Frontiers in Dermatology and Venereology - a Series of Theme Issues in Relation to the 100-Year Anniversary of Actadv

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 Cutaneous andgenitalinfections Atopic dermatitis Skin malignancies Genodermatoses Forthcoming issues Blistering skindisorders Current issue • • • • • • • • • • • • • Genetics ofInheritedIchthyosesandRelatedDiseases, Kambe, G.Kokolakis,K.Krause Bullous DrugReactions, Current ConceptsofDermatitisHerpetiformis, Drug DevelopmentinPemphigoidDiseases, Den An EarlyDescriptionofa“HumanMosaic”InvolvingtheSkin:A Ichthyosis: A Collagen XVIIProcessingandBlisteringSkinDiseases, Skin Fragility:PerspectivesonEvidence-based Content detailsTBA Theme editors:RoderickHayandKristianKofoed Content detailsTBA Theme editors:MagnusLindber Content detailsTBA Theme editors:V Theme editors: Theme editor:KaisaT Molecular GeneticsofKeratinizationDisorders- Diagnosis andManagementofInheritedPalmoplantarKeratodermas, tal Man Centenary theme issuesinVolume 100of i f estations RoadModelforSkinResearch, Anette BygumandMatthiasSchmuth er onique BatailleandNicoleBassetSeguin of E asanen M. Mockenhaupt Frontiers inDermatologyandVenereology h ler s - Dan los g andCarl-Fr Syn d r omes K. Bieber A. V T Therapies, . Salmi,K.Hervonen What’ ahlquist, HTörmä – edrik W

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Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Blistering skindisorders Psoriasis Itch andpruriticdisorders Previous issues • • • • • • • • • • • Pustular Psoriasis:theDawnofaNewEra,H.Bachelez Psoriasis andCo-morbidity, M. Amin, E.B.Lee,T-F. Tsai, J.J.Wu Psoriasis and Treatment: Past,PresentandFuture Aspects, C.Reid,C.E.M.Griffiths The Woronoff RinginPsoriasisandtheMechanismsofPostinflammatoryHypopigmentation,J.Prinz Psoriasis andGenetics,N.Dand,S.Mahil,F. Capon,C.H.Smith,M.A.SimpsonandJ.Barker 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 editors:LoneSkovandEniköSonkoly Theme editors:ElkeWeisshaar, Tasuku Akiyama andJacek Szepietowski Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Bullous DrugReactions,M.Mockenhaupt Current ConceptsofDermatitisHerpetiformis,T. Salmi,K.Hervonen Drug DevelopmentinPemphigoidDiseases,K.Bieber, R.J.Ludwig Collagen XVIIProcessingandBlisteringSkinDiseases, W. Nishie Skin Fragility:PerspectivesonEvidence-based Therapies, L.Bruckner-Tuderman TABLE OF CONTENTS BLISTERING SKINDISORDERS Kaisa Tasanen Theme Editor: 122–134 102–107 115–121 108–114 94–101 Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV doi: 10.2340/00015555-3398 Table I.Differentialdiagnosisofskinfragility nosis is broad (1) (Table I). As ageneticskinfragility be described using this term, and the differential diag cesses. Correspondingly, manyclassesofdisorderscan T freiburg.de DE-79104 Freiburg, Germany. E-mail: bruckner-tuderman@uniklinik- Faculty and Medical Center – University of Freiburg, Hauptstrasse 7, Corr: Leena Bruckner-Tuderman, Department of Dermatology, Medical Acta DermVenereol 2020;100:adv00053. Accepted Dec18,2019;EpubaheadofprintFeb 6,2020 symptom-relief. Key words: skin blistering; genodermatosis; molecular therapy; status andperspectivesforclinicalimplementation. tive andsymptom-relief therapies,andappraisestheir to approaches als. Thisarticlereviewsdifferent cura preclinical validation inanimalmodels, and clinicaltri developmentextends from invitro process evidence-based therapeutic strategies.Thetherapy on its pathophysiology, and facilitated the design of lysis bullosa group, delivered ample new knowledge led substantial genetic heterogeneity of theepidermo of skinfragility. biomedical hasrevea Recent research as aparadigmforthestudyof causesandmechanisms orders, collectivelycalledepidermolysis bullosa, serve or physicalphenomena.Thegeneticskinfragility dis inflammatory to variations genetic from ranging ses, Department of Dermatology, Medical Facultyand Medical Center –University of Freiburg, Freiburg, Germany Leena Skin Fragility:PerspectivesonEvidence-basedTherapies Centenary theme section:BLISTERING SKIN DISORDERS forces diminished.Skin fragility can have different cau is compromised andits resistanceto externalshear conditions the structural inwhich integrity of the skin a groupofThe termskinfragility disordersdescribes Acta DermVenereol 2020;100: adv00053 physical, mechanical,infectious,ordrug-inducedpro from genetic variations to (auto)immune, inflammatory, factors thatcancauseskinfragilityandblisteringrange dermal–epidermal junction,orintheupperdermis. The in different skinlayers,withintheepidermis,along friction, pressureortrauma. The breakagecanoccur • • • • • • • • Physically induced skin fragility Mechanically induced skin blisters Bullous drug reactions Metabolic conditions with blisters Skin fragility induced by acute inflammation Skin fragility induced by infections Autoimmune blisteringdisorders Genetic skin fragility disorders red skinthatblistersandbreakseasilyuponmild he termskinfragilityreferstopathologicallyalte BRUCKNER-TUDERMAN This isan open access article under the CC BY-NC license. www.medicaljournals.se/acta testing to REVIEW ARTICLE ------types isbasedonthemorphological levelofseparation and Kindlersyndrome(6)( Table II). The divisioninto (EBS), junctionalEB(JEB), dystrophicEB(DEB), The EBgroupencompasses 4maintypes:EBsimplex Epidermolysis bullosaclassification current diagnosticsandmanagementfollows. therapy developments,ashortintroductiontoEB,its the designanddevelopmentoftherapies. than anticipated; afact that has major consequences for unleashed bymechanicalstressonEBskinisfargreater ever, thecomplexityofcellularandmolecularprocesses explains all symptoms still holds true in principle. How sumption thatasinglepathogenicgenevariant/mutation rather wellunderstood(1–3). The initialsimpleas and diseasemechanismsofthedifferent EBtypes are EB hasbeenstudiedintensively, andthegenetic causes TIC SKIN FRAGILITY DISORDER EPIDERMOLYSIS BULLOSA AS APARADIGMA bullous disorders(4,5). diagnostics, managementandmonitoringofautoimmune of moleculardiagnosticteststhatareinstandarduse acquired blisteringdiseaseshasledtothedevelopment example, molecularcharacterizationofautoantigensin of skin fragility that is clinically relevant (2, 3). For delivered newinformationaboutthepathophysiology paradigm forthesedisorders,andresearchintoEBhas disorder, epidermolysisbullosa(EB)servesasauseful developments and appraises theirclinical implementation. new these reviews article This symptoms. its alleviate and search is developing novel approaches to cure the disease the disease. No cure is yet available, but international re worsen can fibrosis, or inflammation as such phenomena, may be involved in epidermolysis bullosa, and secondary ding of their causes and mechanisms. At least 20 genes as epidermolysisbullosa, have provided better understan reactions. Studies of genetic skin fragility disorders, such compromised immunesystem, infections oradverse drug can have many causes, ranging from genetic variants to a breaks easily upon mild friction or trauma. Skin fragility The term skin fragility describes skin that blisters and SIGNIFICANCE As backgroundforthediscussionandappraisalof Journal Compilation ©2020ActaDermato-Venereologica. - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV DEB. (F)Trauma-induced blistering, inflammationandscarringontheshinsofa12-year-oldgeneralized girlwithmoderatesevere DEB. with girl 8-year-old an of hand the in digits of fusion and scarring Strong (E) (DEB). EB Dystrophic F) (E, JEB. generalized severe and loss of nails in the hand of a 7-year-old girl with moderate JEB. (D) Typical extensive skin fragility in the buttocks area and back of a newborn with erosions Blisters, (C) (JEB). EB Junctional D) (C, newborn. a of extremities and trunk the 2-year-oldon a of blisters footDisseminated the (B) in child. types ofepidermolysis bullosa(EB). Fig. 1.Typical clinicalpresentationsindifferent cision aspossible,isrecommendedforallpatientswith pre molecular much as with A diagnosis, well-defined Modern diagnosticsofepidermolysisbullosa syndromal EBsubtypeswithmulti-organ involvement. as EB. The new classification includes for the first time were clearlyregardedasskinfragilitydisorders,butnot group, butalsomilddisorderswithminimalskinfragility, in thepast5years.Someofverysevereformsthis related to the EBS group that has expanded significantly tion paperisinpreparation(6). The mainchanges are classifica new the classification; consensus the revised in London.Expertsfromallovertheworldupdatedand national EB consensus classification meeting took place vary toagreatextent(Fig.1).In April 2019,aninter skin lesionsandtheassociatedorgan manifestationscan contains anumberofsubtypes,inwhichtheextent induced skinblisteringandfragility, buteachofthem levels. A commonhallmarkforallEBtypesistrauma- membrane. In Kindler syndrome, blisterscan form at all sement membrane,andinDEBjustbelowthebasement blisters formwithintheepidermis,inJEBba within the dermal–epidermaljunctionzone. In EBS,the Table II.Majortypesofepidermolysisbullosa(EB) *The blisteringcan occur at any or all of theabove levels. Kindler syndrome (KS) Dystrophic epidermolysis bullosa (DEB) Junctional epidermolysis bullosa (JEB) Epidermolysis bullosa simplex (EBS) EB types (abbreviation) Level ofblistering Mixed* In the upperdermis Along the basement membrane Intra-epidermal - - - - including psychosocialcare,arehighlyrecommen interdisciplinary andmulti-professionalmanagement, of lifetheaffected individualsandtheirfamilies, skin fragilityandpainfulwoundsdiminishthequality organs iscommoninmoresevereEB,andsincechronic guidelines). Furthermore,sinceinvolvementofother (http://www.debra-international.org/clinical-guidelines Different wound management modalities