhibitors the nervesactinskin,spinalcord,andbrain. Fig. 1diagramswheretheseantipruriticdrugstargeting itch hasledtodevelopmentofnoveltargeted therapies. of the involvement of these receptors and their ligands in Discovery symptom. pesky this involved intransmitting tivity andactivation,causingneuralsensitization(2–4). lead to functional and structural changes in brain connec the spinal cord. Finally, in the brain, chronic pruritus can spinal circuitsleadtoneuralsensitizationatthelevelof receptors. Dysfunctionandattenuationoftheinhibitory dermal innervation,anddysfunctionofcutaneoustouch sensitization is the result of inflammation, abnormal epi hypersensitive to pruritic stimuli (2). In the skin, neuronal phenomenon causes theitch-selective neurons tobecome tional mechanism referred to asneural sensitization. This At thelevelsofskin,spinalcord,andbrainisanaddi in the brain (2). Yet, the sensation of itch is not that simple. thalamus, beforebeingfurtherprojectedtovariousareas spinal cord,andtraversingthespinothalamictractto the in synapsing skin, the in originating fibers nerve C byunmyelinatedThe sensationofitchistransmitted TREATMENTS TARGETING THENERVES system and drugsthataffect theimmunesystem. more effective. These include drugstargeting theneural itch, newer treatments have been developed that are much chronic, unrelenting itch. With agreater understanding of antihistamines are not an effective therapy for patients with Although a mainstay of anti-itch therapy for many decades, eliminate. to difficult be can that sensation pesky a is Itch SIGNIFICANCE 2 Aprepitant, an NK-1 inhibitor originally developed At eachstepofthispathwayisanarrayreceptors Miami Itch Center, University of Miami Miller School of Medicine, Journal Compilation ©2020ActaDermato-Venereologica. - - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Table I.Newantipruriticdrugstargetingtheneuralsystemwithcorrespondingongoingclinicaltrials a statistically significant decrease in pruritus in patients controlled, phaseIIclinicaltrials,serlopitantexhibited sed in clinical trials (Table). Inrandomized, I placebo- may bebetteralternativesandarecurrentlybeingasses patients (2,7) to administer to difficult it making interactions, drug aprepitant isexpensiveandhasamultitudeofpotential and cutaneous T-cell lymphoma(5,6).Unfortunately, Nav1.7: voltage-gated sodiumchannel1.7. 2: protease-activated receptor-2; KAL: ketamine-amitriptyline-lidocaine; system. NK-1: meurokinin-1; TrkA: tropomyosin receptor kinase A; PAR- targeting the neural antipruritic drugs 1. Siteofactionnew Fig. Ileal bileacid transporter inhibitor γ-aminobutyric acidanalog PAR-2 inhibitor TrkaA antagonist κ-opioid agonist µ-opioid antagonist/κ-opioid agonist Neurokinin receptor-1 inhibitor Category Serlopitant and tradipitant, newer NK-1 inhibitors, NK-1 andtradipitant,newer Serlopitant GSK2646264 Pregabalin Doxycycline CT327 SHR0410 MR13A9 CR845 Asimadoline Nalfurafine Nalbuphine Tradipitant Serlopitant Drug name Cholestatic pruritus bullosa Recessive dystrophic epidermolysis Hives Psoriasis Pruritus in hemodialysis patients Pruritus in hemodialysis patients Atopic dermatitis Cholestatic pruritus Chronic kidneydisease Uremic pruritus Atopic dermatitis Uremic pruritus Prurigo nodularis Atopic dermatitis Epidermolysis bullosa Prurigo nodularis Chronic pruritus of unknown origin Psoriasis Atopic dermatitis Prurigo nodularis Indication - nalbuphine, a mixed µ-opioid antagonist and κ-opioid and antagonist µ-opioid mixed a nalbuphine, something thatdermatologistsfeelcomfortabletouse. not is administration intranasal of mode its However, option especiallyincasesofrefractorychronicitch. potential (13).Butorphanolpresentsagreattreatment onset ofaction.Mostimportantly, ithaslittleabuse rapid a has and intranasally administered is efficacy. It agonist, treatspruritusofvaryingetiologieswithhigh κ-opioid and antagonist µ-opioid a both Butorphanol, agonists. κ-opioid and antagonists µ-opioid Mixed in treatingitch. µ-opioid antagonists and κ-opioid agonists are effective tors in itch remains poorly understood (11). Specifically, recep δ-opioid of role the while pruritus, to relate they (12). with AD patients of epidermis the in seen receptors κ-opioid of the periphery, forexampleadecreaseintheexpression to chronicitch(2).Similarly, animbalancecanoccurin receptors resultinneuronalsensitization,whichcanlead cord, imbalance in the activation status of µ- and κ-opioid the peripheral nerve fibers in the skin (11). In the spinal the centralandperipheralnervoussystems,including pruritus. µ-, κ-, and δ-opioid receptors exist throughout been shown to play a significant role in the treatment of pain medications,butmorerecently, opioidshavealso Opioids are classically thought of as highly effective Opioids placebo-controlled, phaseIItrial(10). statistically significant decrease in itch in a randomized, laris (8, 9). In patients with AD, tradipitant showed a with treatment-refractoryitchaswellprurigonodu More recentdevelopmentsaresimilardrugslike as well-studied been have receptors κ-opioid and µ- A newgenerationoftreatmentsforitch 2 3 2 1 2 2 2 2 3 2/3 3 2 3 2 3 Phase Oral Oral Topical Oral IV IV Oral Oral Oral IV Oral Oral Oral Oral Oral Oral Oral Oral Administration Acta DermVenereol 2020 NCT02966834 NCT03928093 NCT03968562 NCT03857568 NCT03802617 NCT04018027 NCT03995212 NCT03617536 NCT03281538 NCT03636269 NCT03998163 NCT03497975 NCT03568331 NCT03836001 NCT03546816 NCT03677401 NCT03841331 NCT03540160 NCT # 37 - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV www.medicaljournals.se/acta the proteasemucunian,which activatesPAR-2, aswell well-known inducerofnonhistaminergic itch,contains its extracellularN-terminus. Forexample,cowhage,the tein coupled receptor activated by proteolytic cleavage of Protease-activated receptor-2 (PAR-2) isatypeofG-pro Protease activatedreceptor-2 inhibitors was notstatisticallysignificant(20). receiving reduction intheiritch,andthedifferencetients also had significant anti-pruritic effects with 53% of pa vehicle the However, (NRS). Scale Rating Numerical patients receiving a meaningful itch reduction of 4.3 in also showedarobustreductionofpruritus,with58% Phase IIbtrial with thesame TrkA antagonist(SNA-120) (19). pruritus Another in reduction significant tistically CT327, atopical TrkA antagonist,demonstratedasta treatment (2). therefore presentsacompellingtarget forantipruritic vity ofperipheralsensorynervestopruriticstimuli,and Together, the TrkA-NGF pathwayleadstohypersensiti of theskinto nonhistaminergic cowhage-induceditch. trophic factor. Furthermore,NGFcausessensitization gene-related peptide(CGRP), and brain-derivedneuro (TRPV1) andincreasednervesensitivitytoSP, calcitonin sensitization oftransientreceptorpotentialvanilloid1 myosin receptorkinase A (TrkA). This leadstoneural growth factor(NGF),whichbindstoitsreceptor, tropo Epidermal keratinocytesandeosinophilsreleasenerve Tropomysin receptor kinase A antagonists for treatmentofpruritusinhemodialysispatients. are undergoing phase I and II clinical trials, respectively, been published (18). Likewise, SHR0410 and MR13A9 for pruritusassociatedwith AD, butresultshavenotyet for irritablebowelsyndrome,completedphaseIItrials underway (Table I). use ofCR845inotherpruriticconditionsarecurrently those receivingplacebo(17).Clinicaltrialsevaluating comparedto itchscores inworst tion frombaseline times aweekafterdialysishad68%greaterreduc three CR845 receiving patients Specifically, disease. for pruritusassociatedwithend-stagechronickidney effects antipruritic significant had agonist, κ-opioid a phase IIclinical trial (17),intravenous (IV)CR845, of pruritus; however, clinical trials are underway. In a Food andDrug Administration (FDA)forthetreatment no κ-opioid agonists have yet been approved by the U.S. patients withuremicpruritus(16).IntheUnitedStates, available in Japan, is an effective antipruritic agent in agonist κ-opioid a Nalfurafine, agonists. Κ-opioid couraging results(Table I)(14,15). uremic pruritus and prurigonodularishaveshownen agonist. Clinical trials measuring its efficacy in treating 38 In aphaseIIbclinicaltrialofpatientswithpsoriasis, Asimadoline, a κ-opioid agonist originally developed E. FowlerandG.Yosipovitch ------GABA in development. In mice, targeting inhibitory α2 and α3 itch (24). More specific GABAergic drugs are currently proven effective intreatingvarioustypesofneuropathic acid (GABA)(aninhibitoryneurotransmitter),have γ-aminobutyric of analogs pregabalin, and Gabapentin GABAergic drugs the PAR-2 interleukin(IL)-8pathway(23). ritic mechanism is most likely due to its attenuation of addition to its ability to reduce inflammation, its antipru antipruritic properties in the treatment ofacne vulgaris. In various chronicitchconditions. whether the efficacy of PAR-2 inhibitors in treatment of controlled clinicaltrialsarewarrantedtodetermine in a placebo-controlled study (22). Randomized, placebo- reduction inratingsofcowhage-induceditchintensities significant a to led inhibitor PAR-2 topical different a model of AD (21).Inhumans,aone-timeapplication of mouse a in behaviors itching of reduction the in ficacy have a more specified mechanism of action, producing a with somepotentiallyserious adverseeffects. although still often used as first-line treatment, can come were the most effective therapeutic agents available, and ticoids, methotrexate,cyclosporine,andazathioprine systemic immunosuppressiveagents,suchasglucocor pecially in inflammatory pruritic conditions. Classically, The immunesystemplaysanimportantroleinitch,es SYSTEM TREATMENTS TARGETING THEIMMUNE be interestingtoseeifithasaneffect onitch. phase Iclinicaltrialsforneuropathicpain(27),andwill P12, aNav1.7antagonist,iscurrentlybeingstudiedin 1.7 antagonistsarestillinclinicaldevelopment.Neu- transmission forbothitchandpain(26).Currently, Nav dependent pruritus,andmodulatesspinalcordsynaptic making itagoodtarget fortreatment(2). similarly activatePAR-2, causingsymptomsofitchand as PAR-4, causing pruritus. Several other proteases can histaminergic pruritus. Furthermore, this α2/α3 GABA is infactinvolvedbothhistamine-dependentand-in acute itchinmice(26). This studyindicatedthatNav1.7 (Nav) 1.7withhighselectivitysuppressedchronicand An antibody inhibiting voltage-gated sodium channel Nav 1.7 to comewithoutanyunwantedadverseeffects (25). (25). Most importantly, these antipruritic effects seemed AD andindogswhoweresensitizedtohousedustmites modulator reduced chronic pruritus in a mouse model of Interestingly, doxycycline,anantibiotic,hasshown Recently developedimmunosuppressive treatments PZ-235, apepducinthatinhibitsPAR-2, showedef A receptors reduced acute histaminergic and non- A - - - - -

