European Consensus Statement on Phenotypes of Pustular Psoriasis

Navarini, A. A., Burden, A. D., Capon, F., Mrowietz, U., Puig, L., Köks, S., Kingo, K., Smith, C. and Barker, J. N. (2017) European consensus statement on phenotypes of pustular psoriasis. Journal of the European Academy of Dermatology and Venereology, 31(11), pp. 1792-1799.

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Deposited on: 04 July 2017

Accepted Article This by is protectedarticle reserved. Allrights copyright. doi: 10.1111/jdv.14386 lead to differences between this version and the throughbeen the copyediting, pagination typesetting, which process, may and proofreading hasThis article been accepted publicationfor andundergone peerfull but review not has Alexander A. Navarini Authors EuropeanConsensus Statement on PhenotypesPustular of Psoriasis Title Article type :Review Article DR. PUIG(Orcid LLUÍS ID : 0000-0001-6083-0952) Affiliations *shared authorship # address correspondence to [email protected]. Puig ERASPEN network ERASPEN . European RareAnd Severe Expert Psoriasis Network (ERASPEN) 7. Department of Dermatology and Venerology, Tartu University Hospital,Tartu, Estonia 6. SantCreuPau,de laSanta Department i Dermatology, of Hospital Universitat 5. Psoriasis Center at the Department of Dermatology, University Medical Center, 4. Genetics and Divisionof Molecular Medicine, King’sUKCollege, London, 3. Infection of Institute Immunity, and Inflammation Glasgow. Universityof 2. Department of Dermatology, University Hospitalof Zurich, Gloriastrasse 31, 8091 1. 5,* , Sulev Köks Autònomade Barcelona, Spain. Barcelona, Schittenhelmstraße Campus Kiel,Schleswig-Holstein, 24105,7, Kiel, Germany. SwitzerlandZurich,

6 6 , Külli Kingo Külli ,

1,*,# , A. David Burden , A.David 6 ,Smith Catherine 2,* , Francesca Capon Version of Record. Please Version as this cite of Record. article 3 and Jonathan N. Barker 3,* , Ulrich Mrowietz , Ulrich