are defined in and moisturizingtheskinbelongtodailybasicmeasures. on needs.Protectionfromtrauma,cleaning, disinfecting, of symptomatic treatment modalities is used, depending Since thereiscurrentlynocureforEB,acombination Current diseasemanagement are recommended(7). gene panel-based diagnostics or clinical exome analysis, generation sequencing(NGS)technologies,suchasEB sive clinical presentation, genetic diagnostics using next complete-eb-guidelines.html). ded (www.debra-international.org/clinical-guidelines/ for subsequent genetic analysis. In cases with inconclu gene(s) candidate of definition and level blistering the of identification enables this step; first a as biopsy skin a of mapping immunofluorescence involves procedure personalized therapies (8). The recommended diagnostic trials; it will also be needed for application of future diagnosis isoftenaprerequisiteforinclusioninclinical 8). Furthermore,asnoveltherapiesemerge, molecular including prognosticationandgeneticcounselling(7, EB. A cleardiagnosisfacilitatesdiseasemanagement, (A, B) EB simplex (EBS). (A) Blisters, erosions and scaling Evidence-based therapiesforskinfragility Theme issue:Blistering skindisorders 95 - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV EBS: EB simplex; JEB: junctional EB; DEB: dystrophic EB; RDEB; recessive DEB. Theme issue:Blistering skindisorders Table III.Currentlyrecruitingclinicaltherapytrialsforepidermolysisbullosa(EB)(asofJune2019) transversal approachfocusingonteachingandtraining, a on high-levelpatientmanagementandresearch;(ii) taken: (i)adiseaseapproachwith8sub-thematicgroups ERN-Skin (https://ern-skin.eu/). Two approachesare knowledge andexpertisewithintheframeworkof by theirnationalauthoritiesandcommittedtopool healthcare providers from 18countries who are endorsed supportive environment.ERN-Skinencompasses56 who should have the comfort ofstaying at home in their knowledge andexpertise“travel”,notthepatients, treatment. An importantprincipleisthatthemedical nes toevaluatethediagnosisofapatientandplan advisory board of specialists from different discipli dedicated IT platform,telemedicinetoolsandavirtual (https://ec.europa.eu/health/ern). The ERNsprovidea seases withaconcentrationofknowledgeandresources and research. The goalistotacklecomplexorraredi rare diseases for high-quality diagnostics, management, launched EuropeanReferenceNetworks(ERNs)for management plans.In2017,theEuropeanCommission agnostics togeneticcounsellingandinterdisciplinary and caregivers, aswell as services ranging from di The centresprovideinformationandadvicetopatients with thepatientgroups(www.debra-international.org). Clinet” (www.EB-Clinet.org), whichworkstogether of thesearememberstheEB-ClinicalNetwork“EB- Numerous expertcentresforEBexistworldwide.Most Expert centres andEuropean Reference Networks 96 Anti-hidrotic Anti-pruritic Analgesic Accelerator ofwound healing Anti-inflammatory Anti-fibrotic Symptom-relief therapies Cell therapy Regenerative cell-based therapies Protein therapy PTC read-through Antisense oligonucleotides Gene therapy Therapies with curative aim Therapy type L. Bruckner-Tuderman Botulinum toxin Neurokinin-1 receptor Antagonist, oral Ropivacaine, topical Amniotic membrane RGN-137, a thymosin beta-4 gel, topical Sirolimus, topical BPM31510 3.0% cream, topical Oleogel-S-10, topical use use Pharmacokinetics, safety of diacerein after maximum Losartan, systemic Epidermal grafts generated using the Cellutome System Allogeneic ABCB5-positive stem cells mesenchymal stemcells Allogeneic stem cell transplantation and ”off-the-shelf” related donor Serial mesenchymal stemcell(MSC)infusionsfrom a PTR-01, recombinanthumancollagenVII Gentamicin, topical Gentamicin, intravenous QR-313, topically applied antisense oligonucleotide human collagen VII protein. human collagen VII protein. incompetent herpes simplex virus vector expressing KB103, topically appliednon-integrating, replication- dermal fibroblasts FCX-007, Genetically modified autologoushuman Genetically corrected cultured epidermal autograft cultured epidermal autograft Transplantation surgeryof genetically corrected Investigational drug - - - quality oflife. The therapiesthathavereachedaclinical cure, willalleviatesymptoms,offer reliefandimprove regenerative therapiesthat,althoughtheydonotbring the focushasturnedtoso-calledsymptom-reliefand more rapid development of treatments that bring relief, and translationarebeingtested.Becausepatientsdemand replacement, geneediting,andmodifyingtranscription Therefore, avarietyofmethodologiesrelatingtogene stem cells,achievinglong-termtherapeuticeffects, etc. technological challengeswithvectors,targeting skin faces development therapy Gene expected. than ficult with “intentiontocure”arefarmorecomplexanddif progresses it becomes clear that therapy strategies cure-EB.org). debra-international.org; www.ebresearch.org/, www. priorities andfundingpatient-orientedresearch(www. patient advocacygroups,whichareveryactiveinsetting Development of new treatments is strongly promoted by and novelevidence-basedtherapiesareurgently needed. rare skindiseases,theunmetmedicalneedremainshigh, of field the in developments structural the all Despite EMERGING NOVELTHERAPY APPROACHES deals withEB. clinical outcomes.Oneofthe8sub-thematicgroups E-health, registries and research, deep phenotyping and EBS All EB types All EB types RDEB JEB, DEB EBS All EB types All EB types EBS RDEB EB after hematopoieticcell transplantation RDEB* All EB types All EB types RDEB* JEB RDEB* DEB with mutationsinexon 73 of COL7A1 DEB RDEB* RDEB* JEB withCOL17A1mutations EB type As thetherapeuticeraforskinfragilitydisorders ClinicalTrials.gov ID: NCT03453632 ClinicalTrials.gov ID: NCT03836001 ClinicalTrials.gov ID: NCT03730584 ClinicalTrials.gov ID: NCT02286427 ClinicalTrials.gov ID: NCT03578029 ClinicalTrials.gov ID: NCT03016715 ClinicalTrials.gov ID: NCT02793960 ClinicalTrials.gov ID: NCT03068780 ClinicalTrials.gov ID: NCT03472287 EudraCT No.: 2015-003670-32 ClinicalTrials.gov ID: NCT02670837 ClinicalTrials.gov ID: NCT03529877 ClinicalTrials.gov ID: NCT01033552 ClinicalTrials.gov ID: NCT02582775 ClinicalTrials.gov ID: NCT03752905 ClinicalTrials.gov ID: NCT03526159 ClinicalTrials.gov ID: NCT03392909 ClinicalTrials.gov ID: NCT03605069 ClinicalTrials.gov ID: NCT03536143 ClinicalTrials.gov ID: NCT02810951 ClinicalTrials.gov ID: NCT02984085 ClinicalTrials.gov ID: NCT03490331 Trial identificationnumber - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV phenotype inEBSkeratinocytes. The corrected kerati the onewithaKRT14mutation,tocorrectcellular cing-based approach7exons werereplaced,including exons attheRNA level.Inan exvivoRNA trans-spli Different approachescanbeusedtoskiporreplace RNA-based therapies remained foratleast76weeksoffollow-up(20). patients. The take was55–87%,andtheclinicaleffects revertant skinwereappliedtotreatDEBwoundsin 3 cultured epidermalautograftsgeneratedfromclinically split-thickness revertantgrafts(19).Morerecently, EB wasreported,JEBskintransplantedwithsmall of treatment therapy”-based gene “natural first the ago, found byawell-trainedexpert. Approximately 5years classic EBtypesrevertantmosaic skin patchescan be is relativelycommoningeneticdisorders,andmost gained anormalphenotype(18).Revertantmosaicism that hasacquiredasecond,compensatingmutationand with amutationandpathologicalphenotypeintocell saicism, i.e.thespontaneousconversionofasomaticcell The term “natural gene therapy” describes revertant mo Natural genetherapy outcome marker(Table III). treatment of DEB addresses wound-healing as a primary keratinocytes/epidermis, and a pilot trial usingtopical (www.krystalbio.com). The vector preferably targets virus 1(HSV-1) vectorexpressinghuman collagen VII non-integrating, replication-incompetent herpes simplex (14–17). A newlyintroducedtechnologyemploysa cells gene-correctediPS with approaches encompass vitro and at a preclinical level. Further research strategies RDEB keratinocytes (12) and RDEB fibroblasts (13) has shownpromiseincorrectingCOL7A1mutations cells. GeneeditingusingtheCrispR/Castechnology stem of efficiency transfection/transduction optimal to with technologicalissuesrelatingtovectorsafetyand However, the classical gene therapy approaches still deal durable wound-healing(www.abeonatherapeutics. com). gene corrected keratinocyte grafts,many of themhave 7 patientswithRDEBhavebeentreatedCOL7A1- in DEBformaintenanceofwoundhealing(11). Sofar, child with JEB (9,10). A similar approach is being tested proximately 80%ofthe skin surface in a very severely ill therein). Recently, thismethodwasusedtoreplaceap method totreatJEBorDEBskin(9,10andreferences aprincipallyvalid was developedmanyyearsagoas subsequent graftingofgene-correctedepidermalsheets genecorrectioninkeratinocytesand Retrovirus-mediated Gene therapies marized inTable III. trial stageandarerecruitingparticipantssum in - - - - - Premature terminationcodons (www.wings-tx.com). mutations specific carrying patients DEB in approach phase 1/2 multicentre clinical trial plans to test this potentially improve DEB skin functions (22, 23). A leads toapartiallyfunctionalcollagen VII thatcould antisense oligonucleotide-inducedskippingofexon73 number ofmutations.Invitro experimentsshowedthat VII geneisinteresting,sinceexon73harboursahigh in theaffected protein.OftheEBgenes,collagen deletion isnotlikelytocausemajorstructuralchanges collagen genesaretypicallyin-frameandsmall. Their are particularlysuitableforthisapproach,sinceexonsof this is usually at least partly functional. Collagenopathies sequence encodedbytheskippedexonissynthesized; Subsequently, apolypeptidethatlackstheaminoacid to skipthemutatedexonintranscriptionprocess. Another optionistoemployantisenseoligonucleotides