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Table II.Newantipruriticdrugstargetingtheimmunesystemwithcorrespondingongoingclinicaltrials relief oftheirpruritusbyday6(29). of patientsreceivingcrisaboroleexperiencedcomplete pruritic effect wasseenasearlyday2,andthat20% clinical trials(29). This studyshowedthatthisrapidanti- ment thanvehicle in a post hoc analysis of two phase III in significantly more patients receiving crisaborole oint pruritus in these patients. Pruritus relief was observed saborole hasproventobeeffective inrapidlyreducing moderate-to-severe AD. an Applied as ointment, cri rase-4 (PDE4)inhibitorapprovedforthetreatmentof Crisaborole isatopicalnon-steroidalphosphodieste Phosphodiesterase-4 inhibitors trials steadilyunderway(Table II)(28). to includevariousitchyskinconditions,withclinical biologic therapiesisstillongoingandvastlyexpanding higher level of efficacy and safety. Moreover, the era of IgE Janus kinase 1 Histamine 4receptor Janus kinase 1/JAK 2or 3 Interleukin-17A Oncostatin M receptor-β Interleukin-31RA Interleukin-13 Interleukin-4Ra Phosphodiesterase-4 Target Abrocitinib Ligelizumab Upadacitinib Tofacitinib Ruxolitinib Ixekizumab Nemolizumab Lebrikizumab Pitrakinra ZPL389 Baricitinib Secukinumab KPL-716 Nemolizumab Tralokinumab Dupilumab Crisaborlole Apremilast Drug name Indication Atopic dermatitis Atopic dermatitis Chronic spontaneousurticaria Atopic dermatitis Atopic dermatitis Atopic dermatitis Psoriasis Atopic dermatitis Psoriasis, genital pruritus Prurigo nodularis Atopic dermatitis Atopic dermatitis Atopic dermatitis Atopic dermatitis Atopic dermatitis Plaque psoriasis Lichen simplex chronicus Lichen planus Chronic idiopathicpruritus Chronic idiopathicurticaria Prurigo nodularis Atopic dermatitis Atopic dermatitis Atopic dermatitis Cholinergic urticaria Chronic spontaneousurticaria Atopic dermatitis Plaque psoriasis Psoriasis vulgaris Scalp psoriasis - - - scale (VAS) wereachievedinpatientswithplaquepso reductions inpruritusasmeasuredbyavisualanalogue of crisaborole,sodidtheirqualitylifescores(30). clinical trials,aspatients’ itchimprovedwiththehelp of life scores. In a post hoc analysis of two phase III seen between pruritus and dermatology-specific quality a numberofdifferent targets includingimmunecells, mune responses and inflammation. Cytokines can act on Interleukins (IL)arecytokineswhichhelpmediateim Interleukin antagonists in phaseIV trials(Table II). patients withscalppsoriasisiscurrentlybeingstudied in therapy antipruritic an as apremilast of efficacy The riasis receiving apremilast, an oral PDE4 inhibitor (31). Similarly, improvedqualityoflifescoresandgreater been has link strong and significant a Furthermore, A newgenerationoftreatmentsforitch Phase 3 2 3 3 1 3 2 3 2 2 2 3 2 3 2 2 3 4 Vehicle Oral Oral Subcutaneous Oral Oral Topical Oral Topical Subcutaneous Subcutaneous Subcutaneous Subcutaneous Oral Oral Subcutaneous Subcutaneous Subcutaneous Subcutaneous Subcutaneous Subcutaneous Subcutaneous Subcutaneous Topical Oral Oral Acta DermVenereol 2020 NCT03796676 NCT03720470 NCT03422822 NCT03627767 NCT03575871 NCT03915496 NCT03580369 NCT03580356 NCT03738397 NCT03568318 NCT03569293 NCT03607422 NCT03646604 NCT03745638 NCT03745651 NCT03517566 NCT03948334 NCT03952559 NCT03428100 NCT03334435 NCT03733301 NCT03435081 NCT03568136 NCT03858634 NCT03816891 NCT03989349 NCT03985943 NCT03989206 NCT03921411 NCT03526861 NCT03761537 NCT03587805 NCT03749148 NCT03749135 NCT03721172 NCT03553433 NCT # 39 - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV www.medicaljournals.se/acta the skin.OSMR:oncostatinMreceptor. in nerves antagonists onsensory of interleukin(IL) 2. Effect Fig. subunit andsubsequentsignaling(28,43).Inaphase α receptor IL-4 the to binding affinity, preventing high and tralokinumab. investigation fortreatmentof AD includelebrikizumab AD. Two biologicdrugstargeting IL-13thatare under pies targeting this cytokine are of greatinterest in treating implicated inthepathwayof AD. Developmentofthera IL-13. published (40,42). a phaseIIclinicaltrial,howeverresultshavenotbeen pitrakinra inmoderatetosevere AD wasinvestigatedin administrationofment ofasthma(41).Subcutaneous (40). Pitrakinrahasmostlybeenstudiedinthetreat signaling IL-13 and IL-4 inhibiting subunit, α receptor cholinergic urticariaarecurrentlyunderway(Table II). assessing its efficacy in chronic spontaneous urticaria and trials Clinical conditions. pruritic other in efficacy true placebo-controlled trialsarenecessarytoevaluateits randomized, However, (39). pemphigoid bullous and with prurigonodularis(35–37),uremicpruritus(38), dupilumab canbehelpfulinthetreatmentofpatients ditions isofgreatinterest.Casereportshaveshownthat patients’ qualityoflife(33,34). symptoms of AD, rapidlyreducingitch,andimproving clinical improving significantly AD, of treatment the helper (Th)2immunity. Dupilumabhasrevolutionized cytokines IL-4andIL-13,keyinvolvedin T- α subunit of the IL-4 receptor, blocking the signaling of IL-4. IL-13, IL-31,andIL-17. to treatingitcharediscussedbelowandincludeIL-4, Some of the newer cytokines used as targets in regard keratinocytes, and evensensorynerves (Fig. 2)(32). 40 Lebrikizumab targets soluble IL-13 andbindswith Similar todupilumab,pitrakinraalsotargets theIL-4 Currently, theuseofdupilumabinotherpruriticcon Dupilumab isamonoclonalantibodytargeting the This cytokineproducedby Th2 lymphocytes,is E. FowlerandG.Yosipovitch - - - and bullouspemphigoid,makingitadesirablepharma phoma, mastocytosis,chronicspontaneousurticaria, such as AD, prurigonodularis,cutaneous T-cell lym­ have beenassociatedwithavarietyofitchyconditions physiology ofchronicpruritus.IncreasedlevelsIL-31 IL-31. This cytokineisheavilyimplicatedinthepatho­ (46). PhaseIIItrialsarecurrentlyunderway(Table II). tients treatedwithtralokizumabcomparedtoplacebo decrease inpruritusassessedbyNRSwasseenpa significant a Additionally,(DLQI). Index Quality Life of Atopic Dermatitis(SCORAD),andtheDermatology Scoring score, EASI in improvements significant cally subcutaneously every other week, patients received clini tralokinumab (46). At a dose of 300 mg administered moderatetosevere with for patients treatedwith AD from a phaseIIstudy have indicatedpromisingresults effectsits Results neutralizing (45). α-2, subunit ceptor re IL-13 and α-1 subunit receptor IL-13 to binding its pruritus asearly asdaytwo,continuing until day16(44). lebrikizumab showeddose-dependentimprovementsin study,IIb phase a in However, (43). study this in cebo were not statistically significant when compared to pla percent reductionsinbaselineitchasassessedby VAS score whencomparedtoplacebo. As forpruritus,mean of 50%reductionineczemaareaandseverity(EASI) ticosteroids showed a significantly greater achievement idiopathic pruritus(Table II)(54). lichen simplexchronicus,plaque psoriasis,andchronic associated with chronic idiopathic urticaria, lichen planus pruritus reducing in KPL-716 of efficacy the assessing their itch (53). Additionally, a pilot phase IIstudy is nodularis to assess the efficacy of KPL-716 in reducing clinical trialiscurrentlyrecruitingpatientswithprurigo antipruritic effect in patients with AD (52). A phase II and oncostatinM(OSM)signalinghasshownan M receptorbeta(OSMR-beta),interfereswithIL-31 in AD, butnoresultshavebeenpublishedtodate(51). circulating IL-31,hascompletedaphaseIclinicaltrial positive results(50). nodularis, aphaseIItrialwasrecentlycompletedwith placebo-controlled clinicaltrial(49). As forprurigo to severe AD inaphaseII,randomized,double-blind, moderate with patients in improved significantly was as atreatmentfor AD andprurigo nodularis. Pruritus (48). Thus far, nemolizumab has only been studied tinocytes, macrophages,dendriticcells,andbasophils is locatedonavarietyofcellsincludingneurons,kera signaling, worksbybindingtoIL-31receptor A, which cological target fortreatmentofthesepatients(4,47). receiving lebrikizumabincombination with topicalcor II randomized,placebo-controlledtrial(43),patients Tralokinumab potentlybindstoIL-13,prohibiting KPL-716, amonoclonalantibodyagainstoncostatin BMS-981164, amonoclonalantibody targeting Nemolizumab, the first drug developed to inhibit IL-31 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV When ligands bind to their receptors, JAKs are activated When ligandsbindtotheirreceptors, JAKsareactivated ates signaltransductionofcytokines andgrowthfactors. inhibitors blocktheJAK/STAT pathway, whichmedi activation of transcription (STAT) pathway (2). JAK tially by the janus kinase (JAK)/signal transducer and Pruritus inducedbycytokinesismediatedatleastpar Janus kinaseinhibitors as week2inthosetreatedwithixekizumab(62). significant improvement in genital itch was seen as early (59.7% versus8.3%,p a numericalratingsale)thanpatientsreceivingplacebo reduction (greaterthanorequalto3pointon achieved a significantly greater clinically meaningful itch of patientswithgenitalpsoriasisreceivingixekizumab ble-blind, placebo-controlledtrial,agreaterpercentage reducing genitalpruritus.InaphaseIII,randomized,dou cept, respectively, achievedanNRSof0atweek60(61). 