3 onbehalf of the 4,* , Luis Accepted Article This by is protectedarticle reserved. Allrights copyright. Vienna,MedicalStingl University Georg, Vienna,of Austria; Ståhle Mona, Karolinska University Hospital,Stockholm, Sweden; SorinCarol Davila George, Bucharest,of Medicine, Romania; University Skov Lone, Gentofte Hospital, University Copenhagen,of Copenhagen , Denmark; Dermatology, of UniversityRöcken Martin, Department Tübingen Germany; , Reich Kristian, Dermatologikum hamburg, Hamburg, Germany; Prinz UniversityJörg, LMU Hospital Munich, Germany; Ele,PransTartu University, Estonia; Tartu, StudiNaldiCentro GISED, Bergamo, Luigi, Italy; Lipsker Dan,Facultéde de Médecinel UniversitédeStrasbourg, Strasbourg,France; Kõks Sulev, Tartu University Hospital,Tartu, Estonia; Koh Hong Yi, Singapore General Hospital,Singapore, Singapore; KingoKülli, UniversityEstonia; Tartu Tartu, Hospital, Griffiths Christopher, The University ofManchester, Manchester, United Kingdom; Gniadecki Robert Bispebjerg, Hospital, Copenhagen University, Copenhagen , Denmark; Girolomoni Giampiero, Università degli studi di Verona, Verona, Italy; Gilliet Michel, Centre hospitalieruniversitaire vaudois, Lausanne, Switzerland; Ghoreschi Kamran, University ofDepartment Dermatology, Tübingen ,Germany; LarsE.,French Zürich, UniversitätsSpital Zürich, Switzerland; EyerichMünchen,Kilian, Universität Technische Munich, Germany; HumanitasCostanzo Antonio, ResearchHospital, Italy;Milano, Nepi,ChiricozziPisa, University Italy;of Andrea, Bachelez Saint Hervé, Louis University Hospital, Paris, France; network: The ERASPEN Accepted Article This by is protectedarticle reserved. Allrights copyright. psoriasis. Indeed, plaques always have a measure neutrophilof granulocytes that can be pustulesexample,beFor observed can phenotype as anextreme withinof plaques distinct both clinically histologically, both and but pustules and plaquescan occur together. Psoriasis traditionally comprises both erythrosquamous and pustular lesions. These are Introduction and/or and soles occur can withor without PV. has primary, sterile, (> 3months), persistent onpalmsmacroscopically pustules visible macroscopicallypustules affectingthe nailapparatus. Palmoplantarvisible pustulosis (PPP) continua of Hallopeau is (ACH) characterized by primary, (> persistent 3 sterile,months), either be a relapsing (>1 episode)or persistent (> 3 condition. months) Acrodermatitis plaques). GPPcan occur with or systemic without inflammation, or with without PV and can pustules onnon-acral skin (excluding cases isrestrictedwhere to pustulation psoriatic Generalized Psoriasis Pustular (GPP) is defined as primary, sterile, macroscopically visible phenotypes thatwill be used as a baseline for further, prospective studies PP.of initial on considerations phenotypes the of PP consensus and a classification of clinical work reviews historical aspects of conditions,these new genetic findings and presents our andanalyse pathophysiologygenetics prepare This prospective for and the clinicaltrials. consensuscriteriadefine diagnosis, deeplyfor phenotype PP of patients, largegroups The EuropeanRare andSeverePsoriasis Expert Network (ERASPEN) was founded to groups of patients as well asclinical trials. dermatology encumbering [1-5], phenotypicallythe textbooks collection of well-matched PP arenot well defined. Descriptions of each ofform PP are discordant among standard PV,phenotypes thethe geneticIn contrast to of on level. tobedistinct seem treatments, and vulgaris (PV). However, PP and PV are phenotypically respond different, differently to develop.pustules Because of clinical co-incidence, PP is currently grouped with psoriasis neutrophilof granulocytes in epidermisthe toextent suchanclinically that sterile visible Pustular psoriasis (PP) is a group of inflammatory conditions skin characterized by infiltration Abstract TheRichard,WarrenUniversity Manchester, Kingdom; of Manchester,United CentrumKerkhofMedisch StVanNetherlands; Nijmegen, Radboud, de Universitair Peter, Accepted Article This molecule inhibits the activation of NF- of activation inhibits the This molecule whichencodes ananti-inflammatory protein asknown the interleukin 36 receptor antagonist. This by is protectedarticle reserved. Allrights copyright. A minorityPP cases of are causedby rareand damaging ofmutations the Genetic architecture of PP: studies. PPof and genetic clinical studies, trials, healthcare planning and prevalence/incidence and a consensus classification of phenotypes that will be utilized for further, unbiased study genotype PP of Here patients. we present someconsiderations on clinical the features of PP needandthis unmet unbiasedcollaborative start the of phenotypeclinical investigation and grantwith aPPRC of Association Europeanthe of Dermatology address andVenereologyto PP. TheandSevere EuropeanRare Psoriasis (ERASPEN) ExpertNetwork wasfounded thereforeto setout and aEuropeanfind ideally clinical consensus criteriainternational offor does notalleviatethe problem and discovery geneticeven difficult.makes more We where are recruited patients Pooling international heterogenousfrom. groups ofpatients Therefore,basic science includinggenetic studies diverging results dependingmay reach on pustulardiagnosis conditions of includingPP vary andno hasbeendeveloped.consensus This difficult than ismore be expected,becausemight clinicalthe criteria for description and from Therefore, asinglecentre. pooling samples of international among centres is crucial. Unfortunately,the rarity PP of does not usually allow collection of samplesufficient numbers these conditions closelypathogenetic for involved. factors diseases altogether separate from psoriasis.This prompted severalgroups investigateto psoriasis. Therefore, the questionarose whether these conditions should be regarded as revealed that some of thegenetic variants underlying PP donotnon-pustular occurin psoriasis spectrum, which were thuslabelled pustularpsoriasis (PP). Newer have data ultimatelyled assumptionto the that primaryseveral pustular conditions are part of the (particularlyby aswas bydescribed dermoscopy), also and BarberKönigsbeck. [7] This a not uncommon clinical observation to find some pustules in inflammatory plaques ofPV not formally these beenprovenwhether can into clinically Butitturn is observablepustules. (Munro’s subcorneal andKogoj’smicroabscesses spongiform pustules can[6]) It hasform. detected When histologically. intense inflammation neutrophils of ispresent, collections families withfamilies autosomalrecessive transmission the of[9]. disease A of total 16 IL36RN receptorthe andIL1RL2 preventingits association with IL1RAP the co-receptor. defectswere identifiedfirst in5 unrelated individualswithGPP Tunisian9 andin [8] κ B by interleukins 36B byinterleukins α , β and γ IL36RN , byto, binding IL36RN gene,