could havepotentialforclinicalimplementation(21). RNAindicating thattrans-splicing-mediated therapy nocytes formedastableepidermisinxenograftmodel, ture oftheirphysiologicalfunctions, haveatendencyto (collagens, laminins,keratins) arelarge and,bythena many oftheproteinsthat are mutatedand/ormissing of metabolism(29).Incase ofEB,thechallengeisthat have beendesignedandtested forseveralinbornerrors Protein therapies,inparticularenzymereplacements, Protein therapy production (28). with PTC mutations, it induced collagen VII protein through. read- PTC induce also can drug, anti-inflammatory an suppress PTCanditslowtoxicity(27). Amlexanox, be superiorinthiscontextduetoitshighpotency a minor gentamicin constituent, has been suggested to tency toinducecontactsensitization.GentamicinB1, of adverse effects, such as renal and ototoxicity, or po challenge with this category of drugs is the spectrum in RDEBandtopicalgentamicinJEB(Table III). A the suitability andtolerabilityof intravenous gentamicin vitro andinvivo(25,26).Humantherapytrialsassess COL7A1 and for aminoglycosidetreatment.Gentamicinssuppressed the read-throughand,therefore,notallPTCaresuitable nucleotides of the mutations influence the efficiency of induce PTCread-through.However, theneighbouring to beadequatelyfunctional. Aminoglycoside antibiotics i.e. a polypeptide with a minor modification that is likely presumably generate afull-lengthtranslationproduct, Overriding the mutation during transcription would mediated mRNA decayisoftencausedbyPTC(24). codons (PTC)arosefromtheknowledgethatnonsense- The ideaofread-throughprematuretermination In vitro, incollagen VII-negative DEBcells Evidence-based therapiesforskinfragility mutations with some efficacy in efficacy some with mutations LAMB3 Theme issue:Blistering skindisorders read-through 97 - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Blistering skindisorders that producelarge amounts ofcollagen VII. Preliminary been modified with the use of gene-corrected fibroblasts or vehiclewasinjected(36). Recently, theapproachhas wound healing in DEB, regardless of whether fibroblasts (35). Onestudyobserveda comparable improvementof very painful andimprovementof the skinverylimited approach werepoorerthanexpected. were The injections in humans the tolerability and efficacy of this therapeutic junction andameliorateditsstability(32–34).However, ced collagen VII thathomedintothedermal–epidermal cells intoRDEBmicedemonstratedthattheprodu blasts orhumanbonemarrow-derivedmesenchymalstem Early investigations with intradermal injections of fibro Intradermal cellinjections tions arebeingtestedfordisease-modifyingcapacity. treatments. Currently, bothlocalandsystemic applica been re-groupedintothecategoryofdisease-modifying They areveryunlikelytobringcure,andhaverecently turned out to be more challenging than initially expected. From manydifferent angles,celltherapiesforEBhave Regenerative cell-basedtherapies repurposed drugs. pies; and(iii)systemictherapieswithbiomolecules cell-based therapies;(ii)topicalpharmacologicalthera relief therapiesaredelineatedbelow:(i make thepatientsfeelbetter. Three groupsofsymptom these treatmentsistoimprovefunctionsoftheskinand growth factorsthat drive EBphenotypes (8). The goalof for using cells or targeting, for example, cytokines or in vitro andpreclinicalstudieshavelaidthefoundation from basic research on disease mechanisms in EB. Many rationale forsuch symptom-relief approaches comes modify diseaseactivityandtoalleviatesymptoms. The community hasreactedbysearchingforpossibilitiesto sure from patients for treatments increases. The scientific years toentertheclinicsand,atsametime,pres 31). We realizethatcurativetherapieswillneedmany treatment-related issueshassurprisedmostscientists(8, development oftherapiesforEB,thecomplexity With increasing experience in preclinical and clinical DISEASE-MODIFYING APPROACHES phoenixtissuerepair.com). of recombinantcollagen VII inRDEB(Table III;http:// effects (30). A clinicaltrialiscurrentlytestingthesafety the dermal–epidermaljunction,withoutmajoradverse resulted inhomingofsomecollagenintotheskinand tions ofrecombinantcollagen VII inDEBmodelmice seems surprisingthatintravenousandintradermalinjec to therequiredsiteofaction. With thisbackgroundit intravenous administrationandhomingoftheprotein form aggregates. These characteristicsdonotfacilitate 98 L. Bruckner-Tuderman ) regenerative ------( relief inadultswithRDEBisassessedacurrenttrial subpopulation of mesenchymal stem cells for symptom- ABCB5-positive an of efficacy The (41). skin the into cells madethemfeelbetter, but broughtnocollagen VII administered humanallogeneicmesenchymalstem Treatment ofchildrenwithRDEBintravenously modulatory allogeneicmesenchymalstromalcells(40). transplant cyclophosphamideandinfusionsofimmuno that combines reduced-intensity conditioning, post- ning regimenshavebeentested,mostrecently aregimen life-threatening (39).Subsequently, different conditio gility induce expression of specific cytokines and T-cell- in EB.InEBS,keratinmutations andkeratinocytefra cascades inflammatory for role unanticipated an vealed followed bypreclinicaland clinicalvalidation,hasre approaches. Recentbasicresearch, Anti-inflammatory Systemic diseasemodifyingtherapies oleogel inpatientswithEB,regardlessofsubtype(48). placebo-controlled phase 3 study assesses the efficacy of wound healinginvitro andinvivo (46,47). An ongoing rentiation (45),enhancere-epithelializationandfacilitate bark. Betulin was shown to support keratinocyte diffe ties, namelybetulin-basedoleogelisolatedfrombirch plant-derived compound with anti-inflammatory proper study population(44). blisters indiacereincream-treatedskinpartofthe EBS cells,thenapilotclinicaltrialdemonstratedfewer properties ofdiacereinanditspotentialforstabilizing ton. aggregation andlossofstabilizationbythecytoskele ratin 5 and 14 mutations that cause intermediate filament in EBS(43). The celldisruptionisaconsequenceofke inflammatory response caused by epidermal cell rupture nale involvesthecapacityofdiacereintodampen as possibletreatmentforEBSskin(43,44). The ratio Diacerein from rhubarb root extracts has been implicated Topical pharmacologicaltherapies treatment inapreclinicalsetting(42). cells have shown some potential as systemic anti-fibrotic complications ofbonemarrowtransplantationcanbe not aspositivehopedforand,iswellknown,the Disappointingly, thetherapeuticeffect anddurationwere for different geneticdiseases,includingsevereDEB(38). Bone marrow transplantation has been tested as treatment Systemic stemcelltherapies fibrocell.com). potential ofthisapproachremainstobeseen(37;www. novo collagen VII into the treated areas, but the full information indicatesthattheinjectionsbringsomede www.rheacell.com Wound-healing inEBcanbesupportedbyanother In vitroanti-inflammatory both demonstrated data ). In addition, cord-blood derived stem ). Inaddition, cord-blood derivedstem ------

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV personal communication). Tamai, (K. strictures gastrointestinal and fibrosis skin a HMGB1-derivedpeptide resultedinimprovementof damaged skin(58).Firsttreatments ofRDEBmicewith the bonemarrowintocirculation andfromthereinto inflammatory population of mesenchymal stem cell from anti- specific a release to ability its in lies relevance its and pathological processes (57). In the context of EB, functions andhasbeenimplicatedinbothphysiological improve systemic fibrosis in DEB. HMGB1 has variable mobility groupbox1(HMGB1)-derivedpeptidemay therapy forDEB. anti-fibrotic systemic for potential have may signalling TGFβ modulating biomolecules matrix extracellular the RDEBmice(56). These observations indicatethat TGFβ levels and fibrotic traits, and enhanced survival of tion of lentivirally overexpressed human decorin reduced RDEB (55).Inapreclinicalstudy, systemicadministra levels areknowntocorrelatewithclinicalseverityin leucine-rich proteoglycandecorin.Endogenousdecorin (Table III). ability oflosartantoalleviatesymptomsinhumanDEB also likelytogeneratepreliminaryinformationonthe in childrenwithmoderate-to-severeDEB. The studyis trial currentlyassessessafetyandtolerabilityoflosartan of digitsdelayed(53). As alogicalnextstep,clinical were reduced, progression of fibrosis inhibited and activity fusion TGFβ and inflammation mice, model RDEB treatment. The expectationsweremetinlosartan-treated a major manner (8, 53, 54), losartan appeared suitable as TGFβ signalling hyper-active and inflammation Since (52). antagonism AT-1via signalling TGFβ receptor inhibit to ability its constellations. disease some on based is The mechanism of high blood pressure also has anti-fibrotic potential in DEB on the preclinical level (52). This drug for treatment of strictures and contractures, includingfusion of digits. in DEB, such as inflammation-caused itch or formation symptoms relieve potentially could fibrosis and mation inflam inhibit that drugs Therefore, (51). organs many prominent and the secondary progressive is fibrosis affects inflammation systemic since disease, systemic a as body of scientific literature, severe DEB can be regarded approaches. Basedonanample therapy Antifibrotic individuals withofEBS(50). IL17 intervaltherapywithapremilastworkedwellin3 systemic treatments show promise. For example, anti- NSAIDs are not beneficial, first pilot studies with specific Although non-specific anti-inflammatory therapies with tering, which leads to a stronger inflammatory response. is generatedbyitch,scratchingandsubsequentskinblis itch asabothersomesymptom(49,50). A viciouscircle mediated inflammatory responses, which manifest with In additiontotheabovesmall(bio)molecules,ahigh small the is signalling TGFβ of modulator Another A repurposed