45.3% ofpatients originally receiving placebo oretaner being switchedtoixekizumab at 12weeks,45.1% and out thestudyachieved an itch NRS of 0. Similarly, after of patients receiving ixekizumab every 4 weeks through severity throughtheendofstudy. Byweek60,48.2% receiving ixekizumabmaintainedimprovementsinitch those receivingetanerceptorplacebo(60). the drugreportedimprovementofprurituscomparedto receiving patients of percentage greater significantly a As early as the first week of treatment with ixekizumab, phase III trials showed rapid, significant improvements. in treating psoriasis, especiallypsoriaticitch in which targeting IL-17A.Ixekizumabhasproventobeeffective 59). mab intreating AD arecurrentlyongoing(Table II)(58, of treatment,demonstratingitsrapideffect (57). greater reductioninitchingasearlythesecondweek significantly a achieved secukinumab taking patients In fact,inapooledanalysisofthesetwophaseIIItrials, 56). (55, inhibitor TNF-α a etanercept, and placebo to compared itch reducing in effective more significantly secukinumab in psoriasis showed that secukinumab was of efficacy the assessing trials clinical double-blind III, tively bindsandneutralizesIL-17A (55). Two phase tude ofeffect inreducingpsoriaticitch(5). based oncurrentstudies,haveshownthelargest magni FDA-approved forthetreatmentofplaquepsoriasis,and lymphoid cells(55).Drugsinthiscategoryarecurrently which recruitneutrophils, Th17 cells,dendritic cells, and by IL-17A to secrete other pro-inflammatory mediators, arestimulated Keratinocytes cells. mast and possibly marily producedby Th17 cells,alongwithneutrophils IL-17. Additionally, ixekizumabisalsoeffective inrapidly In along-termextensionstudyofthistrial,patients Ixekizumab is a high affinity monoclonal antibody also Phase II clinicaltrials assessing the role of secukinu Secukinumab isamonoclonalantibodythatselec This is a pro-inflammatory cytokine that is pri is that cytokine pro-inflammatory a is This < 0.001) (62).Furthermore,a ­ ------density, which may aid in rescuing inhibitory itch mecha fiber nerve epidermal peptidergic increased tofacitinib IL-23, andIL-31. thatThis studyalsodemonstrated decreased mRNA expressionofitchy cytokines IL-22, psoriasis aswell AD (66,67). been effective for treating pruritus in both patients with of thestudyatweek52(64). Topical tofacitinibhasalso quality oflife,whichweremaintainedthroughtheend also achieved a significant improvement in health-related atment initiation(64,65).Patientsreceivingtofacitinib histamine-1 receptor, areoftengiventopatientsendor Antihistamines, mostofwhich areantagoniststothe Histamine-4 receptor antagonists placebo (73). Dermatitis (PSAAD)comparedtopatientsreceiving in thePruritusandSymptoms Assessment for Atopic decrease of magnitude greater significantly statistically placebo. Likewise,patientstakingabrocitinibachieved a point orlarger reductioninitchNRSversusthosetaking proportion ofpatientstakingabrocitinibachieveda 4 placebo-controlled trial, a statistically significant greater ment of AD. InaphaseIIIrandomized,double-blind, JAK1, hasdemonstratedexcellentresults in thetreat Abrocitinib, another JAK inhibitor specifically targeting are currentlyinprogress(Table II)(72). AD in upadacitinib of efficacy the measuring trials III decreased ratingsofitchinpatientswith AD (71).Phase significantly upadacitinib trial, placebo-controlled zed, of actionisselectiveforJAK1.InaphaseII,randomi Upadacitinib isanewerJAKinhibitorwhosemechanism (70). Phase IIIstudies are currently underway (Table II). ficantly improved AD and resulted in decreased pruritus phase II,double-blind,randomizedtrial,baricitinibsigni Baricitinib selectivelyinhibitsJAK1andJAK2.Ina improvement intheiritchafteronlyonemonth(69). chronic idiopathicpruritus,oraltofacitinibledtomarked causes ofpruritus. Infivepatients with refractory, non-inflammatory even itch, of cases other treating by tofacitinib(68). nisms, proposinganovelmechanismforitchreduction in patientswithpsoriasis,assoononedayaftertre phase IIItrialsshowingthattofacitinibimproveditch ment ofpsoriasis,withresultsfromtworandomized JAK1 andJAK3.Ithasbeeninvestigatedforthetreat­ Tofacitinib, anoralJAKinhibitor, worksbyblocking AD andpsoriasis(Table II). for use in chronic inflammatory skin conditions, such as More recently, thesemedicationsarebeinginvestigated of inflammatory conditions such as rheumatoid arthritis. oftarget toregulatetranscription cell nucleus (63). genes which leadtophosphorylationofSTATs, whichenterthe In a mouse model of psoriasis, tofacitinib significantly Additionally, JAKinhibitorsmayshowpromisein JAK inhibitorsarecommonlyusedinthetreatment A newgenerationoftreatmentsforitch Acta DermVenereol 2020 41 ------

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV www.medicaljournals.se/acta REFERENCES Sun Pharma,Pfizer, Leo,Kiniska,andMenlo. Eli Lilly, Pfizer, Bayer, Cerave and received research grants from Menlo, TREVI, Sienna, Galderma, Sanofi, Regeneron, Novartis, GY or beenaconsultant has Boardmemberof Ad AbbVie, Kiniska, ACKNOWLEDGEMENT their qualityoflife. their patients, to successfully treat them and improve clinicians canobtainagreaterarsenaloftreatmentfor therapy. With educationanddevelopmentofnewtargets, always simpleandeverypatientrequiresindividualized ongoing. Unfortunately, treatmentforchronicitchisnot development ofnewerandbettertreatmentsforitchis mechanisms isperpetuallyunderway, discoveryand is betterunderstoodandresearchintonewtargets and approaching. Nowthatthepathophysiologyofpruritus receptors, itchycytokines,andsmallmoleculesisswiftly A new era of antipruritic drugs targeting specific neural New therapiesforitcharecontinuouslybeingdeveloped. CONCLUSION in thesepatients. and thusitwillbeinterestingtoseeitseffect onpruritus (77), omalizumab to comparison in IgE bind to affinity Studies haveshownthatligelizumabhasamuchhigher in treating chronic spontaneous urticaria (Table II). efficacy its investigate to trials clinical III phase going A monoclonalanti-IgEantibody, ligelizumab,isunder Anti-IgE those receivingplacebo(76). pruritus reductionbetween patients taking ZPL389 and controlled study did not show a significant difference in from a phase II randomized, double-blind, placebo- studied as a treatment for AD (Table II). However, results manner (75). attenuated scratchingresponses ina dose-dependent antagonist H4R an with pretreatment AD, of model shown somepromiseintreatingitch(74).Inamouse targeting the histamine-4 receptor (H4R), however, have specifically Antihistamines therapies. antipruritic as sing itchdespitenoclearevidenceoftheireffectiveness 42 4. 3. 2. 1. ZPL389, an oral H4R antagonist, is currently being currently is antagonist, H4R oral an ZPL389, Hashimoto T, Yosipovitch G. Itching as a systemic disease. Fowler E, Yosipovitch G. Chronic itch management: therapies Yosipovitch G, Rosen JD, Hashimoto T. Itch: From mechanism Tey HL, Wallengren J, Yosipovitch G. Psychosomatic factors J AllergyClinImmunol2019;144: 375–380. Asthma Immunol2019; 123: 158–165. beyond thosetargetingtheimmunesystem. Ann Allergy, 2018; 142:1375–1390. Immunol Clin Allergy J approaches. therapeutic (novel) to in pruritus. Clin Dermatol 2013;31: 31–40. E. FowlerandG.Yosipovitch - 11. 10. 21. 20. 19. 18. 15. 12. 17. 16. 14. 13. 9. 8. 7. 6. 5. Bigliardi PL, Bigliardi-qi M. Chapter 18: Peripheral Opioids.Peripheral 18: Chapter M. Bigliardi-qi PL, Bigliardi Heitman A, Xiao C, Cho Y, Polymeropoulos C, Birznieks G, Ständer S, Kwon P, HirmanJ, Perlman AJ, Weisshaar E,Metz Yosipovitch G, Ständer S, Kerby MB, Larrick JW, Perlman AJ, Leslie TA, Greaves MW, Yosipovitch G.Current Topical and Booken N, Heck M, Nicolay JP, Klemke CD, Goerdt S, Utikal Barr TP, Garzia C, Guha S, Fletcher EK, Nguyen N, Wieschhaus Ständer S, Siepmann D, Herrgott I, Sunderkötter C, Luger Sienna Biopharmaceuticals Inc. Sienna Biopharmaceuticals Roblin D, Yosipovitch BoyceG, B, Robinson J, SandyJ, ClinicalTrials.gov. Safety, Pharmacokinetics and Preliminary Mathur VS, Kumar J, Crawford PW, HaitH,Sciascia T. amul Tominaga M,Ogawa H,Takamori K.Possible rolesof epider Cara Therapeutics Announces Positive Top-Line Data From Kumagai H,EbataT, Takamori K,Muramatsu T, Nakamoto Trevi Therapeutics. Trevi Therapeutics Announces Positive Dawn AG,Yosipovitch G.Butorphanolfortreatmentofin Treatment [Internet]. Boca Raton: CRC Press/Taylor & Fran AkiyamaT,E, Carstens In: and Mechanisms – Itch editors. atopic dermatitis. J Am Acad Dermatol 2018; 79: AB300. disease severity inpatientswithchronicpruritusrelatedto Polymeropoulos M. Tradipitant improves worst itch and J AmAcadDermatol 2019; 80: 1395–1402. in a nodularis phase 2, randomized, trial. placebo-controlled M, et al. Serlopitant reduced pruritus in patients with prurigo 78: 882–891.e10. 2018;Dermatol Acad Am J trial. clinical 2 phase controlled Resultspruritus: ofarandomized, multicenter, placebo- Schnipper EF, et al. Serlopitantfor the treatmentof chronic //link.springer.com/10.1007/978-3-662-44605-8. Availablep.339–356. 2015. Heidelberg; Berlin http:from: ofItch[Internet].Springer-Verlag Pharmacology editors. Systemic Therapies for Itch.In:Cowan A,Yosipovitch G, 2011; 164:665–683. erythrodermic cutaneous T-cell lymphoma. Br J Dermatol J. Oral aprepitantinthetherapy ofrefractory pruritusin AJ, et al. PAR2 Pepducin-Based Suppression of Inflamma of Suppression Pepducin-Based PAR2 al. et AJ, novel antipruritic strategy. PLoS One 2010; 5: 3–7. TA. Targeting the neurokinin receptor 1 with aprepitant: A in SecondHalf of2019.Sienna Press Release. Phase 2b Study and Plans to Initiate Phase 3 Psoriasis Trials in on Psoriasis Impact Significant Demonstrated (0.05%) Announces Its Topical, Non-Steroidal TrkA Inhibitor SNA-120 with psoriasis. Acta Derm Venereol 2015; 95: 542–548. and safety of CT327 in a phase 2b clinical trial in patients efficacy and studies, experimental from Results psoriasis: effective, novel therapy forthetreatment of pruritusdueto Mainero V, et al. Topical TrkA kinase inhibitor CT327 is an simadoline&rank=5. https: //clinicaltrials.gov/ct2/show/NCT02475447?term=a Availablefrom:18]. Jun 2019 [cited [Internet]. Dermatitis with Atopic Associated inPruritus Asimadoline of Efficacy positive-top-line-data-part-phase-23. releases/news-release-details/cara-therapeutics-announces- 2017. Available from: http: //ir.caratherapeutics.com/news- Disease-Associated Pruritus [Internet]. Cara Therapeutics. Kidney Chronic in I.V.CR845 of Trial 2/3 Phase of A Part 337 haemo in itch severe on hydrochloride, nalfurafine ofanovel Effect H. Suzuki H, kappa-receptoragonist, TreviPNToplineDataPR.10_.13_.16_.FINAL_.pdf. www.trevitherapeutics.com/wp-content/uploads/2019/01/ Results from Phase 2 Trial in Prurigo Nodularis. 2016. https:// nih.gov/books/NBK200922/. Availablep.1–10. 2014. cis; //www.ncbi.nlm.https: from: tion and ItchinAtopic Dermatitis Models.JInvest Dermatol 25: 1251–1257. placebo-controlled study. Nephrol Dial Transplant 2010; dialysis patients: A Phase III, randomized, double-blind, 2017; 46: 450–458. of nalbuphine ER tablets for uremic pruritus. Am J Nephrol ticenter, randomized, double-blind,placebo-controlledtrial tractable pruritus. J Am Acad Dermatol 2006; 54: 527–531. Dermatol 2007; 127:2228–2235. mal opioid systems inpruritus of atopic dermatitis.JInvest ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV 39. 34. 29. 38. 33. 28. 24. 41. 37. 32. 27. 23. 40. 36. 35. 31. 30. 26. 25. 