Accepted Article This by is protectedarticle reserved. Allrights copyright. with GPP andheterozygous personswith total, In in can alsooccur 10 patients than singleheterozygous mutations. more found that about 93% with of patients GPP ofand features ACH had a damaging withoutpatients PV and 17% inGPP with PV Finally, [15]. aninteresting study China from pattern was confirmed by aEuropean study finding mutations in lack disease be onsettends and higher[11] to systemic less inflammation inthose whofrequent statusMutation hasalso been found correlate to withclinical phenotype,as the age of assomecontroversial, studies noassociation all atwithPPPfound [13]. 20%[11], ACHand of 2% PPP of cases [12]. The however, is latter, somewhat found inboth European and Asianpopulations, and approximately account for GPP 25% of the Infevers database(http://fmf.igh.cnrs.fr/ISSAID/infevers/) [10].These disease alleles are p.Glu112Lys, p.Ser113Leu, p.Thr123Arg, p.Thr123Met andp.Gly141MefsX29) andlistedin p.His32Arg, p.Lys35Arg, p.Arg48Trp, p.Pro76Leu, p.Glu94X, p.Arg102Gln, p.Arg102Trp, since been mutations have uncovered (p.Arg10X, p.Arg10ArgfsX1,p.Leu27Pro, p.Leu21Pro, confirmed by by confirmed individuals European of but descent innot Asian Potential patients. clinical relevancewas (c.11T>G[p.Phe4Cys]c.97C>T and [p.Arg33Trp]) wereidentified inGPP ACH/ or PPP exact expression pattern of promotestrafficking vesicular between trans-Golgithe and network endosomes.the The adaptor protein complex 1 (AP-1), which is an evolutionary heterotetramer conserved that Another gene involved in GPP, PPP and ACH is adaptive immunity plays in PP. inWhilst is PV this followed by anadaptiveimmune it response, whatremains unclear role bimodal ofmodel immune in activation psoriasis acting [20], as autoinflammatory factor. IL-36 isclose IL-1to hasthat beenimplicated as the early in pathogenetic mechanism the relation or overlap with PP. found in some cases 19][18, of pustularthe drug rash AGEP, which couldsuggest a close by additionala at mutations second locus[17]. Heterozygous Although mutation [16]. of downstreamof signaling. pattern-recognition receptor TLR-3 (Toll-like 3) receptor and resulted in inhibitiona marked IL36RN IL36RN defects. Also,ofGPP 82%patients who sufferfromconcomitant PV had didnot IL36RN AP1S3 alleles are mostly inherited in an autosomal recessive the fashion, disease compared to 10% of those affected by GPP with PV [14].The same silencing that disrupted silencing the that translocation endosomal theinnate of AP1S3 IL36RN in skin is at yet unknown.in Twoskin isat changes have been reported, whichhaveexplained beenreported, changes couldbe AP1S3 IL36RN [21]. It encodes a subunit of thea subunitencodes of [21]. It in46%mutations GPP of IL36RN AP1S3 AP1S3 alleles were also founder mutationsfounder IL36RN