drug, losartan, has shown such benefits in contribute to DEB-associated fibrosis in - - - ACKNOWLEDGEMENT worldwide accesstotherapy. big challengeswillhavetobetackled,suchascostand are availableforwideclinicalimplementation,thenext outcomes andtoreduceadverseeffects. Oncetherapies gene, cellanddrugtherapiestowinthebestclinical easy toimaginetherapeuticregimensusingalternating principles: curativeandsymptom-relieftherapies.Itis likely to encompass combinations of different therapeutic ristics andprominentdiseasemechanisms. They are patient’s mutationconstellation,phenotypiccharacte EB willrepresentindividualizedmedicinebasedonthe know today, thepredictionisthatfuturetreatmentsfor we all on Based identified. targets therapeutic new and stem cellproperties. These mustbefurtherelucidated, ter understanding of the disease mechanisms and skin REFERENCES interest todeclare. of conflict no has She International. Debra by and Programme, E-Rare theEU DFG, Foundation Research from theGerman The author’s research has been supported for manyyears by grants made usrealizethatmuchworkisstillneededforbet of theclinicaleffects. Manyofthepilotstudieshave to practicalclinicalimplementationandtheduration technical issues, safety considerations, or issues related all strategiesstillfacesubstantialchallenges,including have advanced topreclinicalandclinicaltesting,but valid treatmentmodalitiesformostsevereEBtypes clinics intheforeseeablefuture. To date,biologically hopes that first evidence-based therapies for EB will enter rapid developmentsofresearchmethodologiesraiseour The multitudeofapproachestoEBtreatmentsandthe IMPLEMENTATION APPRAISAL ANDPERSPECTIVES FOR CLINICAL 4. 7. 3. 6. 2. 8. 5. 1. Schmidt E, Spindler V, Eming R, Amagai M, Antonicelli F, Has C, Liu L, Bolling M, Charlesworth AV, El Hachem M, Escá Has C, Nyström A, Saeidian AH, Bruckner-Tuderman L, Uitto Has C, Bauer JW, Bodemer C, Bolling M, Bruckner-Tuderman Nyström A, Bruckner-Tuderman L. Matrix molecules and skin Bruckner-Tuderman L. Newer treatment modalities in epi in modalities treatment Newer Bruckner-TudermanL. CT,J,Yamagami TakahashiEllebrecht H, M, Kasperkiewicz Has C,Bruckner-Tuderman L.Thegeneticsof skinfragility. Baines JF, etal.Meetingreportofthepathogenesis pem zone. Matrix Biol 2018;71–72:313–329. tissue componentsinthecutaneousbasementmembrane J. 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Hum MolGenet2014;23:3907–3922. the role of TGF-beta signalling in modifying disease severity. sive dystrophicepidermolysisbullosaphenotype highlight 2015; 7:1211–1228. losa and uncovers new disease mechanisms. EMBO Mol Med Evidence-based therapiesforskinfragility Theme issue:Blistering skindisorders Sci Rep 2015;5:11008. 101 - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV doi: 10.2340/00015555-3399 which commonlydevelops inelderlypeople(4,5).In goid (BP),amajorautoimmune blisteringskindisease, benign epidermolysisbullosa (GABEB)”. disease waspreviouslycalled “generalizedatrophic gene mutationsshowsarelativelymildphenotype,the hair andteeth(3).SinceJEBassociatedwithCOL17A1 manifests asblisterformationandabnormalitiesofthe junctional epidermolysisbullosa(JEB),whichclinically mutations intheCOL17A1generesultasubtypeof laminin 332andtype VII collagen(2).Loss-of-function BP230, plectin, via dermis underlying the to filaments of basal keratinocytes. It links keratin intermediate COL17 is one ofthe hemidesmosomal components (1). α-chains 180-kDa identical 3 of composed lagen T E-mail: [email protected] Graduate School of Medicine, N15W7, Kita-Ku, Sapporo 060-8638, Japan. Corr: Wataru Nishie, Department of Dermatology, Hokkaido University Acta DermVenereol 2020;100:adv00054. Accepted Dec18,2019;EpubaheadofprintFeb 6,2020 linear IgAbullousdisease;epidermolysisbullosa. Key words: ectodomain shedding; BP180; bullous pemphigoid; tering skindiseases. cleavagerelates tovage ofCOL17,andhowblis such view the summarizes current understanding of clea associated with Thisre dynamicstructural changes. on induction theproteolysed is fragments, andsuch restingly, cleavage of COL17 may induce neoepitopes with blisterformationInte inpemphigoid diseases. plasmin and granzyme B, which may be associated rious MMP9,neutrophil including proteases, elastase, membrane formation. COL17 can be targeted by va cleavage of COL17maybeassociated with basement feration of keratinocytes. Furthermore, theC-terminal thought to beassociatedwith the migration andproli COL17ectodomainectodomain is shedding. shedding by familyADAM surface proteins in a process known as of COL17canbephysiologically cleavedfrom thecell nal epidermolysis bullosa. Theextracellular domain tions of junctio intheCOL17A1geneinduceasubtype autoantibodies. Inaddition, loss-of-function muta may betargetedimmune blisteringby skindiseases, inseveralauto membrane protein intheskin,which, Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan Wataru NISHIE Collagen XVIIProcessing andBlisteringSkin Diseases Centenary theme section:BLISTERING SKIN DISORDERS Collagen XVII(COL17)isahemidesmosomaltrans Acta DermVenereol 2020;100: adv00054 Autoimmunity toCOL17 induces bullouspemphi BPAG2, isatype-II-orientedtransmembrane col ype XVII collagen (COL17), alsoknownas BP180/ This isan open access article under the CC BY-NC license. www.medicaljournals.se/acta REVIEW ARTICLE ------ - - surface andisdetectablein solubleformincultureme domain ofCOL17isconstitutively shedfromthecell In culturedkeratinocytes, the120-kDaextracellular NC16A domain COL17 ectodomainisconstitutively cleavedwithinthe SETTINGS COL17 PROCESSING INPHYSIOLOGICAL with suchprocessing. processing andtheblisteringskindiseasesassociated review summarizesthecurrentunderstandingofCOL17 may beassociatedwithblisteringskindiseases. This settings. Inaddition,dysregulatedprocessingofCOL17 of COL17maybeinvolvedinvariousphysiological in acontext-dependentmanner. Therefore, processing tinocytes are dynamic, and theymigrate or differentiate dermal-epidermal junction(DEJ).However, basalkera hesion betweenthedermisandepidermisat important structuralmoleculethatmaintainsstablead (GABEB) andBP, suggestthatCOL17isafunctionally linear IgA bullousdisorder(LABD)(4). including mucousmembranepemphigoid(MMP)and antibodies inotherautoimmuneblisteringskindiseases, this region(7,8).COL17mayalsobetargeted byauto immunoglobulin G(IgG)-classautoantibodiesdirecting and previousstudieshaverevealedthepathogenicityof collagenous 16th A (6), domainofCOL17 (NC16A) tightly withinthejuxtamembranousextracellularnon- involved. MajorepitopesforBP autoantibodiescluster on theentirebody, andthemucousmembranesmaybe BP, itchyurticarialerythemaandtenseblistersdevelop with suchprocessing. associated diseases the and processed is COL17 which by seases; thus, it is important to understand the mechanism di skin blistering of development the with may associated be processing COL17 of Dysregulation differentiation. various settings, including wound-healing, proliferation and the expression of COL17 is tightly regulated, depending on However, diseases. skin blistering to lead COL17 of tions the dermis and epidermis. Genetic and acquired dysfunc im an is portant molecule, BP180) which maintains as stable adhesion known between also (COL17, XVII Collagen SIGNIFICANCE The twoCOL17-associatedblisteringdisorders,JEB Journal Compilation ©2020ActaDermato-Venereologica. - - - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV modified frompreviousstudies(13, 14). Permission given by publisher. antibody (red: 332 6F12) co-localizeextracellularthe in transmembrane.TM: normal human skin. of matrix havefigures μm. The 40 bar: DAPI. Scale Blue: partially been laminin and HK139) antibody (green: ectodomain COL17 shed The (B) Inc.). Immunologists, of Association American The 2010: (Copyright domain. NC16A the of sequences and COL17 of Schematics (A) Fig. 1.Collagen XVII (COL17) processinginphysiological settings. healing mainlybycontraction(18). Therefore, further greatly betweenhumansandmice,withwoundsinmice nalling (17). However, wound healing processes differ shedding isassociatedwithdampeningofmTOR sig pression of re-epithelialization by COL17 ectodomain re-epithelialization afterskinwounding(16). The sup of COL17ectodomainsheddingsomewhataccelerated quences that impair ectodomain shedding, the inhibition mice whoseNC16A domain includesaminoacidse physiological settings(15).Ingenetically manipulated COL17 inpathologicalsettingsmaydiffer fromthatin man skin (13, 15). Interestingly, the cleavage site(s) of ectodomain fragmentsexistintheDEJofnormalhu co-localize withlaminin332 (Fig. 1B),(14)andcleaved human keratinocytes cleave COL17 ectodomains, which Unique antibodieshaverevealedthatmigratingnormal ectodomains. COL17 cleaved the detecting specifically antibodies cleavage-site-specific of production the bles cleavage siteswithintheNC16A domainofCOL17ena rather thanonaminoacidsequences. The detectionof preferentially, basedonthedistancefromcellsurface family proteins,whichcleavesubstrateproteinsmore 13). The resultsareconsistentwiththenatureof ADAM ferent regionswithintheNC16A domain(Fig.1A)(12, analyses haverevealedthatthecleavageoccursatdif by ADAM 9,10and17(11), andmassspectrometry dium (9,10).COL17ectodomainsheddingismediated ------motif, and these sequences initiate the folding of COL17 motif, andthesesequencesinitiatethefolding ofCOL17 coiled-coil sequencesjustbeforethefurinconsensus COL17? As illustratedinFig.1A,therearepotential is thephysiologicalroleoffurinconsensusmotifin motif isnotusedunderphysiologicalsettings(10). What ced bythisdistinctmotif;however, thefurinconsensus gested thatectodomainsheddingofCOL17maybeindu consensus sequence:‘’RIRR’’. Earlystudieshavesug Within theNC16A domain,COL17hasadistinctfurin Cleavage inunfoldedCOL17 in thisarticle. basement membrane formation in skin, as described later expected tobephysiologicallyassociatedwithcorrect present innormalhumanskin,C-terminalprocessingis Although itremainsuncertainwhetherLABD-97is led linearIgA bullousdisorder(LABD)-97(Fig.2A). 