22. Kaye A, Gordon SC, Deverapalli SC, Her MJ, Rosmarin D. Du Yosipovitch G,Reaney M, Mastey V, Eckert L,AbbeA, Nelson Yosipovitch GoldLF, G,Stein LebwohlMG,Silverberg JI,Tall Silverberg JI,Brieva J. caseofdupilumab Asuccessful Y,EfficacyHan al. et WenY,H, H, Chen Su J, Zhang X, Liu Reich A, Szcz J, Samotij D. Biologics for Itch: IL-4/IL-13, Matsuda KM, Sharma D, Schonfeld AR, Kwatra SG. Gaba Wenzel S, Willbraham D, Fuller R, Getz EB, Langphre M. Effect Mollanazar NK, Elgash M, Weaver L, Valdes-Rodriguez R, Hsu Cevikbas F, Buhl T, Mess C, Buddenkotte J, Steinhoff M. Products [Internet]. Neurim Pharmaceuticals. [cited Cao T, Tan ES, Chan YH, Yosipovitch G, Tey HL. Anti‑pruritic Montes-Torres A, Llamas-Velasco M, Pérez-Plaza A, Solano- Rambhia PH, Levitt JO. Recalcitrant prurigo nodularis treated Beck KM,Yang EJ, Sekhon S, Bhutani T, LiaoW. Dupilumab Bagel J, Lebwohl M, Stein Gold L, Jackson JM, Goncalves J, Stander S, Yosipovitch G, Bushmakin AG, Cappelleri JC, Lee JH,Park CK,ChenG,Han Q, Xie RG, LiuT, etal.A Ralvenius WT, NeumannE,Pagani M,AcuñaMA,WildnerH, Cao T, Tan WD, Kim H, Tey HL. Efficacy of a topical proteinase- L, et al. Peak Pruritus Numerical Rating Scale: psychome 2019; 5:339–341. treatment for severe uremic pruritus. JAAD Case Reports Allergy Clin Immunol2017; 140: 888–891.e6. dermatitis: A meta-analysis of randomized clinical trials. J and safety ofdupilumabfor thetreatmentof adultatopic 2017; 6:263–272. IL-31, IL-17, andIL-23 Rep CurrDermatol Antagonists. to allergen challenge in asthmatic patients: resultsof two of an interleukin-4 variant on late phase asthmatic response 155: 121–122. patients with prurigo nodularis. JAMA Dermatology 2019; S. Reduced itch associated with dupilumab treatment in 4 & Francis, BocaRaton; 2014. T, editors.Itch:MechanismsandTreatment. CRCPress/Taylor Akiyama In:CarstensE, Communication. and Neuroimmune Chapter 13Role ofInterleukin­ research/#neup12. 2019 Jun 24]. Available from: http: //www.neurim.com/ Indian J Dermatol Venereol Leprol 2018; 84:458–460. of acne vulgaris: A randomized single‑blinded pilot study. efficacies of doxycycline and erythromycin in the treatment Dermatitis. JClin Med 2015;4: 593–613. López G,Sánchez-Pérez J. BiologicalTreatments inAtopic 471–473. successfully withdupilumab. JAAD CaseReports 2019;5: treatment forgeneralized prurigonodularis. JAMA Derma Study). J Am AcadDermatol 2017; 76: AB119. in Patients with Moderate Plaque Psoriasis (UNVEIL Phase IV Levi E, et al. Efficacy of Apremilast on Quality of Life Measures pruritus and quality of life in patients with atopic dermati Luger T, Tom WL,etal.Examiningtheassociationbetween sensor for pain and itch relief. Cell 2014; 157: 1393–1404. monoclonal antibody that targets a Nav1.7 channel voltage Benke D, etal.Itchsuppressioninmiceand dogsby mo Acad Dermatol Venereol 2017;31: e191–e192. a randomized placebo-controlled double-blind study. J Eur activated receptor-2 inhibitoroncowhage-inducedpruritus: JAMA Dermatology 2018; 154: 1225–1226. pilumab for the treatment of recalcitrant bullous pemphigoid. tology 2019; 155: 118–120. 181: 761–769. moderate-to-severe atopicdermatitis.BrJDermatol 2019; tric validation and responder definition for assessing itch in 2019; Accepted. tis treated with crisaborole. J Eur Acad Dermatol Venereol rase 4inhibitor. ActaDerm Venereol 2018; 98:484–489. with crisaboroleointment,anon-steroidal,phosphodieste man AM, Zane LT. Early relief of pruritus in atopic dermatitis 2018; 9:1–15. dulation of spinal α2 and α3GABAA receptors. Nat Commun J AmAcadDermatol 2016; 75: 619–625.e6. pentin andpregabalinforthetreatmentof chronicpruritus. 2019; 139:412–421. 31andOncostatinMinItch ------48. 43. 47. 57. 42. 46. 56. 53. 51. 45. 44. 55. 54. 52. 50. 49. Furue M, Yamamura K, Kido-Nakahara M, Nakahara T, Fukui Simpson EL, Flohr C, Eichenfield LF, Bieber T, Sofen H, Taïeb Bağci IS, Ruzicka T. IL-31: A new key player in dermatology Yosipovitch G, Soung J, Weiss J, Muscianisi E, Meng X, Gil ClinicalTrials.gov. APhase2aStudytoInvestigate theEffects Wollenberg A, Howell MD, Guttman-Yassky E, Silverberg JI, Therene C, Brenaut E, Barnetche T, Misery L. Efficacy of Efficacy L. Misery T, Barnetche E, Brenaut C, Therene ClinicalTrials.gov. A Study to Assess the Efficacy, Safety, and ClinicalTrials.gov. ATwo-Part, Phase1,Single-Dose Study Popovic B, BreedJ, Rees MJ, Gardener DG, LMK,Kemp Vinall Dermira Presents Data From Phase 2b Study of Lebrikizumab Langley RG, Elewski BE, Lebwohl M, Reich K, Griffiths CEM, ClinicalTrials.gov. A Study to Assess the Efficacy, Safety and Mikhak Z,Bissonnette R,Siri D, Tyring SK,Tessari E,Gandhi ClinicalTrials.gov. Safety and Efficacy of Nemolizumab in PN Ruzicka T, Hanifin JM, Furue M, Pulka G, Mlynarczyk I, Wol Y. Emerging role of interleukin-31 and interleukin-31 recep atopic dermatitisinadequatelycontrolledby topicalcorti moderate-to-severe with adults in antibody) monoclonal anti-IL-13 (an lebrikizumab of safety and Efficacy al. et A, and beyond. J Allergy Clin Immunol 2018;141:858–866. rm=pitrakinra&rank=1. //clinicaltrials.gov/ct2/show/NCT00676884?te https: from: Atopic Eczema [Internet]. 2019 [cited Jun 16]. Available of Repeated Administration of AeroDerm in Subjects With 2019; 143:135–141. Immunol Clin Allergy J mAb. anti–IL-13 an tralokinumab, Kell C,Ranade K,etal.Treatment ofatopicdermatitiswith 138: 38–45. literature review and meta-analysis. J Invest Dermatol 2018; Systemic Treatments ofpsoriasisonpruritus:asystemic Tolerability of KPL-716 inReducing PruritusinPrurigoNodu Healthy Subjects and Adults With Atopic Dermatitis [Inter of IL-31 mAb (Anti-Interleukin 31 Monoclonal Antibody); in phase 2a studies. Lancet 2007;370:1422–1431. 2017; 429:208–219. Biol Mol J IL-13Rα2. and IL-13Rα1 to binding of inhibition IL-13-neutralising monoclonal antibody tralokinumab as B, etal.Structural characterisation reveals mechanismof in Patients With Atopic Dermatitis at Fall Clinical Dermato two Phase 3 trials. N Engl J Med2014;371:326–339. of results – psoriasis plaque in Secukinumab al. et PappK, Diseases [Internet].[cited2019Jun 23].Available from: htt Tolerability ofKPL-716 Reducing in Pruritic Chronic in Pruritus 2019; 139:S96. reduced pruritus in atopic dermatitis. J Invest Dermatol R, et al. KPL-716, anti-Oncostatin M receptor beta antibody, PN%0AThe. in Nemolizumab of Efficacy and ClinicalTrials.govSafety – Full View – Text PN in Nemolizumab of Efficacy and Safety [Internet]. [cited2019Jun16].Available from: 6/16/2019 clinical-dermatology-conference/) lebrikizumab-in-patients-with-atopic-dermatitis-at-fall- releases/dermira-presents-data-from-phase-2b-study-of- Oct 31]. Available from: https://www.biospace.com/article/ logy Conference [Internet]. BioSpace. 2019 [cited 2019 (TREBLE). J Am Acad Dermatol 2018; 78: 863–871.e11. costeroids: A randomized, placebo-controlled phase II trial 99: 1–2. placebo-controlled clinical trials. Acta Derm Venereol 2019; patient symptomdiarydata fromtwophase 3,randomized, and pain in patients with moderate-to-severe psoriasis: loteau I, et al. Secukinumab provides rapid from relief itching 716&rank=2. //clinicaltrials.gov/ct2/show/NCT03858634?term=KPL- ps: 716&rank=1. //clinicaltrials.gov/ct2/show/NCT03816891?term=KPL- laris [Internet]. [cited2019Jun23].Available from: https: trials.gov/ct2/show/NCT01614756. net]. [cited 2019 Jun 16]. Available from: https: //clinical atopic dermatitis. NEnglJ Med 2017; 376:826–835. lenberg A, et al. Anti–interleukin-31 receptor a antibody for Immunol 2018; 73: 29–36. tor in pruritus in atopic dermatitis. Allergy Eur J Allergy Clin A newgenerationoftreatmentsforitch Acta DermVenereol 2020 43 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV www.medicaljournals.se/acta 62. 61. 68. 60. 67. 65. 59. 66. 64. 63. 58. 44 Yosipovitch G, Foley P, Ryan C, Cather JC, Meeuwis KA, Burge Kimball AB, LugerT, GottliebA,PuigL,Kaufmann R,Burge Hashimoto T, Sakai K, Sanders KM, Yosipovitch G, Akiyama Griffiths CEM, Reich K, Lebwohl M, Van De Kerkhof P, Paul C, Bissonnette R, Papp R, Bissonnette KA,Poulin Y, M,Raman Gooderham Ständer S, Luger TA, Cappelleri JC, Bushmakin AG, Mamolo ClinicalTrials.gov. Investigation of Efficacy of Secukinumab in Mamolo C, Bissonnette R, Khan S, Lan S, Ports W, Poulin Y. Feldman D, Thaçi SR, M,Augustin Gooderham M,dela Villarino A V., Kanno Y, O’Shea JJ. Mechanisms and conse ClinicalTrials.gov. Secukinumab for Treatment of Atopic R, et al. Ixekizumab improved patient-reported genital pso extension. ActaDerm Venereol 2018; 98:98–102. severity: resultsfrom aPhaseIIIclinicaltrialandlong-term R, etal.Long-termimpactofixekizumab onpsoriasisitch Lancet 2015; 386: 541–551. UNCOVER-3): Results fromtwophase3randomised trials. or placebo in moderate-to-severe psoriasis (UNCOVER-2 and Menter A, et al. Comparison of ixekizumab with etanercept 902–911. a phase IIa randomized trial. Br J Dermatol 2016; 175: M, MallbrisL,etal.Topical tofacitinib foratopicdermatitis: results from a Phase 3 tofacitinib program. Acta Derm Ve a measurementtoolforpruritusinpatientswithpsoriasis: C, Zielinski MA, et al. Validation of the itch severity item as &rank=36. gov/ct2/show/NCT03568136?term=secukinumab&draw=3 [cited 2019 Jun 10]. Available from: https: //clinicaltrials. Patients With Moderate to Serve Atopic Dermatitis [Internet]. 2013; 68: AB192. a phase IIA trial for plaque psoriasis. J Am Acad Dermatol on pruritus and patient satisfaction with study medication in An evaluation of the effect of topical tofacitinib (CP-690, 550) 1162–1170.e3. severe plaque psoriasis. J Am Acad Dermatol 2016; 75: 2 randomized phase III trials in patients with moderate to health-related quality of life up to 52 Cruz C,MallbrisL,etal. Tofacitinib improves pruritusand cukinumab&draw=3&rank=72. https: //clinicaltrials.gov/ct2/show/NCT02594098?term=se Dermatitis [Internet]. [cited 2019 Jun 10]. Available from: nereol 2018;98:340–345. Immunol 2017; 18: 374–384. quences of Jak-STAT signalingintheimmunesystem.Nat 2018; 15: 1645–1652. vs placebo in a randomized, double-blind study. J Sex Med riasis symptomsand impact ofsymptomson sexual activity E. FowlerandG.Yosipovitch weeks: Results from - - - 73. 69. 72. 75. 71. 77. 74. 70. 