Accepted Article The condition known today as observations. current understanding conditionsof these has drifted somewhat away these from first (Table 1).This prompted us reviewto the first descriptions PP, of which revealed ourthat discrepancies on subtypes, localizations, pain, presence of arthritis and other features reviewedstandarddefinitionsWe PPof in dermatology the several and textbooks found Historical considerations described inPP are gain-of-functionresultin changesabnormal which of activation NF-kB. role and inapoptosis NF-kB signaling. The two (p.Glu138Ala mutations and p.Asp176His) playprotein that a complexes CARD of aggregation mediates 14.It family,domain member This by is protectedarticle reserved. Allrights copyright. time upon time exposure tocold.Theto patient suddenly developed lesionred andpainful a the conditionas Raynaud’s The phenomenon. earstoes, and nose were also affected from infancy, patientthe had suffered repeatedly with peripheral hypoxia. Hallopeau interpreted glove maker, shortly Radcliffe-Crocker after had described similar cases in 1888 Since[28]. Hallopeau of continua Acrodermatitis definitionprompted the distinct of conditions [25, below).(see26] streptococcal has infection been as noted provocative a Somefactor. of these havetriggers pregnancy, withhypocalcaemia associated hypoparathyroidism, and drugs.Especially GPPtrigger pyrogallic other factors for namelythan acid wereidentified, infections, occurred.flares Subsequent descriptions of GPP featured many without patients PV. Also, obvious causes.Theeruptions paralleled activity psoriasis.Ina the 10years, period of of 9 withassociated pyrogallic the acidtreatments, subsequently they re-occurred without gave way topeelingand desquamation. Even though the first attacks were temporally becoming the attack was lived, skin paleras inflamed pustules Each the inflammation. short almost universal andconstantly by accompanied (40°C) fever and other signsof systemic oedema, which becamethen studded with multiple (Figurepustules 1a). The wereflares applications. Subsequently, they developed recurrent episodes of bright erythema and von Zumbusch Two[24]. siblingswith PV stable hadbeen treated withpyrogalIic acid [23]. CARD14 CARD14 [10, 22] mutations have alsobeen infound GPP and PPP [13] as well asin PV is also localized is inkeratinocytes and encodes the for caspase recruitment generalized pustular psoriasis (ACH)[27] wasdescribed in 1890 ina69 year old was described by Leopold Accepted Article This by is protectedarticle reserved. Allrights copyright. nowadays call“ Sometimes, wephenomenon plaques(apresent. developedwithin pustules psoriatic yearsassociation wasoften 74 a and familial 7to of from varied onset it.Theprecede ageof series ofin patients great detail. Heobserved that PV is often associated PPP andwith can Barberpsoriasis.pustular at Dermatology John’s Institute St[7]of a describedin London Palmoplantar pustulosis generalize and overlap with GPP. localized andunilateral siteeruption the spreads” extremityon either as the a digit, aninfected of sore, or traumatic asa From whitlow. this fingersand (Figure 1b) toes. Barber stated “true butvascular component seeminglyrather distal ofspontaneous neutrophilinflammation the might have led to inflammation.the Other authors’ later descriptions did not include a Raynauds’of the attacks thisdiscussioncasethat and he phenomenon inhis suggested that pustular lesions were causallyto connected hyperaemiathe that he had observed after pulmonary congestion, the pustules resolved briefly. Hallopeau interpreted his observation The was oral mucosa involved aswell. Interestingly, during a period influenza of and involve whole the body withsheets of pustules that only abated after a period of 6 months. toenails and periungual the were tissues greatly The inflamed. diseasethen spread to developed on the nail, representing subungual pus. Subsequently, the patient lost several presentation, the patient’s toe nailturned red and whitish islets with polycyclic borders the cyanosis. This inflammation atstarted the of matrix the nails.Months after the first theon palm, as well aspurulent inflammation of the same fingers that had been affected by beneficial in PPP measure On [30]. theother hand, hestrictly ACH apart set from GPP / triggeredLater byit infection. streptococcal was tonsillectomy isathat substantiated conditions, lesionswith mixed both of features occurrencefamilial conditions, and onset that PPP isapustular of psoriasis and form as evidence theco-incidencecited two the of pustular.pus wasat first serous Invariably,He wasand not sterile. convinced the is the fluid brownish (Figurescabs 1c) that subsequently Barber exfoliate. alsonoted sometimes, that theyleavenota visiblecavity behind. pustulesevacuated,are When the up and dry form ofmicroarchitecture upon and epidermis the pus, the evacuationof that the inPPP pustules and upwards around the ankles. He observed that the neutrophilic infiltration destroys the also lateral on the surfaces of the hands and feet, on wrists,the overthe Achilles tendons, PPP, as shown in Supplementary Table 1. psoriasis cumpustulatione (PPP) is the most common of the three archetypical forms of of forms archetypical three the of common most the is (PPP) ”, or ‘psoriasis withpustules’). developedPustules acrodermatitis continua velperstans acrodermatitis