20). The 97-kDa processed COL17 polypeptide is cal the NC4domain,whichmigratesaround97kDa(19, attheC-terminalregionaroundbe furtherprocessed led aslinearIgA dermatosisantigen(LAD-1),may The cleaved120-kDaectodomainofCOL17,alsocal C-terminal cleavageofCOL17 COL17 ectodomainsheddinginhumanskin. studies areessentialtoaddressthephysiologicalrolesof Collagen XVIIprocessingandblisteringskindiseases Theme issue:Blistering skindisorders 103 - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Blistering skindisorders NC16A sequencesinthecleavedCOL17ectodomains cleavage sitesrevealthatthe antigenicityoftheremnant cleaved LAD-1. within theNC16A domaininduces neoepitopesonthe COL17 (Fig. 2B) (19,22), indicating that cleavage more preferential reactivity to LAD-1 than tofull-length BP andinmanycasesofLABD, autoantibodiesshow react with LAD-1. It is notable that, in some cases of bodies targeting theC-terminal regionsofCOL17may preferentially react(12,13).Similarly, MMP autoanti of theNC16A domain,withwhichBP autoantibodies sequences partiallycontains LAD-1 2A). (Fig. LAD-1 as main yieldsa120-kDaectodomainpolypeptide,known As described, cleavage of COL17 within the NC16A do neoepitopes inprocessed COL17 ectodomains Cleavage withintheNC16A domaininduces DISEASES COL17 CLEAVAGEANDBLISTERING SKIN the qualityofmolecule. NC16A domainofCOL17isimportantformaintaining Thus, cleavageatthefurinconsensusmotifwithin from unfoldedCOL17areexpelledthecells(21). brane. Finally, cleaved120-kDaectodomainsderived apparatus beforebeingincorporatingintothecellmem furin atthe‘’RIRR’’ furinconsensusmotifintheGolgi cumulates incells. The unfoldedCOL17iscleavedby COL17 foldingisimpairedandunfoldedac When coiled-coildisruptivemutationsareintroduced, as acollagentriplehelixintheNtoCdirection(21). data have beenpartiallymodifiedfromapreviousstudy(23).BP:bullouspemphigoid. Permission given by publisher. and LABD-97 than to full-length COL17. Note that LAD sera numbers 2, 5 and 10 react more strongly to LABD-97. N: linear normal control. The IgA immunoblotting bullous disorder (LABD)-97 polypeptides. (B) LAD IgA-class Fig. 2.Neoepitope development in the cleavedcollagenXVII (COL17) ectodomains. (A) Schematics of linear IgA dermatosis type 1 (LAD-1) and autoantibodies show more intense reactivity to the cleaved COL17 ectodomains LAD-1 104 W. Nishie In silico predictions based on detected - - - - protease secretedbyimmune cells,ishighlyexpressed a recentstudyhasreported thatgranzymeB,aserine 97-kDa LABD-97 fragments (19, 20, 28). In addition, of COL17ectodomains,yielding 120-kDaLAD-1and is knowntocleavewithinthe NC16A andNC4domains plasmin (19)areabletocleaveCOL17.Ofthese, revealed thatneutrophilelastase(26),MMP-9(27)and phil elastaseandMMP-9(4,5).Invitro studieshave enzymes areknowntoexist,includingplasmin,neutro proteolytic several fluid, blister BPand In skin lesional COL17 cleavingenzymesinbullouspemphigoid an epitope mapping study of LABD autoantibodies (25). after C-terminalcleavage(23),whichisconsistentwith domainappearthat epitopesonthe15thcollagenous neoepitope development (23). A previous study reported gesting thatC-terminalcleavagehasadditionaleffects on reactivity toLABD-97thanLAD-1(Fig.2B),sug Interestingly, LABDautoantibodiesmayhavegreater ally have strong reactivity to LABD-97 (Fig. 2B) (24). with LAD-1 than with full-length COL17, they usu Since LABD autoantibodies react more preferentially the LABD-97fragment C-terminal cleavageofCOL17inducesneoepitopeson duces dynamicstructuralchangesinCOL17(23). suggesting thatcleavagewithintheNC16A domainin (COL15) domainwithpreferentialreactivitytoLAD-1, more, monoclonalantibodies target the15thcollagenous increase despite thedifferent despite increase (13).Further cleavagesites - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV linear IgA bullous disorder (LABD)-97 is absent in R1303Q have beenpartiallymodifiedfrompreviousstudies (28).LAD-1:linearIgAdermatosis type 1. Permission given by publisher. from mal human epidermal keratinocytes and (NHEKs) keratinocytes from a R1303Q derived proteins matrix extracellular on (NC16A-3) antibodies NC16A anti-COL17 using Westernblotting (D) (PHM-12+CIV22). antibodies collagen IV mechanical blister. (C) A disorganized and duplicated basement membrane is a characteristic histopathological feature, which can be detected by anti-type (A) The R1303Q mutation is located within the NC4 domain. (B) A previously reported 32-year-old COL17 R1303Q Fig. 3.Collagen XVIIformation. blistering diseaseassociated withdisorganizedbasementmembrane (COL17) R1303Qmutation induces mosomal componentsCOL17and/orBP230. Although BP isinducedbyautoantibodiestargeting thehemides of tolerancetobullouspemphigoidautoantigens Impaired cleavageofCOL17mayinducethebreaking formation inskin(28). thought tobeessentialfornormalbasementmembrane the C-terminalprocessingofCOL17,suchis mutations (Fig.3B).SinceR1303Qimpair R1303Q with patients ofJEB characteristic membrane is 31). Histopathologically, duplicationofthebasement (Fig.3)(30, fingerprints of loss a with associated ers blisters, tooth and nail abnormalities, and sclerotic fing thatisclinicallycharacterizedbymechanicalvelops COL17A1 gene,amildandlocalizedformofJEBde R1303QmutationsoccurintheWhen homozygous disorganized basementmembraneformation Impaired C-terminalcleavageofCOL17mayinduce and collagen VII (29). molecules present at the DEJ, including α6/β4 integrins other cleaves butitalso thisenzymecleaveCOL17, does only not that and skin BP lesional in cells infiltrated in +/+ keratinocytes, suggesting that the C-terminal cleavage of COL17 is impaired. The figures - - - been elucidated,thereforethisstudybroughtimportant autoantigens inducethebreakingoftolerancehadnot no blisteringwasobserved. Whether impairmentsofBP neously developedanti-Col17autoantibodies,although the micearepronetoscratchingthemselvesandsponta this is another shedding-deficient model. It is notable that essential fortheectodomainsheddingofmouseCol17, the humanNC16A domain ofCOL17.SinceNC14A is NC14A domainofCol17, a domainthatcorrespondsto tically manipulated mouselacking the immunodominant lerance. In 2015, Hurskainen et al. (37) pemphigoid autoantigens may induce the breaking of to it remainsunclearwhethertheimpairedexpressionof the tolerancetoCOL17andBP230(35,36).However, (33, 34). Furthermore, impaired Treg function may break IV inhibitors(DPP4i)areariskfactorfortheonsetofBP anti-type IIdiabetesmellitusdrugdipeptidylpeptidase surgery (32).Inaddition,recentstudieshavereportedthat including thermal burns, ultraviolet (UV) irradiation and to molecules may bebrokenbyvarioustriggering events, may bebrokenincertainindividuals.Immunetolerance no full elucidation of why tolerance to these autoantigens formation has been studied extensively, there has been the pathomechanismofautoantibody-dependentblister +/+ Collagen XVIIprocessingandblisteringskindiseases junctionalepidermolysisbullosapatient. The Theme issue:Blistering skindisorders +/+ patient (28). The

produced a gene arrow arrow indicatesthat indicates a 105 - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Blistering skindisorders REFERENCES The authorhasnoconflictsofinterest todeclare. of futurestudy. as well as pathological, settings, and will be the focus of COL17isinvolvedinvariousnormalphysiological, differentiate andproliferate.Undoubtedly, theprocessing dependent manner, forbasalkeratinocytestomigrate, this adhesionneedstobetightlyregulatedinacontext- dermis andepidermisattheDEJinskin.However, is avitalplayerinthestableadhesionbetween JEB andpemphigoiddiseaseshaveproventhatCOL17 CONCLUSION previously. after beingcleavedfromthecellsurface,asdescribed with thefactthatshedCOL17ectodomainissoluble localized withIgE(39). This observationisconsistent the dermis,inwhichCOL17ectodomainfragmentsco- but thatitisprominentonmastcellsandeosinophilsin recently reportedthatIgEisrarelyobservedattheDEJ, the positivityrateisnothigh(40).Notably, Freireetal. in vivo IgE deposition at the DEJ may be observed in BP, autoantibodies arepresentinBP sera(38,39). Although ported that both IgG-and IgE-class anti-COL17 NC16A has not been fully elucidated. Previous studies have re in contrast,thepathomechanismforurticarialerythema development ofblistershavebeenstudiedextensively; The roles ofIgG-class anti-COL17 autoantibodies in the lesional skin Cleaved fragmentsonimmunecellsinbullouspemphigoid of tolerancetoCOL17. information onthepathomechanism behind thebreaking 106 7. 5. 3. 6. 4. 2. 1. 