76. Pfizer Announces Positive Top-Line Results from Phase 3 Phase from Results Top-Line Positive Announces Pfizer Oetjen LK, Mack MR, Feng J, Whelan TM, Niu H, Guo CJ, et ClinicalTrials.gov. Evaluation of Upadacitinib in Adolescent Cowden JM, Zhang M, Dunford PJ, Thurmond RL. The his Beck L,HongC,HuX,ChenS, CalimlimB, Teixeira H,etal. Arm JP, BottoliI,Skerjanec A,FlochD, GroenewegenA, Dunford PJ, Williams KN, Desai PJ, Karlsson L, McQueen Guttman-Yassky E, Silverberg JI, Nemoto O, Forman SB, Werfel T, Layton Yeadon G, I,Jimenez L,Osterloh M,Whitlock press-release-detail/pfizer_announces_positive_top_line_re Available from: https: //www.pfizer.com/news/press-release/ 2019. Pfizer.com. [Internet]. Dermatitis Atopic Severe to (PF-04965842), in Patients Aged 12 and Older with Moderate Study of Investigational Oral JAK1 Candidate,Abrocitinib al. SensoryNeuronsCo-optClassicalImmuneSignalingPat padacitinib&rank=7. https: //clinicaltrials.gov/ct2/show/NCT03569293?term=U from: Available 16]. Jun 2019 [cited [Internet]. (Eczema) and Adult Patients With Moderate to Severe Atopic Dermatitis 298–303. a mousemodelofpsoriasis.ActaDerm Venereol 2019;99: T. Antipruritic effects of janus kinase inhibitor tofacitinib in trial. AnnAllergyAsthmaImmunol2018; 121: S21. fromaPhase2Brandomized,dermatitis; placebo-controlled Upadacitinib effect onpruritusinmoderate-to-severe atopic 1371–1385. IgE antibody, in atopic subjects. Clin Exp Allergy 2014; 44: anti- high-affinity novel a (ligelizumab), QGE031 of safety Maahs S, etal.Pharmacokinetics, pharmacodynamicsand 176–183. experimental pruritus. J Allergy Clin Immunol 2007; 119: superior totraditional antihistaminesintheattenuationof D, Thurmond RL. Histamine H4 receptor antagonists are study. J Am AcadDermatol 2019;80: 913–921.e9. randomizeddouble-blinded, multiple-dose placebo-controlled moderate-to-severe atopic dermatitis: A phase 2 parallel, Wilke A, Prescilla R, et al. Baricitinib in adult patients with J AllergyClinImmunol2019;143: 1830–1837.e4. dermatitis. atopic ZPL-3893787with antagonist patients in receptor 4 H histamine the of safety and Efficacy al. P,et and_older_with_moderate_to_severe_atopic_dermatitis. candidate_abrocitinib_pf_04965842_in_patients_aged_12_ sults_from_phase_3_study_of_investigational_oral_jak1_ hways to Mediate Chronic Itch. Cell 2017; 171: 217–228.e13. 2010; 130:1023–1033. Dermatol J Invest inflammation. dermal Th2-dependent in pruritus and inflammation mediates receptor H4 tamine - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV University of Munich, Germany This isan open access article under the CC BY-NC license.www.medicaljournals.se/acta tine. The aimofthisreviewistohighlightanddiscuss when targeting unmetneeds thatimpactonclinicalrou physicians treatingCP currently faceseveralchallenges clinical research efforts in this field, CP researchers and years have witnessed a marked increase in basic and the challengingmanagementofCP (7). Although recent to CP vary from patient to patient, which contributes to festation, diagnosticmeasuresandtherapeuticresponse quality oflife(QoL)(5,6). The aetiology, clinicalmani a substantialburdenandrelevantimpairmentoftheir many and the USA (2–4). Those affected often report C Münster, Germany. E-mail:[email protected] nic Pruritus, University Hospital Münster, Von-Esmarch-Str. 58, DE-48149 Corr: Acta DermVenereol 2020;100:adv00028. Accepted Oct15,2019;PublishedJan9,2020 trials; clinicalresearch. Key words: these matters. in addressing pruritusphysicians treating face chronic and pruritus clinicalresearchers andthe challenges shortcomings inthe dailypatients with care of chronic novel of identification in depthcurrent This articlediscusses therapy targets. to lead may which patients, tial to identify relevantnew in affected mechanisms target these matters.Clinical has theresearch poten and clinical is ofresearch the utmost importance to nomic burdenassociated with pruritus. chronic Basic to enhancethe knowledge of the humanisticandeco protocols, diagnostic and andtherapeutic procedures as the needto standardizesuch translational research Therearestill tionseveral unmetneeds, challenging. king clinical and research management of this condi of chronic pruritus variesfrom patient to patient,ma festation, associated burden and response to therapy 1 Manuel P. PEREIRA Challenges inClinicalResearchandCare inPruritus pathophysiology, underlying aetiology, clinical mani Chronic pruritus isafrequent global condition. The Münster, Münster, number ofindividualssuffering fromCP withinGer volume ofpruritus onGoogle suggest an even larger (1). Population-basedanalysesofthenationwidesearch approximately one-sixth of the populationinGermany Alexander ZINK Journal Compilation ©2020ActaDermato-Venereologica. Department of Dermatology and Center for Chronic Pruritus, University Hospital Münster, Hospital University Pruritus, Chronic for Center and Dermatology of Department 6 weeksorlonger, ishighlyprevalent,affecting hronic pruritus (CP), defined as pruritus lasting for Sonja Ständer, Department of Dermatology and Center for Chro- itch; patient-reported outcome; guideline; clinical 4 3 andSonja STÄNDER Faculty of Health, University Witten/Herdecke, and 1 , Claudia ZEIDLER 1 1 , Michael STORCK Centenary theme section:ITCHANDPRURITIC DISORDERS REVIEW ARTICLE 2 , ------Konstantin AGELOPOULOS

4 Department of Dermatology and Allergy, School of Medicine, Technical to thecomplexityofmanagement ofthesepatients. economic backgroundsand therapygoals,contributing of medicalhistory, comorbidities, co-medication,socio- Adding tothesefactors,patients withCP varyinterms have yettobeexaminedinepidemiological studies(2–4). body, the on localizations specific ving issues these but weather ontheprevalenceofpruritus,especiallyinvol further suggestedasubstantialimpactofclimateand extensive diagnosticwork-up(9).Recentstudieshave cases theoriginofpruritusremainsunknowndespite causes forthepruritus(multifactorialCP),whileinfew psychosomatic conditions.Somepatientsshowmultiple neurologicalorpsychiatric/ dermatological, systemic, (9). As for the underlying aetiology, CP may arise from chronic prurigoorlichensimplexchronicus(IFSIIII) II), oraccompaniedbychronicscratchlesions,suchas on inflamed skin (IFSI I), on normal appearing skin (IFSI nal ForumfortheStudyofItch(IFSI),CP maypresent grounds may suffer from CP. According to the Internatio (8). Moreover, patients ofbothsexes andall ethnic back of allagegroups,includingchildren,maybeaffected though theprevalenceofCP increaseswithage,patients phics, clinicalpresentationandunderlyingorigin. Al­ CP isaheterogeneousconditionintermsofdemogra­ CONDITION CHRONIC PRURITUS:AMULTIDIMENSIONAL challenges andunmetneedsinclinicalcare. methodologies used in CP research,aswell as current of novel effective therapies shouldbe targeted by physici understanding of associated burdens and the development procedures and therapeutic regimens, as well as a better experimental and clinical research protocols, diagnostic researchers. Unmet needs, such as the standardization of patient, constitutinga challenge for clinicians and clinical pies and impairmentof quality of life vary from patient to itch, symptoms,skinmanifestations, responsetothera pects of chronic itch, including the underlying origin of the represents a high burden for those affected. Various as Itch lasting for 6 weeks or more is considered chronic and SIGNIFICANCE ans and researchers dealingwithchronicitch. 2 Institute of Medical Informatics, University of University Informatics, Medical of Institute 1 Acta DermVenereol 2020;100: adv00028 , Wolfgang G. PHILIPP-DORMSTON doi: 10.2340/00015555-3348 - - - 3 - - - , Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue: Itch and pruritic disorders Table I.Clinicalresearchmethodologiesusedinitch mechano-sen and heat activate β-alanine and cowhage while (CMi-fibres), C-fibres mechano-insensitive tes activa Histamine C-fibres. of subpopulations several of characterization the to led has β-alanine) cowhage, stimulation with pruritogens (e.g. histamine, capsaicin, to investigatethefunctionsofperipheralnerves.Skin in Table I. of theresults. An overviewofthesemethodsisgiven data andforobtainingacomprehensiveunderstanding medical informaticsisessentialfortheinterpretationof The collaborationwithbiostatisticiansandexpertsof biological researchhavebeenestablishedandvalidated. ment dataobtainedfrommorphologicalandmolecular vestigating specific pathophysiological features that aug In clinical-translationalresearch,different methodsin better understanding of the mechanisms underlying CP. Basic and clinicalresearchhas led in recent decades to a Understanding thepathophysiology RESEARCHANDCARE CLINICAL CHALLENGES IN with regardtotheseissues. difficulties and challenges the discusses article this of example, digitaltoolstoimprovecare. The next section shortcomings andtoadoptinnovativestrategies,as,for CP is integrated into the health system in order to identify should alsobeinvestigatedhowthecareofpatientswith for the treatment of CP, and psychometric research. It lational studies,clinicaltrialsinvestigatingnovelagents important areaistheperformanceoflongitudinaltrans burden andimpactofCP onaffected patients. Another and therapeutic procedures, and assessing the humanistic clinical management,suchasstandardizingdiagnostic clinical researchersshouldfocusonvariousaspectsof velopment andchronicityofCP inhumans.Moreover, of pathophysiologicalmechanismsinvolvedinthede clinical researchcontributestoabetterunderstanding managementisneeded.Inparticular, andits ritic diseases CP, ofpru severalaspects investigating clinicalresearch Due tothecomplexityandmultidimensionalnatureof UNMET NEEDSINCLINICALRESEARCH 46 Intraepidermal nerve fibre density Conditioned pruritic modulation Functional magnetic resonance imaging/positron Quantitative sensorytesting Transcutaneous electrical stimulation Alloknesis Hyperknesis Cutaneous stimulation with cowhage or ß-alanine Cutaneous stimulation with histamine Methodology emission tomography Several methodologieshavebeendevelopedinorder M. P.Pereiraetal. Morphological determinationof epidermal nerve fibre numbers(skin biopsy) Central descendinginhibitionof pruritus Psychophysical testing of subpopulations of peripheral nerve fibres (C-fibres, Aδ-fibres,Aβ-fibres) and signs Electrical-evoked itch via selective activation of peripheral nerve fibre classes Itch response to non-pruritogenic stimuli: touch/brush strokes. Functional testingof itch sensitization Increased itch in response to (chemical, electrical) pruritogens orpinprickstimulation Chemical-evoked itch via activation of mechano and heat-sensitive C-fibres (CMH-fibres) aswell A-fibres. Chemical-evoked itch via activation of mechano-insensitive C-fibres (CMi-fibres), mast cell degranulation Identification of activated anddeactivated cerebral centresuponpruriticstimulation Mechanism of central sensitization using graded thermal andmechanical stimuli phenomena with punctuate or dynamicmechanical stimulation (von Freyfilaments, cotton swab) ------subpopulations andhintsatpossiblesignsofcentralsen fibre nerve peripheral different of function of loss or determination ofneuropathicpain,informsaboutgain is assessed(15). This procedure,originallydevelopedfor togradedthermalandmechanicalstimuli response which testing (QST).Itisabatteryofpsychophysicaltests,in is usedforclinicalitchresearchquantitativesensory Another functionalwell-establisheddiagnostictoolthat