[29]. Also,[29]. in ACH patients some tends to begins Accepted Article This by is protectedarticle reserved. Allrights copyright. The drug-triggered Uncommonforms ofPP The suggesting35], [34, that andGPP areIH disease. thesame pregnancy. remits post-partum. It Some have cases been to have found described in 1872 by vonHebra and a is generalizedpustular eruption anytime during arefever present. The anti-streptolysinare titers elevated. skin, with acral predominance. Leukocytosis andsometimes leukocytoclastic vasculitis and AGEP [25,32, 33]. PAG produces scattered subcorneal pustules with red halo on normal AGEP 19, [18, 31]. GPP,similar to and recently same in the mutations Many the of pustuloses described over years the exquisitely are rare, to point the that their part syndrome’sclinicaltrigger acomplex of being a orfor factors, manifestation.specific were thoughtto considerationmerit asseparate entities basedon a distinct phenotype, possible associated clinical features. The comprisepustuloses a variety of conditions that beeninvolveall skin, the areas of described have allinage groupsa wideand have rangeof (Table 2),and all three PP types canbe classified in this list aswell. conditions These can pustuloses. At least29 primary different have been pustuloses over described theyears cause and remain sterile (Figure 1d). The latter are the central observedfeature in primary as a response bacterial, to viral or infection,fungal but theycan also withoutform apparent There aremany painstakingand comparison concludedACH. condition isidentical that [40], with this generalized. fingernails,but neverloss of indeed ledtoand became detailedain Barber, to be elicited by injury. This condition,comparably toACH,affected thefirst nail apparatus onnoted he fingersthat the slowly a He [39]. patients erosive dermatitis thought progressing forgotten today is Radcliffe-Crocker’s the fever sets it apart from palmoplantar pustulosis 38]. [37, A condition that isalmost andTheinvariablethesudden infection associationincluding streptococcal with onset, fever. withoutpustules erythema or scale [37] and occurs together with systemic symptoms described everyyears. few theIt affects tense palms and soleswith multiple monomorphic is exquisitelybutusually be thethroat.by continues rare infection, to It of streptococcal existence has been discussed controversially. pustular bacterid other pustuloses acute generalized exanthematous pustulosis Pustulosis acuta generalisata acuta Pustulosis [36] [36] that was by identified Andrews andMachacek is also triggered exist that partially that exist withor ACH overlap PPP. GPP, [41] not Pustules candevelop associated with psoriasis. dermatitis repens dermatitis (PAG) is clinically to related GPP and IL36RN thathedescribed in1888 three Impetigo herpetiformis were found in some cases ofcases some in found were (AGEP) is clinically very IL36RN mutations (IH) was was (IH) Accepted Article This by is protectedarticle reserved. Allrights copyright. representing thedermatological perspective Francefrom (Saurat 3 Four widely were used textbooks chosenas of sources of PPclinical descriptions wellas literature in textbook-derived and simple universally applicable criteria. diagnostic of finding consensus on phenotypic descriptions PPof and condensing the peer-reviewed as as a“corephenotyping was These(FC) agenda met group” with experts invited. the specific as experts PPfor wereasked to participate (LP, AN,AC). UM, ADB, Inaddition, ageneticist Identification expert of 5 Among group: representative Europeancountries, clinicians known Determination of consensus criteria: Methods numberof asufficient of PP patients. phenotypes andlatervalidation oradaptation of these definitions by evaluation prospective completelynot This a suggests clear overlap. need unmet aconsensusfor definition of Taken together, it isnot surprising that the first descriptions of PP and laterobservations do understanding of these conditions. Membership is free and allows access to several toolstotheseunderstanding ofallows andto several conditions. Membership is free access of liquid and standard biopsies (esp. DNA) to achieve better clinical and pathophysiologic patients. Its aimsmain areharmonization phenotyping of PPofacross Europeand collection ERASPEN (www.eraspen.eu) is an open, collaborative network for clinicians caring for PP ERASPEN network and membership: of the consensus core group. integrated in a revised version of the diagnostic criteria, again based on unanimous Diagnostic criteria were circulated within wider ERASPEN the network and were comments and diagnostic criteria for PP. A consensus level 100% of was both required and reached. or her view. The group then discussed all points and finally defined consensus definitions most relevant phenotypingfor ofPP and subsequently contributed all relevant points inhis was a nominal modified group process. Eachexpert prepared onepre-defined aspect main collectively togenerate consensus diagnostic criteria. The method to generate consensus synonyms. Clinical and features photographs of typical and atypical cases were reviewed features” in“pustular psoriasis acrodermatitis / continua / In preparation for the literaturethe medicalmeeting, was searched for “phenotype /clinical Ed. [2]), Germany (Braun-Falco 5 th Ed. [1]) and USA (Fitzpatrick 8