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J Invest Dermatol 2015; 1831–1842 e1837. mune bullousdisease. J Allergy Clin Immunol2018;142: Collagen XVIIprocessingandblisteringskindiseases Theme issue:Blistering skindisorders 107 - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV doi: 10.2340/00015555-3400 distinguished (1): isotype oftheautoantibodiesinfollowingPDcanbe and specificity the presentation, clinical on Depending molecules locatedatthedermal–epidermaljunction. terized andcausedbyautoantibodiestargeting adhesion (M E-mail: [email protected] Germany. Lübeck, DE-23538 160, Allee Ratzeburger Lübeck, of versity Corr: Acta DermVenereol 2020;100:adv00055. Accepted Dec18,2019;EpubaheadofprintFeb 6,2020 autoantibodies. sita; translational medicalresearch; disease models; animal Key words: bullous pemphigoid; epidermolysis bullosa acqui- will lead to personalized treatments. andcurative clinical observations. Ultimately, it ishoped thatthis lopment; and(v)drugdevelopment basedon careful drug deve drug repurposing;(iv)screening-based development; (ii) omics-based drug development; (iii phigoid diseases,namely:(i)hypothesis-driven drug some pathways leadingto drugdevelopment inpem Thisreviewsummarizes beenlaunched. have recently numerous pre-clinicalstudiesandearlyclinicaltrials and saferemainsanunmetmedical need. However, the development ofnovel treatments thatareeffective significantly, improved have pathogenesis their into le the diagnosticsofpemphigoid diseases and insights locatedlecules atthedermal–epidermaljunction. Whi Lübeck Institute of Experimental Dermatology and Center for Research on Inflammation of the Skin, University of Lübeck, Lübeck, Germany Katja BIEBER andRalf Drug DevelopmentinPemphigoidDiseases Centenary theme section:BLISTERING SKIN DISORDERS are causedbyautoantibodies targetingadhesionmo diseases ofthe skin and/or mucous membranes.They autoimmune organ-specific are diseases Pemphigoid Acta DermVenereol 2020;100: adv00055 • • • • children and clinically presents with urticarial plaques, epidermal junction.LADis themostcommonPDin linear bindingofIgA autoantibodies atthedermal– Linear IgA disease against BP180(5). ciated immunobullousdiseasewithautoantibodies Pemphigoid gestationis (PG) is a pregnancy-asso 332) andpredominantmucosalinvolvement(3,4). dermal–epidermal junction (i.e. BP180orlaminin a PDwithautoantibodiesagainstcomponentsofthe Mucous membranepemphigoid (MMP) is defined as by autoantibodiestargeting BP180 and/orBP230(2). and predominantly affects elderly people. BP is caused Bullous pemphigoid(BP)isthemostprevalentPD Ralf J. Ludwig, Lübeck Institute of Experimental Dermatology Uni- Dermatology Experimental of Institute Lübeck Ludwig, J. Ralf of pemphigoiddiseases(PD). They arecharac uco)-cutaneous blisteringistheclinicalhallmark J. LUDWIG (LAD) is characterized by the This isan open access article under the CC BY-NC license. www.medicaljournals.se/acta REVIEW ARTICLE ) ------Treatment of all PD centres on unspecific, systemic im DISEASES UNMET MEDICALNEEDINPEMPHIGOID increasing incidenceofPD, especiallyinageingsocie the currentlimitationsregarding treatmentoptions,the to identifythemedicalneed inPD(17).Inadditionto identified recently by patients and physicians in a survey combination ofseveraldrugs(1,11–16). after monthsofimmunosuppressivetherapy, usuallya only achieved is remission often and treat, to difficult and mortality. Both,MMP andEBA arenotoriously teroid treatment,whichcontributestopatientmorbidity patients within6months,requiringlong-termcorticos withdrawal oftreatment,BP relapses inalmost50%of either systemicortopicalcorticosteroids.However, after sions arecommon.Likewise,BP alsorespondswellto usually respondwelltotreatmentandlong-termremis the first line of treatment. Among PD, PG, LAD and p200 munosuppression, wherebycorticosteroidsareusually strategies for patients withpemphigoid diseases. treatment new develop to research translational foster to aim we this With diseases. pemphigoid for development drug facilitate may that pathways propose we mortality, and increased morbidity patient high the to significantly immunosuppression. Since such treatment contributes unspecific on relies still treatment their diseases, phigoid Despite detailed insightsintothe pathogenesis of pem SIGNIFICANCE • • • This “needforbettertreatment options”hasbeen Anti-p200/anti-laminin γ1 pemphigoid (p200) clini γ1 Anti-p200/anti-laminin studied (7,8). availability ofpre-clinicalmodelsystemsitiswell- clinically veryheterogeneousPD,butduetothe Epidermolysis bullosaacquisita(EBA)isarareand the so-calledstring-of-pearlssign(6). tern withblisteringalong the edge oflesions,forming younger thanthosewithBP (10). gether withlichenplanus.PatientsLPP arealso by anti-BP180antibodies,butinLPP theseoccurto Lichen planuspemphigoides(LPP)is,likeBP, caused usually respondswelltotreatment(9). cally mimicsBP, butpatientsareyoungerandp200 erosions, and blisters, frequently in a ring-shaped pat Journal Compilation ©2020ActaDermato-Venereologica. ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Table I.Examplesofdrugsevolvingfromtheoutlinedpathways todrugdevelopmentinpemphigoiddiseases induced tissuedamageinPD(27,28). considered asoneofthemaindriversautoantibody- Nonetheless, thecomplementcomponentC5ahastobe develops independentofcomplementactivation(26). from developmentofclinicaldisease(25),orwherePD whereby somecomplementreceptorsconferprotection complement hasamorecomplexroleinpemphigoid, systems (23,24).Recentdata,however, suggeststhat of PDhasbeenwelldocumentedinpre-clinicalmodel ctional contribution of complement to the pathogenesis tion isoneofthediagnosticpillarsPD(22). The fun Complement depositionatthedermal–epidermaljunc in bullouspemphigoid antibodies anti-C1s development: drug Hypothesis-driven fruitful discussion. from thecommunity, whichitishopedwill lead toa Hence, theauthorsarelookingforwardtocomments initiate adiscussiononhowthisgoalisbestachieved. examples. Another importantaimofthisarticleisto development forpatientswithPDbyprovidingthese detail below. The aimofthisreviewistopromote drug novel treatmentsforPDaregivenanddiscussedinmore observations. Examples ofeach ofthese pathways to ment; and(v drug repurposing;(iv)screening-baseddevelop development; (ii)omics-baseddrugiii to newdrugs,asfollows:(i simplistic, itcouldbeusefultocategorizethesepathways development inPD(Table I,Fig.1). While itmaybe There aremanypathways that may contribute todrug TREATMENT OFPEMPHIGOIDDISEASES PATHWAYS TONEWDRUGS FOR THE aiming forpersonalizedandcurativetreatment. continuously improvethetreatmentoptions,ultimately in PD. Thus, ongoingtranslational researchisrequired to these clinical trialswill not fullyaddressthemedical need and clinical trials in PD(20, 21). Unfortunately, however, studies translational of number significant a prompted effective and safe. This increasing medical need has also develop noveltreatmentstrategiesforPDthatareboth ties (18,19),furthercontributestothemedicalneed BP: bullous pemphigoid;DMF: dimethyl fumarate; LTB4: leukotriene B4; PD: pemphigoiddisease; SYK:spleentyrosine kinase. Hypothesis-driven Pathway todrugdevelopment Omics-based Omics-based Drug repurposing Drug screening Clinical observations ) drug development based on careful clinical ) drugdevelopmentbasedoncarefulclinical Target (compound) C5/LTB4 (Coversin) C1s (Sutimlimab) SYK (BAY61-3606) DMF (Skilarence) Doxycycline Not disclosed Autoantibodies ) hypothesis-drivendrug Evidence Pre-clinical, Phase Itrial in patients with BP (31) Pre-clinical, invitro (30) Pre-clinical, Pre-clinical, Case report(s)(series)(15) Pre-clinical, Pre-clinical, Case report series (59) - - antibodies to C1s,whichinitiatetheclassicalcomple the late60 sence ofcomplementdepositsinBP wasdiscoveredin of thecomplementsystemintoclinicaltrials. The pre the clinical and experimental findings on the importance complement inhibitors is the long time needed to translate most strikingabouttheclinicaldevelopmentofthese2 in BP, withpromisinginitialdata(32). What isperhaps LTB4 inhibitor coversinis currently beingconducted Furthermore, aphaseIIclinicaltrialusingthedualC5/ tion, withonlymildtomoderateadverseevents(31). found to be safe and tolerable in this elderly popula which the anti-C1s antibody TNT009/BIVV009 was trial inpatientswithBP wassuccessfullycompleted,in skin cryosections (30). More recently, a phase I clinical mune complex-induced complement fixation on human anti-C1s antibodies, dose-dependentlyinhibitedtheim ment activation cascade, were developed (29). These unbiased exploitationofnoveltherapeutictargets can ample, genetics,proteomicsandRNA sequencing,an With theavailabilityofnoveltechnologies; forex disease tyrosine kinase as a target for treatment of pemphigoid Omics-based drugdevelopment:validationofspleen inhibitors. adverse events compared with non-targeted complement are expected to be both more effective and have fewer ted (35,36). These targeted complement therapeutics preferentially bindtositeswherecomplementisactiva complement therapeuticshavebeen developed, which the skinattimeofdiagnosis(30).Recently, targeted sions. Incontrast,allofthepatientshadC3depositsin compounds didnotchangeafterclearanceofskinle cohort ofpatients,concentrationsthesecomplement observed inage-andsex-matchedcontrols.Inthesame C4a andC5ainpatientswithBP wereidenticaltothose seases. More specifically, plasma concentrations of C3a, observed, bothinpatientsandanimalmodelsofthedi be restrictedtotheskin,whereC3depositsareregularly described over20yearsago(34). of thecomplementsystemindiseasepathogenesiswas in vivo(67) in vivo(37,38) in vivo(47) in vitro(69) in vitro(60) Based ontheseconsiderations,function-blocking Interestingly, complementactivationinPDseems to th ofthelastcentury Drug developmentinpemphigoiddiseases Development state Ongoing Phase IIa in BP (68) Phase Iclinicaltrial completed Target validated inPD mouse model Phase IIclinical trial inpreparation (20) Phase IIIclinical trial successfully completed (43) Pre-clinical Pre-clinical Pre-clinical (60) Theme issue:Blistering skindisorders (33), andthecentralrole 109 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Blistering skindisorders 110 K. BieberandR.J.Ludwig Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV as (middle image Subsequently EBA. with mice and wascontrastedhealthymice skin between the in expression RNA provided,example the RNA-sequencingIn example proteomics. for or measurement, omics. Here specimen, biological i.e. affected vs. non-affected skin from patients or pre-clinical model systems (left-hand image reduced complement deposition along the dermal-epidermal junction. (b) Development of new pemphigoid