symptoms, thusconstitutingalimitationofthismethod. mulation, whichleadstobiasedratingsofevokedsensory undergoing experimentalprocedureswithelectricalsti with CP (14).Ofnote,patientsareoftenanxiouswhen healthy individuals,arguing forhyperknesisinpatients in patientswithCP ofdifferent originscomparedwith Hz 2,000 and 5 at stimulation upon induced be could intensities itch Higher (13). respectively Hz, 2,000 and ted byelectricalstimulationatafrequencyof5,250 using theNeurometer subpopulations of peripheral nerve fibres. For example, electrical stimulation, allows the selectiveactivationof variability islow(12). Another method,transcutaneous high inter-individual variability, whileintra-individual in CP (11). Onelimitationofthismethodologyisthe CMH-fibres of sensitization for arguing controls, with pruritus, ispresentinseveraltypesofCP compared to cowhage-inducedpruritus,butnothistaminergic related Hyperknesis (10). (CMH-fibres) C-fibres sitive which isalsousedinroutinecare,hassomelimitations. ker protein gene product 9.5 (17). This simple method, intraepidermal nervesarestainedwiththeaxonalmar (16). Inthisexamination,askinbiopsyisobtainedand reveal potentialepidermalneuroanatomicalalterations to order in useful is density fibre nerve intraepidermal clinical itchresearch.Inparticular, determinationofthe expression ofreceptorsandmediatorsareessentialin for investigationoftheanatomycutaneouscellsand laboration ofpatients. Morphological methodologies col the as well as personnel, qualified highly requires tine care,ithassomelimitations.Itistime-consuming, (11). Although QST iswidely usedinneurologicalrou arguing fordisorderedperipheralneuronalmechanisms with CP of different origins have an altered QST profile, sitization. In itch research it could be shown that patients ® C, Aδ and Aβ fibres are activa are fibres and Aβ C, Aδ ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Table II.Examplesofinstrumentsforitchassessment conditioned pain modulation (CPM), in which a noxious shown byimagingstudies(21,25). The paradigm of tion via a noradrenergic and a serotonergic pathway, as processing ofpruritusacrossdistinctCP conditions. to establishsimilaritiesanddifferences incerebralbrain patients withCP ofdifferent origins,areneededinorder to poorimagingquality. More imaging studies, enrolling leading procedure, the during still lying difficulty have undergo (e.g.children) examination,whileothers anMRI prostheses or implanted devices (e.g. defibrillator) cannot In addition,patientswithclaustrophobia,ferromagnetic dologies, whichareavailableonlyinspecializedcentres. some pitfalls.fMRIandPET areveryexpensivemetho of cerebral processing of pruritus, this methodology has nal imaging studies have enhanced our understanding neuroplasticity inchronicstates(24). Although functio have beenobservedinpatientswithCP, showingthe tion inCP (23). Also, structuralchangesingreymatter with healthyindividuals,arguing forcentralsensitiza activation uponstimulationwithhistamine compared pes (22).PatientswithCP alsoshowdifferences inbrain differences incerebralprocessingofdistinctpruritusty and non-histaminergic pruriticstimulation,pointing to and distinctbrainareasareactivateduponhistaminergic response topruritus(21).Interestingly, bothoverlapping motor response and emotional states are activated in regions associated with sensory recognition, cognition, exposed topruriticstimulationduringthescans. Brain Most studies have been performed on healthy volunteers transmission andprocessingofpruritusinuppercentres. tomography (PET) studies have been used to investigate netic resonanceimaging(fMRI)andpositronemission was obtained fromanimal studies (20). Functionalmag Most currentknowledgeonspinaltransmissionofitch rations ofperipheralnervefibres. examination, whichdoesnotinformonfunctionalalte other body sites is difficult. It is a purely morphological lower leg(18,19),thusinterpretationofvaluesfrom dition, referencevaluesareavailableonlyforthedistal be processedinatimelymannerthelaboratory. Inad to needs and fixative the to sensitive is probe skin The ItchyQuant 5-D itchscale (5 dimensions itch Dynamic Pruritus Score (DPS) Itch Severity Scale (ISS) Labelled magnitudescale (LMS) Verbal rating scale (VRS) Numerical rating scale (NRS) Visual analogue scale(VAS) Instrument scale) Upper centresexertadescendinginhibitorymodula Central processingofpruritusisverychallenging. Description Monodimensional scale for assessment of itch intensity; combination of VAS and cartoon depictions of scratching; developed Patient global impression of change for assessment of itchimprovement; usedin clinical trials and routine care (electronic and Multidimensional scale for assessment of itch intensity; used inclinical trials (paper version) Monodimensional scale for assessment of itchintensity; used in experimental research (paper version) Categorial scale for assessment of itch intensity; used in clinical trials and routine care (electronic and paper versions available) Monodimensional scale for assessment of itchintensity; used in clinical trials androutinecare (electronic and paperversions Monodimensional scale for assessment of itchintensity; used in clinical trials androutinecare (electronic and paperversions Multidimensional questionnaire for assessment of itchcharacteristics; used in clinical trials (paper version) for populations with cognitive limitations(elderly, children); usedinroutinecare (paper version) paper versions available) available) available) ------30). Mono-dimensionalscales,namelythevisualana using generalpatient-orienteditchquestionnaires(29, symptoms andscratchingbehaviour)canbeassessed ribution ofpruritus,aswellaccompanyingsensory depression andsleepimpairment,therapygoals. of thedisease,QoL,reactivedisorders,suchasanxiety, aspects ofCP, includingprurituscharacteristics,course developed inordertogatherinformationonseveral of standardizedquestionnairesandscaleshavebeen reported outcomes(PRO)playapivotalrole. A plethora Since pruritus has a subjective dimension, patient- Standardization ofassessmentinstruments its roleinthechronicityofdisease. of themechanismsdescendingmodulationinCP and More studiesareneededtoenhancetheunderstanding ted, with conflicting results regarding its effect (27, 28). dized questionnairesareusedtoscreenforanxietyand itch isshowninTable II. An overviewofotherinstrumentsfortheassessment difference, making the interpretation of results difficult. background) may influence the minimal clinical relevant aetiology ofthepruritus,recallperiod,socioeconomic initiating a therapy (34). However, many factors (e.g. the relevant difference ofitchintensitychange,e.g.after have beenputintounderstandingtheminimalclinical such as sex or ethnic background (1, 33). Some efforts vary from patient to patient according toexternalfactors, tion ofitchintensityscalesischallenging,sincescores use inelectronicdiaryapplications(32). The interpreta of pruritus(31).Intensityscalesarealsovalidatedforthe rating scale, have been validated to assess the intensity logue scale,thenumericalratingscaleandverbal pruritus elsewhereinthebody, hasalsobeeninvestiga pruritic modulation,inwhichastimulusinhibits pruritus (11). An analogous paradigm of conditioned impaired, whichmaycontributetothechronicityof patients with CP, asinthosewithchronic pain, CPMis experimentally toassessdescendinginhibition(26).In stimulus inhibits pain elsewhere in the body, can be used Pruritus characteristics (e.g. onset, duration and dist As forsecondaryconditionsarisingduetoCP, standar Clinical researchandcareinitch Theme issue: Itch and pruritic disorders 47 - - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue: Itch and pruritic disorders by variousfactors,suchas pruritusintensity, butalso influenced is and construct subjective highly a is QoL 51). (50, suicide of risk higher significantly at are and health problems,suchasdepression, inresponsetoCP, work productivity(48,49). Somepatientshavemental ability toconcentrate,qualityofsleep,everydaylifeand ment ofQoL (45–47)andhasnegativeeffects onmood, CP, similarly to chronicpain,canlead a severe impair Understanding thehumanisticandeconomicburden accepted bypatientsandphysicians. utility fortheclinicalpracticeandwhichtoolsarebetter should focusonshowingwhichinstrumentshavebetter care acrossdifferent countries.Futureclinicalresearch languages inordertobeusedclinicaltrialsandroutine toolsintovariousis thevalidationofassessment the instrumentsofchoice(44). Another importanttask visual analoguescaleandtheItchyQolwereregardedas important parameters to be assessed in routine care. The intensity andQoL shouldberegardedasthe2most In aconsensusconference,itwasagreedthatpruritus European Academy ofDermatologyand Venereology. step was already taken by the Task Force Pruritus of the first Adata. of comparability the allow would it since centres treatingpatientswithCP isofgreatimportance, or alternate-formsreliability. crete implementationswereexaminedusingtest–retest electronic measures, it would be preferable if the con of validity the ensure to order in However, measure”. theequivalenceorvalidity ofacomputerized anew strate equivalence studiesshouldnotbenecessarytodemon changes are not made to the item text or response scales, Gwaltney et al. (40) showed that “as long as substantial measures deliver the same results for a patient encounter. be assumedthattheelectronicversionofsamePRO measures havebeenvalidatedaspapertools,itcannot survey, maybeimplemented(41–43).SincemostPRO ling thepatienttocompletePROmeasuresviadigital of paper questionnaires, an electronic PROsystem, enab reminder functionality (40). To overcome the drawbacks at homebyupto70%,using,forexample,computerized can increase the compliance of completing questionnaires of skippatterns(40).Furthermore,electronicassessment pletion, andreductionofinvaliddatabyimplementation typewriting, reductionofmissing data byrequiringcom reductionoferrorsemergingquestionnaires: through offers a couple ofadvantages compared with paper emerging. Computerized collection of PRO measures pencil questionnaires, but electronic PRO systems are Index (38)andpruritus-specificItchyQol(39)). the impairmentofQoL (e.g.DermatologicalLifeQuality (35)), toassesssleepdisorders(36,37)andmeasure depression (e.g. Hospital Anxiety and Depression Scale 48 Standardization ofitch assessment instruments across PRO measuresareusuallycollectedviapaperand M. P.Pereiraetal. - - - - - physical andmentalwell-being,professionalevery consists of 27 items, including various aspects, such as which wasvalidatedin2009forpatientswithCP and (PBI-P), Pruritus – Index Benefit