palmoplantar pustulosis”and th Ed. [3,4]). rd Ed. [5]), UK (Rook 9 th

Accepted Article This by is protectedarticle reserved. Allrights copyright. 10 12x > (WBC used Americanthe Society of Chest Physicians of definition fever >38°C and leukocytosis NationalbydefinedHealth U.S. for For Center the Statistics. systemic we inflammation, Fordetectable. chronic disease, thresholdthe of 3 durationmonths of lesions was usedas scabs are considered evidence pustulation of insituations when no fresh pustules are infection. Pustules dryingout maybrownish form are thatscabs slowly off.Thesecast brown superinfected dyshidrotic not but eczema, pustules by triggered streptococcal adistant ofnot part PP.form This in bullous or impetigo instance for includespustules in Pustules in PP are considered primary whereas lesions, non-sterile secondary pustulesdo of PPPrimary shouldbeconsideredconditions includingallrelated diseases.forms pustular naked eye the with compatible arebut withwith PP, also other conditions PV. including granulocyteswith (notpredominating) without or Verynot eosinophils. visible small pustules arePustules macroscopically epidermal or visible subcorneal of accumulations neutrophil terminology andDiagnostic criteria of pustular psoriasis: Results: infrastructure. database are anonymized. The sponsor-PI (AN, JB) are responsible for the ERASPEN level, andalldata shared on theEuropean level inERASPEN’s electronic core clinical collect data and collaborate with others. Ethical permissions are onmanaged the national microabscesses ofmicroabscesses Munro. However, primary pustulesdonot partform the of spectrum of distinct entity hasthat neutrophilat the PVincludingis a granulocytes microscopic level, Relationship ofPV to PP: without plaque psoriasis, relapsing type’. clinical diagnosis be ‘generalisedmight pustular psoriasis, with inflammation,systemic presence or absence of associated features (see Table 3).Thus instance for a complete validated further by subtype otherstudies. Each PP on the thebasisof of issub-classified groupings based on robust evidence will bedefined by the ERASPEN consortium and utility. The should terminology not be abandoned lightly, butonly when new clinical still but andis insufficiently ACH as psoriasis GPP, hasclinical of PPP evidence-based As to terminology PP of subtypes, expert the groupagreed that the mostlyhistorical labelling 9 /L) [42]. Accepted Article This by is protectedarticle reserved. Allrights copyright. descriptionabove givenconsideredmay ‘undifferentiated be primarypustulosis’. warrant creationthe of additionalentities. Cases that do notconform to the archetypal collected phenotypes will reveal whether some overlap patterns are sufficiently to frequent By consensus, theseare to be grouped by thepredominant feature. Later analysis of Aof largepart PP be is expected to with forms clinical ACHwith e.g. features, mixed GPP. Mixed forms: butconsidered ACHPPP rather undifferentiated or pustulosis. involved. It can occur with or without PV. Pustules affecting not the nail apparatus are not the nail apparatus, but by the experts’ consensus it is the key structureis that always sterile, macroscopicallypustules visible the affecting nailapparatus. ACHis not restrictedto ACH is a chronic condition that evolves slowly. It forms primary, persistent (> 3 months), Acrodermatitiscontinua Hallopeau (ACH): of developmentnew a of score to GPP severitywasmeasure noted. as thespectrum varies discrete from confluentneedHowever,anunmet to forms. for theAlso, expert groupactual decided against counting pustules of as aintensity,of measure can be triggeredby thisisnotfactors, provocative considered a criterion diagnosis. the for GPP AlthoughwithoutPV, andit known or that with orwithoutsystemic inflammation. is with months. Also, a drug reaction suchasAGEP should be actively GPP ruled out. can occur when leastonceor for diagnosed has relapsedat it persists 3than more the condition when psoriasis plaques characterise generalized psoriasis. GPP pustular shouldonly be Macroscopically visibleprimary sterile pustules occurring on non-acral skin and not within Generalized psoriasis: pustular agreed thatthis be shouldnot considered pustularpsoriasis. “ is used be to term the PV exceptwhen arisewithinpustules or at the edge of psoriasisplaques. In cases,these psoriasis cum pustulatione ” (psoriasis”All pustules). with experts Accepted Article This by is protectedarticle reserved. Allrights copyright. Generalized pustular psoriasis (A), Figure 1: legend: Figure CS and all others critically revised and added to the paper. AN wrote paper,FC, ADB, the LP, UM and AN the consensusdetermined JB,definitions, contributions: Author Psoriasis Association. HSM-2Foundation Kanton and Switzerland. Zurich, of the from bysupported The FCis andVenereology toANandJB. (EADV) ANissupported byBruno Bloch the and Promedica ERASPEN issupported by a PPRC grant from the European Association of Dermatology Acknowledgements: insolidadvances thisfieldwithin arereach. our However, by efforts combining and studiespoweredmulticentre by data efficient collection, PV. availableas are newsystematicpotential treatments, for weareverytrials away far from that promise newgenetic findings with the PP. Eventhoughinterest isrekindled realm of trinity GPP, ACH of and PPP. Inaddition, some other entities [18] be added might to the mutations seem to beenriched in phenotypes mixed well not captured by PP ourtraditional Research on PP is still its at beginning.Revision of the genetic findings reveals that some Discussion and outlook: eruption that would be classified as undifferentiated pustulosis (D). (C)pustulosis and an unclear case a of single episodeof a sterile, localized pustular Acrodermatitis continuaAcrodermatitis Hallopeau (B),Palmoplantar Accepted Article This by is protectedarticle reserved. Allrights copyright. Table1: Textbook definitionsof pustular psoriasis Table 2: Pustular dermatoses (historical classification)