treatments based on complex data sets and assumed to have disease-modifying effects in PD. Both (in vitroassays, that mice deficient (ko) in specific complement proteins are protected from the induction of experimental PD (34), targeting complement activation was observationclinical that complement deposits (ingreen the on Based depicted. are coversin and antibodies anti-C1s as such inhibitors, complement new of development the example, an As research. driven diseases. for thetreatment of pemphigoid drugs to 1. Pathways new Fig. psoriatic agent (left-hand panel drug is also effective in pemphigoid, such as doxycycline, or be hypothesis-driven, as shown for dimethyl fumarate, which has a long history as an anti- be repurposed for PD. The rationale for drug repurposing in pemphigoidcan either be based on clinical observations, i.e. case report series that a given can pemphigoid, other than indications for drugs, licensed Already repurposing. drug on based treatments pemphigoid new of Development (c) (37)). the patients. Using the insights from detection of specific autoantibodies in PD, first attempts were made to develop antigen-specific immunoadsorption. immunoadsorption is limited because all antibodies are removed. Hence, the procedure has to be paused, and does not elute all autoantibodies from levels of the circulating autoantibody titres with disease severity, immunoadsorption/plasmapheresis were introduced to the based management on of clinical PD. observations. However,After the identification of the pathogenic relevance of autoantibodiesinitial screening inthe identified PD potential drugs need and to be thevalidated clinical observation of a correlation of the libraries, for example the Prestwick Chemical Library (66) or the FDA-approved Drug Library from Selleckchem, can be obtained commercially. After the CD28-induced T cell proliferation, IL-21/antiCD40L-induced B cell proliferation and anti-BP180 IgG-induced cytokine release from keratinocytes (51). Drug highly reproducible. InPD, examples for these assay systems are immune complex-induced release of reactive oxygen speciesfrom neutrophils, anti-CD3/ and up-scalable are which systems, model vitro in in performed be can screening drug known, not are targets drug defined putative If screening. drug malignancies (40),forthetreatment ofpemphigus(41) tuximab, initiallydeveloped forthetreatmentofBcell In dermatology, theuseofanti-CD20 antibody ri for bullouspemphigoidtreatment Drug repurposing: doxycycline and dimethylfumarate patient sampleswouldberequired. samples. The advantage ofsuch anapproachisthat fewer patient corresponding in performed be targets may fied For translationintoclinicaluse,expressionoftheidenti for target identification, as well as functional validation. from modelsystems(asreportedforSYK)maybeused storage. Alternatively, orinparallel,multi-omicsdata standardized proceduresforsampleacquisitionand using samples patient well-defined collect to required Therefore, inthefuture,ajointcommunityeffort is in whichtheintronicregionofGALCislocated(39). tion of MMP with GWAS hasbeenpublishedsofar, reportinganassocia sparse forPD. To thebestofourknowledge,onlyone therapeutic target forPD. potential a as validated and identified independently madesimilar observations (38). Thus, SYKhas been was blocked(37).Inparallel,hypothesis-drivenresearch, induction ofexperimentalEBA wasobservedifSYK mice. Inbothexperiments,completeprotectionfrom SYK-deficient in EBAinduced or was inhibitors, SYK was induced in mice that were treated with selective differential kinase(SYK). tyrosine To evaluatethefunctionalroleof i.e. identified, EBA, severalpotentiallydisease-promotinggeneswere expression frommicewithandwithoutexperimental mouse models(7). In detail, contrasting cutaneous RNA however, beensparselyused, and havebeenlimitedto be performed.RegardingPD,suchapproacheshave, Sykb. For functional validation, in vitro systems or pre-clinical model systems (right-hand image Unfortunately, however, omicsdatasetsarequite Sykb expressioninEBA,experimentalEBA Sykb, thegeneencodingforspleen HLA-DQB1*03:01 and rs17203398, ), which also ameliorates experimental PD (right-hand panel ), data analysis is performed, leading to the identification of potential pharmacological targets, such targets, pharmacological potential of identification the to leading performed, is analysis data ), ) are highly prevalent in the skin of patients with pemphigoid disease (PD) (1) and the observation in vitroand - - - middle panel) and middle a phase trial demonstratedI clinical that anti-C1s impairs/ in vivo (left-hand panel). (e) Development of new pemphigoid treatments This was significantly lower, compared with predniso with compared lower, significantly was This patients experiencedagrade3orgreateradverseevent. Regarding adverseevents,18%ofdoxycycline-treated dose 0.5mg/kg)inducedremissionin91%ofpatients. patients within6weeks;whileprednisolone(initial in74%ofdoxycycline, achievedclinicalremission BP (43).Inacomparativeclinical trial,200mgof been demonstratedtobeeffective inthetreatment of main advantagesofdrugrepurposing(42). the decreasedtimeandcostsofdrugapprovalare drugs, licensed the of profile safety known already The indications. other in efficacy for evaluated are pounds patients with BP and allocate these to DMFor placebo. in France,Poland, Turkey andGermanywillrecruit210 patients responsivetocorticosteroid treatment.Centres evaluate the safety and efficacy of adjuvant DMF in BP these findings, the DPem consortium was established to the hydroxycarboxylicacidreceptor2(48).Basedon beneficial effects of DMF in EBA are mediated through in solvent-treatedmice(47).Onamolecularlevel,the disease activity, whileclinicaldiseaseseverity increased EBA manifestations led to a significant improvement in deed, treatmentofmicewithalreadyestablishedclinical DMF may also be beneficial for the treatment of PD. In (46). Based on these properties, we hypothesized that extravasation, anti-oxidantproperties,andmanyothers shift incytokineexpression,asuppressionofleukocyte DMF hasamultitudeofbiologicaleffects, includinga been licensedfortreatmentofmultiplesclerosis(45). an anti-psoriaticagent(44),andmorerecentlyhasalso Germany, thecompoundhasalong-standinghistory as for repurposinginBP isdimethylfumarate(DMF).In higher. Another compoundthatiscurrentlyevaluated lone, wherethenumberofadverseeventswas2-fold “conventional” drug development, already licensed com is agoodexampleofdrugrepurposing.Incontrastto (a) Development of new pemphigoid treatments based on hypothesis- Regarding PD, the antibiotic doxycycline has recently Regarding PD,theantibiotic doxycycline hasrecently ). (d) Development of new pemphigoid treatments based on Drug developmentinpemphigoiddiseases ) may be used. (Example from Samavedam et al. Theme issue:Blistering skindisorders ), are subjected to unbiased 111 - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV soon to be published that have the potential for repurpo Theme issue:Blistering skindisorders observed inthemajorityof patients(58,59). This data, seases, suchaspemphigus, long-lasting remissionswere and incontrasttootherautoimmune skinblisteringdi immunoadsorption in26patients withBP. Interestingly, series have been published, reporting the outcome of tion/plasmapheresis inPD(57).Morerecently, 2case autoantibodies (24)promptedtheuseofimmunoadsorp In addition,insightsintothepathogeneticroleofthese observations andbasicresearchcanimprovediagnosis. PD (1). This, byitself, is a goodexample, ofhowclinical lopment ofserologicaltestsystemsforthediagnosis of thecorrespondingautoantigens(56)ledtodeve mal junction in PD (55) and the identification and cloning The detection of IgG deposits along the dermal–epider pemphigoid Clinical observations:immunoadsorptionforbullous compounds suitedforthetreatmentofPD. novel of identification the to lead will (54), Map tivity approaches todrugdevelopment,suchastheConnec before clinicaltrials. pre-clinical modelsystems(53),wouldbeemployed vitro andinvivovalidation(usingappropriateanimal Subsequently criteria. cut-off pre-defined on based sample size.Candidatecompoundswouldbeselected tokine releasefromkeratinocyteswitharelativelysmall activation ofimmunecellsorautoantibody-inducedcy be toscreencompoundsofachemicallibraryinhibit with IL-21andanti-CD40L (51,52). of T cellsusinganti-CD3/CD28andBcellstimulation kine releasefromkeratinocytes,aswellstimulation (ROS) fromneutrophils,orautoantibody-inducedcyto complex-induced releaseofreactiveoxygenspecies amples of these up-scalable model systems are immune not beenusedfordrugdevelopmentinpemphigoid.Ex of PDarealreadyestablished(51),thesehave,sofar, Despite the fact that up-scalable complex stances where molecular defined targets are not known. systems inchemicalscreensoffers advantagesin pharmacological targets, ofcomplex,up-scalable theuse very wellsuitedtoidentifynewcompoundsforknown (49, 50). While the use of specific (enzymatic) assays is model systemsiswellestablishedfordrugdevelopment up-scalable, but complex, of use the or molecules, cific toidentifyinhibitorsofspe ofchemicallibraries The use Drug screening other indications. options forpemphigoidpatients,using“old”drugsfrom for PDwill lead to the approval ofseveral new treatment sing inPD. We expectthatthispathwaytonoveldrugs 112 To theauthors’ knowledgethereareadditionaldrugs It ishopedthat these models, aswell ascomputational An envisioned work-flow of such an approach would K. BieberandR.J.Ludwig in vitro models in ------approval ofseveralnewtreatmentsforPDcanbeex With theincreasingnumberofclinicaltrialsinPD(21), RESEARCH INPEMPHIGOIDDISEASES FUTURE DIRECTION OFTRANSLATIONAL models ofpemphigus(62). selectively deplete specific autoreactive