Patient the using CP goals wererecordedandevaluatedin2,474patientswith Therapy regimen. therapy efficient an plan to order in goals ofpatients with CP istherefore ofgreat importance and cost-intensive therapy. Knowledge of the treatment As amultifactorialchronicdisease,CP requirescomplex Definition oftreatment goals ultimately toimprovecare. vulnerable patientstomentalhealthprofessionalsand risk. This wouldaidattendingphysiciansinredirecting diseases inpatientswithCP andthusidentifypatientsat researchers is to detect risk factors fordeveloping mental health conditions. An importantchallengeforclinical therapy against,forexample,sleepdisordersormental antipruritictherapy,for symptomatic foradjunct butalso not only for diagnosing the underlying disease of CP and sorders, individual multimodal medical care is needed, patients (52).Inordertocopewiththeseassociateddi improve, psychological suffering is higher in these its consequences.Interestingly, eveniftheirsymptoms matic/psychiatric comorbiditysuffer morefromCP and complications. PatientswithCP andwithapsychoso humanistic burdenofpruriticconditions. of patientswithCP intoaccountwheninvestigatingthe taketheculturalbackground should (6). Clinicalresearch than 500patientswithCP duetodifferent dermatoses found in a study in 9 European countries enrolling more than the specific dermatological diagnosis. This could be influence the reported intensity of pruritus and QoL rather ditions onaffected patientsisthatcross-culturalfactors in therapywereconsidered importantorvery and medical therapy. Reduction in pruritus or confidence been shownthattherapeutic goals relate to the diagnosis as averyimportanttreatment goal(54).Overall,ithas sions (IFSI III) considered the healing of the skin lesions inflamed skin (IFSI I) or pruritus with chronic scratch le contacts, partnership,andsexlife.PatientswithCP on the improvementinaspectsofsociallife,suchas as more important (54). For men, an important goal was as depressivefeeling,nervousness,orburningsensations, symptoms,such reduction inphysicalandpsychological impact ondifferent patientneeds. Women consideredthe IFSI group, pruritus intensity and QoL had a significant dition todemographicdatasuchassexandage,theCP to 4=”veryimportant”)(53).Itwasshownthat,inad the basisofa5-stepLikertscale(0=”notatallimportant” in general. The relevanceoftheseitemsiscalculatedon day performance,socialandleisureactivities,QoL challenge inunderstandingtheimpactofpruriticcon duration, frequencyandlocalizationofpruritus. Another In addition to limiting QoL, there are often psychiatric In additiontolimitingQoL,thereareoftenpsychiatric ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV are neededforthecurrentdemand (7).Prurituscentres more and scarce are centres the However, emollients. such asantihistamines,topical steroidsandtheuseof especially whenrefractory to basic therapeutic measures, offer animportantadvantage inthemanagementofCP, of patientswithCP inspecializedprurituscentrescan medication mustbewelldocumented. The consultation and comorbidities findings, skin and factors causative pression andanxiety, needtobeconsidered,aspossible logical practice. Reactive disorders of CP, such as de history in patients with CP is challenging in a dermato due totimeconstraints,takingacomprehensivemedical diagnostic procedures (e.g. medical imaging). However, patient to local physicians of other specialties for specific Their jobisnotonlytotreattheCP, butalsotoassignthe ted forCP andplayakeyroleinthemanagementofCP. which tobasetherapeuticrecommendations. utmost importanceinordertogeneratequalitydataon cholestatic pruritus,paraneoplasticpruritus)areofthe (e.g.atopicdermatitis, uraemicpruritus, pruritic diseases pruritic conditions.Clinicaltrialstargeting different therapeutic recommendations are needed for the various specific Therefore (58). conditions pruritic systemic pruritus inotherdiseases,suchasatopicdermatitisor effective in the treatment of urticaria,they do notreduce CP aetiologies.Forinstance,whileantihistaminesare challenge thatguidelinesfaceistheheterogeneityof on caseseries,reportsandexpertopinion. Another the recommendationsofcurrentguidelinesarebased investigating anti-pruriticdrugs,andthereforemanyof updated (57). a Europeanguidelinewasalsodevelopedandrecently man guidelinehasbeenregularlyupdated(56),while Ger the then, Since regard. this in step first important published inGermany2006(55)andconstitutedan patients with CP. The first guideline addressing CP was proach acrossspecializedcentresandphysicianstreating to achieveastandardizeddiagnosticandtherapeuticap Owing to the heterogeneity of CP conditions, it is difficult procedures Standardization ofdiagnosticandtherapeutic patients withCP. taken intoconsiderationwhenplanningstudiesinvolving the efficacy of a therapy. Patients’ needs should thus be and goals influence how they perceive their disease and challenge forclinicalresearchers,sincepatients’ needs titis (54). The complexityofpatients’ needsconstitutea cal patients as, for example, patients with atopic derma need levelseemstobehigherthaninotherdermatologi overall Their action. medical efficient and trustworthy with CP focusnotonlyonsymptomrelief,butalso CP.with patients However,patients of majority the by Dermatologists are usually the firstspecialists consul There isstillalackofrandomizedcontrolledtrials ------Owing to a better understanding of the mechanisms under Need fornoveleffectivetherapies a significantreductioninallcosts(60). intensity,QoL also but (PBI-P), benefit therapeutic and pruritus the in improvement significant a only not was start oftreatmentataspecializedprurituscentrethere the after months Six benefits. therapeutic and burden CP wereanalysedregardingtheirQoL,healtheconomic of arecentstudyinwhichdatafrom300patientswith in theinpatientandoutpatientsectors. This istheresult both costs, reduce significantly can centres specialized or severesleepimpairment(59). relevant psychosocialfactors,suchassuicidalideation have orwho procedures requireextensivediagnostic who possibility ofinpatientcareforhighlycomplexpatients outpatient care,specializedcentresshouldalsooffer the radiology, andmedicalinformatics(59).Inadditionto nal medicine,neurology, painmedicine,psychosomatics, and ultimately to better care. However, the multidimen years, leadingtobetterunderstanding ofthiscondition, Clinical researchefforts in CP haveincreasedinrecent CONCLUSION that regulatory agencies can approve these medications. so drugs, anti-pruritic novel of efficacy and safety the research should focus onproducing high-quality data on clinical Hence, need. in patients to agents promising is neededinordertoextendtheavailabilityofthese patients haveaccesstothem.Licensingofthesedrugs trials areavailableinonlyafewcentresandthusnotall target populationissuitableforeachdrug. observations fromroutinecareshouldinformwhich and trials Clinical them. from most the profit can who healthcare system,itisimportanttoselectthepatients and thusnonoveldrugsareavailable. many otherpruriticconditionsclinicaltrialsarelacking, chronic prurigo,uraemicandcholestaticpruritus.For only forafewindications,especiallyatopicdermatitis, challenges. Sofar, clinicaltrialshavebeenperformed inhibitors (e.g.tofacitinib)amongothernovelagents. inhibitors (e.g.apremilast,crisaborole),januskinase phosphodiesterase-4 nalfurafine), nalbuphine, (e.g. tors antagonists (e.g.serlopitant,aprepitant),opioidmodula (e.g. nemolizumab, tralokinumab), neurokinin-1 receptor controlled trials. These includemonoclonalantibodies randomized in tested being are and identified been have lying CP, newpromising agentswithananti-pruritic effect medical specialtiesotherthandermatology, suchasinter should workonaninterdisciplinarybasistogetherwith Guideline-based treatmentofpatientswithCP at At present,innovativedrugsbeingtestedinclinical Since these new agents represent a high cost for the The development of innovative drugs faces important Clinical researchandcareinitch Theme issue: Itch and pruritic disorders 49 - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV 12. 11. 10. Theme issue: Itch and pruritic disorders REFERENCES The authorshavenoconflictsofinterest todeclare. to MP andSST). demy ofDermatologyand Venereology (EADV, No.2016-012 (DFG, No.FOR2690toKA and SST) by theEuropean Aca This articlewassupportedbytheGermanResearchFoundation ACKNOWLEDGEMENTS by researchersandphysiciansdealingwithCP. promising drugs for refractory CP, ought to be targeted tic approachtoCP patients,andthedevelopmentofnovel insufficient standardization of a diagnostic and therapeu as the shortage ofknowledgeon chronicity mechanisms, researchers andattendingphysicians.Unmetneeds,such population affected byCP poseachallengeforclinical sional natureofthisconditionandtheheterogeneous 50 7. 6. 4. 2. 9. 8. 5. 3. 1. Andersen HH, Sorensen AR, Nielsen GA, Molgaard MS, Molgaard GA, Nielsen Sorensen AR, Andersen HH, Stilling Pogatzki-Zahn EM, Pereira MP, Cremer A, Zeidler C, Dreyer T, Pereira MP, Steinke S, BrulandP, StänderH,Dugas M,Au Johanek LM, Meyer RA, Hartke T, Hobelmann JG, Maine DN, Steinke S, Zeidler C, Bruland P,C, Riepe Soto-Rey I, Storck M, Wongvibulsin S, KhannaR,Kwatra SG.Anatomiclocaliza Zink A, Schuster B, Ruth M, Pereira MP, Philipp-Dormston Ständer, Weisshaar E,MettangT, Szepietowski JC,Carstens Matterne U, Apfelbacher CJ, Vogelgsang L, Loerbroks A, Hay RJ, Johns NE, Williams HC, Bolliger IW, Dellavalle RP, Tizek L, Schielein M. Influence of climate on Google internet Matterne U, Apfelbacher CJ, Loerbroks A, Schwarzer T, experimental modelsof histaminergicandnon-histaminergic P, Boudreau SA, et al. A Test-retest reliability study of human 2019; pii: S0022-202X(19)31851-2. inhibition is a hallmark of chronic pruritus. J Invest Dermatol C, et Riepe al. Peripheral and loss sensitisation of descending J Neurosci 2007; 27:7490–7497. for parallel afferent pathways the mediating sensation of itch. LaMotte RH, et al. Psychophysical and physiological evidence J AmAcadDermatol 2018;79: 457–463.e455. Severity and Burden of Pruritus (PruNet) cross-sectional trial. of Dermatology andVenereology Network on Assessment of inflammatory dermatoses: results of the European Academy et al. Humanistic burden of chronic pruritus in patients with WG, Biedermann T, et al. Medical needs and major com Derm Venereol 2007;87: 291–294. paper of the International Forum for the Study of Itch. Acta position a itch: of classification Clinical al. et A, Ikoma E, Weisshaar E. Incidence and determinants of chronic pruri J Invest Dermatol 2014; 134: 1527–1534. an analysisoftheprevalence andimpact ofskinconditions. Margolis DJ, et al. The global burden of skin disease in 2010: analysis. JMedInternet Res 2019;21: e13739. searches forpruritusacross16Germancities:retrospective sectional study. Acta Derm Venereol 2011; 91: 674–679. characteristics of chronic pruritus: a cross- population-based Buttner M, Ofenloch R, et al. Prevalence, correlates and 2013; 93: 532–537. tus: a population-based cohortstudy. ActaDerm Venereol Itch 2017; 2:e06. dermatological office to the specialized itch center. a review. gustin M,etal.Management ofchronicpruritus:fromthe 9622(19)30993-4. United States. J Am Acad Dermatol 2019. pii: S0190- tion and quantitative analysis of the burden of itch in the Dermatol Venereol 2019;33: 151–156. analysis usingGoogleAdWords Keyword Planner. J EurAcad plaints related to pruritus in Germany: a 4-year retrospective M. P.Pereiraetal. ------30. 