Acrodermatitis Palmoplantar pustulosis Generalized pustular psoriasis continua suppurativa Smoking Feet Palms, Pain Atrophy Finger > Toes Subtypes Trunk Localization pustules Sterile Fever Pain Pain Pustules + + + + + + + Pustules Nail + + + + + + loss Pustules Inflamed skin + + + - Nail + + + loss intertriginous Localization (+) - (+) - (+) Arthritis pustules Generalized Falco 5th Braun- Ed. + + + + + + + + + + + - ? - + (+) + + + + 2 [1]

[2] Ed. 9th Rook + + + + + + + ? ? 4 Fitzpatric k 8th Ed. [3, 4] + + + + + + + ? ? 4

3rd Ed. Saurat Saurat [5] + + + + + + ? 5 - -

Baker / Ryan [43] + + + 4

Accepted Article This by is protectedarticle reserved. Allrights copyright. Eosinophilic pustular folliculitis ininfancy Eosinophilic pustular folliculitis [55] Paediatric Generalized Andrew’s bacterid pustular [36] Paediatric Pustular dermatoses Localized

Adult Acute neonatal AcuteSyndrome pustulosis inDown [54] Transient neonatal pustular [53]melanosis Syndrome Syndrome Syndrome Syndrome Syndrome Syndrome Palmoplantar pustulosis Palmoplantar (PPP) [7] [45] Transient pustulosis neonatalcephalic Infantileacropustulosis [44] Acrodermatitis continua suppurativa pustulosa Parakeratosis Erythema toxicum neonatorum Erythema toxicum pustulosa cruris Dermatitis etatrophicans pustularErosive dermatosis scalp the of [47] Miliaria pustulosa (rubra) Keratoderma blenorrhagicum SAPHO-Syndrome [50] Amicrobial Oberlin[49] intertriginous pustulosis Dermatitis repensDermatitis Radcliffe-Crocker [39]. [46] [46] [56] [51] [52] Hallopeau [27] [48] Accepted Article This by is protectedarticle reserved. Allrights copyright. Eosinophilic pustular folliculitis [65] Eosinophilicpustular folliculitis