29. 13. 28. 24. 19. 16. 27. 23. 18. 15. 26. 22. 17. 14. 31. 25. 21. 20. Weisshaar E,Ständer, GielerU, MatterneU, Darsow U. Ent Yosipovitch G,Zucker I,Boner G,Gafter U, Shapira Y, David AAEM EquipmentandComputerCommitteeAAoEM.Techno Andersen HH, van Laarhoven AIM, Elberling J, Arendt-Nielsen Papoiu AD, Emerson NM, Patel TS, Kraft RA, Valdes-Rodriguez Provitera V, Wendelschafer-Crabb CH, Gibbons V, Donadio G, Lauria G,HsiehST, Johansson O, Kennedy WR,LegerJM, van Laarhoven AI,Kraaimaat FW, Wilder-Smith OH,van de Schneider G, Ständer, Burgmer M, Driesch G, Heuft G, Lauria Lauria G, Bakkers M, C, Lombardi R, PenzaSchmitz P, Devigili Rolke R, Baron R, Maier C, Tolle TR, Treede RD, Beyer A, Talbot JD, MC,Boyer Bushnell Duncan GH, M.Diffusenoxious Mochizuki H, Papoiu ADP, Yosipovitch G. Brain processing of Lauria G, Cornblath DR, Johansson O, McArthur JC, Mellgren Pereira MP, Agelopoulos K, Kollner J, Neufang G, Schmelz Phan NQ, BlomeC,FritzF, GerssJ, Reich A,EbataT, etal. Mochizuki H, Tashiro M, Kano M, Sakurada Y, Itoh M, Yanai K. Kakigi H, Mochizuki Central R. Clin of itch. mechanisms Akiyama T, Carstens E. Spinal CodingofItch and Pain. In: in uremic patients. Acta Derm Venereol 2001; 81: 108–111. M. A questionnaire for the assessment of pruritus: validation in healthy humans.J Pain 2017; 18:1437–1450. L. Modulation of itch by conditioning itch and pain stimulation arterial spin labeling fMRI reveal neuropathic and neuro R, Nattkemper LA, et al. Voxel-based morphometry and itch. Acta Derm Venereol 2017; 97:198–207. age- and gender-adjusted normative dataset for immunofluo Vitale DF, Stancanelli A, et al. A multi-center, multinational Mellgren SI, et al. European Federation of Neurological So itch – analogous to DNIC in pain? Pain 2010; 149: 332–337. Kerkhof PC,Evers AW. Heterotopic pruriticconditioningand subjects. Eur JPain 2008; 12: 834–841. andhealthy dermatitis betweenatopic histamine-induced itch of imaging central in differences Significant M. Weckesser 2010; 15: 202–207. a worldwide normative reference study. J Peripher Nerv Syst G, et al. Intraepidermal nerve fiber density at the distal leg: and reference values. Pain 2006;123:231–243. Network on Neuropathic Pain (DFNS): standardized protocol et al. Quantitative sensory testing in the German Research by coldpressor pain. Pain 1987; 30: 221–232. for intersegmentalsuppressionofnoxious heatperception inhibitory controls (DNICs): psychophysical evidence in man Taylor & Francis Group, LLC; 2014. mechanisms and treatment. Boca Raton, FL: CRCPress/ itch andscratching. In:CarstensE,Akiyama T, editors.Itch: 12: 747–758. in the diagnosis of peripheral neuropathy. Eur J Neurol 2005; SI, Nolano M, etal. EFNS guidelines ontheuseof skin biopsy Acta Derm Venereol 2019; 99: 1009–1015. generalized chronicpruritus:hintfor central sensitization? M, Ständer. Selective nerve fibre activation in patients with Assessment of pruritus intensity: prospective study on va positron emission tomography. Pain 2003; 105: 339–346. Imaging ofcentral itchmodulationinthehumanbrain using Neurophysiol 2015; 126:1650–1660. Carstens E, Akiyama T, editors. Itch: mechanisms and tre 17: 903–912, e944–909. andthePeripheralSocieties Nerve Society. 2010; JNeurol Eur a joint task force of the European Federation of Neurological biopsy in the diagnosis of small fiber neuropathy. Report of cieties/Peripheral Nerve Society Guideline on the use of skin (CPT). Muscle Nerve 1999; 22: 523–531. logy review:theNeurometerCurrentPerception Threshold lidity and reliability of the visual analogue scale, numerical 62: 914–927. von chronischen Pruritus (AGP-Fragebogen). Hautarzt 2011; wicklung eines deutschsprachigen Fragebogens zur Erfassung disease. JNeurophysiol 2014; 112:1729–1738. plastic features of brain processingof itch in end-stage renal LLC.; 2014. atment. Boca Raton, FL: CRC Press/Taylor & Francis Group, Eur J Neurol 2016;23: 333–338. intraepidermalrescent nerve densityfiber leg. distal the at ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV 36. 40. 35. 46. 39. 34. 45. 38. 33. 44. 43. 42. 41. 37. 32. Glenville M, Broughton R. Reliability of the Stanford Sleepi Gwaltney CJ, Shields AL, Shiffman S. Equivalence of electro Snaith RP. TheHospitalAnxiety And Depression Scale.Health Carr CW, Veledar E,ChenSC.Factors mediatingtheimpact Desai NS, Poindexter GB, Monthrope YM, Bendeck SE, Reich A,RiepeC,Anastasiadou Z,MedrekK,Augustin M, Erturk IE,AricanO, OmurluIK,SutN.Effect ofthepruritus Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) – Ständer, Stumpf A, Osada N, Wilp S, Chatzigeorgakidis E, Ständer, Zeidler C, Riepe C, Steinke S, Fritz F, Bruland P, et Wagner LI, Schink J, Bass M, Patel S, Diaz MV, Rothrock N, Storck M,Zeidler C,Rehr M,RiepeC,Dugas M,Ständer, et Rogausch A, Sigle J, Seibert A, Thuring S, Kochen MM, Him Johns MW. A new method for measuring daytime sleepiness: Gernart M,Tsianakas A,Zeidler C,RiepeOsadaN,Pihan Qual Life Outcomes 2003; 1: 29. 150: 613–620. of chronicpruritusonquality of life.JAMA Dermatol 2014; pruritus. JAmAcadDermatol 2008; 59:234–244. Swerlick RA, ChenSC.Apilotquality-of-life instrumentfor Venereol 2016;96: 978–980. clinically important difference in chronic itch. Acta Derm scale and numerical rating scale: determination of minimal Szepietowski JC, et al. Itch assessment with visual analogue 2012; 24: 406–412. on the quality of life: a preliminary study. Ann Dermatol Dermatol 1994; 19: 210–216. a simplepractical measure for routineclinicaluse.ClinExp burden. Br J Dermatol 2013;168:1273–1280. present different morbidity, morescratch lesionsand higher Pfleiderer B. Gender differences in chronic pruritus: women J Eur Acad Dermatol Venereol 2016; 30: 1144–1147. burden of Pruritus (PruNet): first meeting on outcome tools. al. European EADV network on assessment of severity and et al. Bringing PROMIS to practice: brief and precise symp al. Validation ofpruritusmeasuresgatheredwiththeelec the Epworth sleepiness scale. Sleep 1991; 14:540–545. 97: 601–606. chronic pruritus in clinical trials. Acta Derm Venereol 2017; D, et al. ItchApp(c): an app-based ediary for assessment of 121: 927–934. tom cancer ambulatory in screening care. Cancer 2015; Venereol 2018;98: 38–43. tronic patient-reported outcomesystemMoPat. ActaDerm Health Qual Life Outcomes 2009; 7:51. assessment ingeneral practice: an implementationstudy. mel W. Feasibility andacceptanceof electronicquality oflife 2008; 11: 322–333. outcome measures:ameta-analytic review. Value Health nic andpaper-and-pencil administration ofpatient-reported 21: 235–244. and the Wilkinson Auditory Vigilance Task. Adv Biosci 1978; ness Scale compared to short duration performance tests chronic pruritus. Acta Derm Venereol 2012; 92: 502–507. rating scale and verbal rating scale in 471 patients with - - - - - 48. 47. 60. 54. 52. 50. 59. 53. 51. 49. 58. 57. 56. 55. Kimball AB, Edson-Heredia E, Zhu B, Guo J, Maeda-Chubachi Kini SP,Kini DeLongLK,Veledar E,McKenzie-Brown AM,Schaufele Steinke S, Müller S, Gutknecht M, Borowski M, Augustin Steinke S, BrulandP, Blome C,OsadaN,Dugas M,FritzF, Schneider G, Grebe A, Bruland P, Heuft G, Ständer. Chronic Konda D, Chandrashekar L,Rajappa M,Kattimani S, Thappa Ständer, StänderHF, Steinke S, Bruland P, Dugas M,Augustin Blome C, Augustin M, Siepmann D, Phan NQ, Rustenbach Halvorsen JA, Dalgard F, ThoresenM,Bjertness E,LienL. Shutty BG, West C, Huang KE, Landis E, Dabade T, Browder Klein PA, Clark RA. An evidence-based review of the efficacy Weisshaar E, Szepietowski JC, Dalgard FJ, Garcovich S, Gie Ständer, Zeidler C,Augustin M,Bayer G,KremerAE,Legat Ständer, U, M,Darsow Streit V, Niemeier Vogelgsang M, moderate-to-severe psoriasis:sleepproblemsareamedi pruritus severity and work productivity in patients with T, ShenW, etal.Understandingtherelationshipbetween equivalent of pain.ArchDermatol 2011; 147: 1153–1156. M, ChenSC.Theimpactofpruritusonquality oflife:theskin M, Ständer S, editors. Versorgung von Patienten mit ch et al.Chronicpruritus:evaluation ofpatientneedsandtre pruritus patients with psychiatric and psychosomatic comor Association withpruritusseverity, sleepquality anddepres DM, Ananthanarayanan PH. Serotonin and interleukin-6: 2016; 67: 640–647. M. ChronischerPruritus:Versorgung inderPraxis. Hautarzt tool. Br J Dermatol 2009; 161:1143–1148. treatment: development and validation of a specific outcomes SJ, Ständer. Measuring patient-relevant benefits in pruritus Derm Venereol 2012;92: 543–546. ideation: a population-based cross-sectional study. Acta Itch and pain in adolescents are associated with suicidal 2013; 19: 1. B, et al. Sleep disturbances in psoriasis. Dermatol Online J Arch Dermatol 1999;135: 1522–1525. of antihistamines in relieving pruritus in atopic dermatitis. FJ, et al. S2k-Leitlinie zur Diagnostik und Therapie des ch und therapeutisches Diagnostisches etal. Ständer H, Vorge Dermatol Venereol 2019;33: e288–e291. bidity arehighlyburdened:a longitudinalstudy. JEurAcad 17: 24–28. sion severity inPrurigo Nodularis. AsianJPsychiatr 2015; ating factor. J Drugs Dermatol 2016; 15:183–188. Deutschen Dermatologischen Gesellschaft;Berlin, 2019. Versorgung in einem Kompetenzzentrum. 50. Tagung der ronischem Pruritus:Kosten undNutzen derspezialisierten Chronic Pruritus.ActaDerm Venereol 2019; 99:469–506. ler U, Gimenez-Arnau AM, et al. European S2k Guideline on Ges 2017; 15: 860–873. ronischen Pruritus – Update – Kurzversion. J Dtsch Dermatol 4: 350–370. hen bei chronischem Pruritus. J Dtsch Dermatol Ges 2006; 363–370. to pruritus classification and sex. Br J Dermatol 2017; 176: atment goalswithaspecialregardtodifferencesaccording Clinical researchandcareinitch Theme issue: Itch and pruritic disorders 51 ------