Intraepidermalneutrophil [62] IgA-Dermatosis Acute generalized exanthematous pustulosis [61] GeneralizedZumbusch psoriasis von pustular [60] Adult Syndrome Syndrome Syndrome Syndrome Syndrome Pemphigus vegetans Impetigo herpetiformis Erythema anulare Pustulosis subcornealis Pustulosis acuta generalisata Acrodermatitis enteropathica Incontinentia pigmenti Congenital Langerhans-cell histiocytosis [57] -like psoriasis [64] [41] Bloch Sulzberger [58] [58] Sulzberger Bloch [26] Sneddon [63] Wilkinson [59] [25] [25] Accepted Article This by is protectedarticle reserved. Allrights copyright. Subclassifier: apparatus Primary, persistent (> 3 months), sterile, macroscopically visible pustulesaffecting the nail Subclassifier: soles Primary, persistent (> 3 months), sterile, macroscopically visible pustuleson palms and/or Subclassifier: Subclassifier: pustulation isrestrictedpsoriatic toplaques) Primary,non-acral sterile, skin (excluding where macroscopicallyon pustules cases visible Generalised Pustular Psoriasis: Table3: Consensus definitions forthe diagnosis of pustular psoriasis with or without psoriasis vulgaris Subclassifier: Acrodermatitis Continuaof Hallopeau: Palmoplantar Pustulosis:

with with or without psoriasis vulgaris with or without psoriasis vulgaris either relapsing (>1 episode) or persistent (> 3 months) with or without systemic inflammation

Accepted Article This by is protectedarticle reserved. Allrights copyright. Y, Shoda J InvestDermatol. 2013. ReceptorAntagonist. Interleukin-36 H, Takahashi M, Yamaguchi A, Takemoto Vu Psoriasis K, without PsoriasisPustular Generalized Majorityof Sugiura [14] 2541. In J Patients. European IL36RN in in Mutations Loss-of-Function Var Missense with Associated Is Psoriasis Pustular Palmoplantar [13] Mossner 1366-1369. 2013;133; Dermatol. Invest J R, Frambach spectrum of psoriasis- a inIL36RNpathogenic underlie variants Setta-Kaffetzi[12] Y, Aroste Wilsmann-Theis MH, Allen N, general AD, of Navarini Burden Allergy Clin Immunol. 2014. phenotype SE, autoinflammatory Choon severe DM, a Berki define S, AA, mutations Hussain Patel VM,[11] Pullabhatla D, Lohr V,pustulargeneralized of and CARD14background gain-of-function genetic variants. J DermatolThe Sci.2014;74; K. Sugiura Pi S, Jacobi[10] Fraitag XY, A, Pei A, Puel BR, 628. Renshaw P, Guigue S, Marrakchi psorias pustular generalized and deficiency antagonist receptor [9] Genetics.Human 2011;89; 432-437. Associated Are IL36RN/IL1F5 Known Disease Skin in Inflammatory Mutations al. et V, Pullabhatla On[ o 8 u ] f r i a d119. i Barber s Fran A and , abscess, HW. S[7] Munro's i Pustular and m Munro p John s William o C. psoriasis n Steffen Mspongiform pustule. AmericanThe Journal ofdermatopathology. 2 i c h of a the[6] e extremities. l Navarini AA, Borradori L, Saurat JH. Dermatologie - Pustulo A , P i[5] Guy's n k - A Medicine Hos n General in d Dermatology Fitzpatrick's r U. Mrowietz e wpalms and soles. 8thed.2012. E , D[4] i M e g lElderinGenera GudjonssonDermatology JT. Fitzpatrick's J, i2012. o [3] Burden AD, Kirby B. Rook's D [2] ChristophersE, Mrowietz U.Dermatologie. 6th ed. 2005. 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