B cells in mouse receptor (CAAR) T cells, which have been shownto ofchimericautoantigen theuse treatmentis based, for PD. Another, potentiallyveryselectiveandantigen- likely becomeamorewidelyusedtreatmentmodality translated into clinical use, immunoadsorption will most If theseinsightsfrompre-clinicalmodelsystemscanbe part) successfullyemployedinanimalmodels(60,61). the NC16A domainandDsg3weredeveloped,(in columns specifically removing autoantibodies targeting which arecurrentlyexclusivelyusedfordiagnosis(22), using insights onthe autoantigens in pemphigus and PD, mice, at least, this limitation has been overcome: by In immunoadsorption. unspecific using performed be bodies. Hence,vigorousandprolongedremovalcannot are removed,ratherthanselectiveremovalofautoanti adsorption is,however, limitedbecauseallantibodies treatments for PD has prompted a very exciting new area treatments forPDhasprompted averyexcitingnewarea of thesebiomarkers. munosuppression couldbe adjustedtotheexpression multicentre diagnostic clinical trials, tapering of im Given, that(someof)thesearevalidatedinprospective induced matrixmetalloproteinase9secretion(63–65). CXCL10- or β, receptor glucocorticoid the of riations presence ofanti-type VII collagenautoantibodies,va the example, for BP; in relapse indicate that identified and retrospectivestudies,severalbiomarkershavebeen diagnostic and therapeutic procedures: insingle-centre be implementedrelativelyquicklyusingestablished considerable time,apersonalizedtreatmentforPDcould from pre-clinicalmodelsystemsintoclinicalusewilltake cure, for PD. While translating these interesting findings pulation couldinducelong-lastingremission,orevena particular, removingtheautoreactiveB/plasmacellpo could betailoredtoeachpatients’ autoantibodies.In immunoadsorption forBP, orthe CAAR-T-cell approach approaches towards the development of antigen-specific Regarding curativetreatments,theabove-mentioned also includethesepatientswouldbehighlywarranted. that trials basket, maybe or specific, Therefore, EBA. clinical trials,despitethehighmedicalneed in MMP and best ofourknowledge,therearecurrentlynoongoing only recruitpatientswithBP. Forallother PD,tothe pected withinthenext3–5years.However, thesetrials case series, as well as the use of concomitant treatments. however, shouldbeinterpretedwithinthelimitationsof Collectively, thehigh medicalneedtodevelopnew Currently, removalofautoantibodiesbyimmuno ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV 14. 12. 10. 15. 13. 11. 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J Invest Dermatol 2000; bullous pemphigoidreleaseinterleukin-6andinterleukin-8 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV prevailing hypothesis isthat DH develops asa late ma manifestation ofcutaneous coeliacdisease,and the considereda DH iscurrently transglutaminase. tissue dependent enteropathy and antibody against response thesamegenetic background,disease share gluten- on theelbows, kneesandbuttocks. DHandcoeliac disease that blisteringcauses itchy, typically rash, isanautoimmuneDermatitis skin herpetiformis(DH) This isan open access article under the CC BY-NC license.www.medicaljournals.se/acta overall, thegeographicaldifferences intheprevalenceof for examplein Asia andin African-Americans (7,8) and, populations, specific in and globe the of areas some in 75 per100,000fromFinland (5). The prevalence islower the highestreportedprevalence ofDHtodatehasbeen 13% ofpatientswithcoeliacdiseasehaveDH(5,6)and subtle thanincoeliacdisease(4).Currentlyapproximately coeliac-type enteropathyalsoexistsinDH,albeitmore of coeliacdisease,manifestingprimarilyintheskin,but ment of the disease (3). DH is considered a specific variant HLA DQ2 or DQ8haplotypes, is anecessity for develop specifically more background, genetic predisposing the glutaminase (TG2)and TG3 existinDH(1,2).Moreover, (TG3), andcirculatingautoantibodiesagainsttissuetrans in the dermis, directed against epidermal transglutaminase hognomonic granularimmunoglobulin A (IgA)response D tal, PO Box 2000, FIN-33521 Tampere, Finland. E-mail: [email protected] Corr: Acta DermVenereol 2020;100:adv00056. Accepted Dec18,2019;EpubaheadofprintFeb 6,2020 free diet; transglutaminase; immunoglobulinatrophy. A; villous Key words: dermatitis herpetiformis; coeliacdisease; gluten- fers agood long-term prognosis. andenteropathy, increasesqualityrash of life,and DH isalife-long gluten-freediet, whichresolvesthe for choice of treatment The diagnosis. the confirm to used finding a is and DH, for pathognomonic is dermis glutaminase. GranularIgAdeposition in the papillary while theautoantigen trans nase, inthegutistissue in DHskinisdirectedagainstepidermaltransglutami incidence of coeliacdisease.TheIgAimmuneresponse of DHisdecreasing contemporarily with the increasing The incidence nifestation coeliacdisease. of subclinical 1 Teea SALMI Current ConceptsofDermatitisHerpetiformis is consideredanautoimmune-baseddisease,sincepat predominantly ontheelbows,kneesandbuttocks.DH University Hospital, Tampere,Finland Journal Compilation ©2020ActaDermato-Venereologica. Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, and TampereUniversity, Technology, andHealth ofMedicine ResearchCenter,Faculty Disease Celiac Teea Salmi,Department of Dermatology, Tampere University Hospi- skin disease, which causes papulovesicular eruption, skin disease,whichcausespapulovesiculareruption, ermatitis herpetiformis(DH)isanintensivelyitching 1,2 andKaisa HERVONEN 1,2 Centenary theme section:BLISTERING SKIN DISORDERS REVIEW ARTICLE ------coeliac disease,wasshown to healsmallbowelmucosal when gluten-freediet(GFD), thetreatmentofchoicein importantly, and DH, in finding common a also was Marks etal.(16)detectedthat coeliac-typeenteropathy link betweenDHandcoeliac diseasewasfoundwhen coeliac diseaseweredescribedbySamuelGee(15). The the classicalabdominalandmalabsorptivesymptomsof early as1884byLouisDuhring(14)and,4yearslater, The clinical manifestations of DH were first described as SKIN MANIFESTATION OFCOELIACDISEASE are presented. of DH,thecutaneousmanifestationcoeliacdisease, and coeliacdiseaseiselaborated,uniquefeatures and prognosis.Inaddition,thecloselinkbetweenDH clinically relevant,conceptsofDHdiagnostics,treatment common inItalyandHungary(12,13). is rareinnorthernEurope(5,6,11) itseemstobemore tary habits.Nonetheless,eventhoughchildhooddiagnosis obscure, apossibleexplanationcouldbechangesindie and, althoughthereasonsforthisincreaseremainlargely Interestingly, thediagnosticageofDHhasincreased (5) highest in females and males aged 50–69 years (5, 6). diagnosed duringadulthood,andtheincidenceofDHis med inEuropeorNorth America (5,10).DHistypically 0.4 to3.5/100000/year, evenin different studiesperfor from ranged have DH of figures incidence (9). the Also mainly byHLA geneticsandwheatconsumptionhabits DH and,likewise,coeliacdisease,havebeenexplained quality of life,and offers agood long-term prognosis. increases enteropathy, and rash the resolves which diet, choice for dermatitis herpetiformis is a life-long gluten-free have coeliac autoantibodies in the serum. The treatment of ling typical IgA deposits, and the majority of patients also diagnosis. The diagnosis is confirmed by skin biopsy revea at present is inflammation or atrophy villous coeliac-type symptoms are rare in dermatitis herpetiformis, intestinal of coeliac disease. Even thoughobviousgastrointestinal Dermatitis buttocks. and herpetiformis is considered a cutaneous manifestation knees elbows, the on occurs which rash, itchy,blistering an is herpetiformis Dermatitis SIGNIFICANCE The focusofthisreviewistodescribethecurrent, Acta DermVenereol 2020;100: adv00056 2 Department of Dermatology, Tampere Tampere Department ofDermatology, doi: 10.2340/00015555-3401 - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Blistering skindisorders rash withsmallblistersand papules affecting mostcom teristic skinsymptoms,which areanintenselypruritic The suspicionofDHtypically arises from thecharac DIAGNOSING DERMATITIS HERPETIFORMIS potential fordevelopmentofDH. coeliac diseaseand,consequently, fewerindividuals with resulted inasmallerpoolofpatientswithundiagnosed hasautoantibody tests,andscreeningofriskgroups to increasedawareness,availabilityofaccurateserum this hypothesis: better diagnostics ofcoeliac disease due incidences of DH and coeliac disease also fits well with this hypothesis,andfurthermore,thedivergent trendof coeliac diseaseduringpoordietaryadherencesupport rarity ofchildhoodDHandthechangingphenotype tive togluteninearlychildhood(30).Moreover, the DH indicatethattheseindividualswerealreadysensi dental enameldefectsdetectedinadultsdiagnosedwith mune responseinitiallytargeting TG2 (29).Coeliac-type as anepitopespreadingphenomenonfromautoim that the TG3 immuneresponsetypicalforDHdevelops lected coeliacdisease.Ithas,moreover, beensuggested disease, affecting individualswithsubclinicalorneg is thatDHdevelopsasalatemanifestationofcoeliac has been detected (5, 6, 28). One prevailing hypothesis coeliac disease a marked increase in the incidence figures Moreover, theincidenceofDHhasdecreased,butin predominance knowntoexistincoeliacdisease(6,28). males than females (5),which contradicts the female 27). Furthermore,DHisslightlymorecommonamong sed duringchildhoodcomparedwithcoeliacdisease(11, with coeliac diseaseingeneral.DHismore rarely diagno and DHpatients(25,26). in thesmallbowelmucosaofuntreatedcoeliacdisease TG2-targeted autoimmune response has been detected to occurintheserumofpatientswithDH(2).Moreover, furthermore, asimilar TG2 antibodyreactionwasshown and foundtobeaccurateincoeliacdisease(24)and, method fordetecting TG2 antibodieswasdeveloped enzyme-linked immunosorbent assay (ELISA)-based as theautoantigenofdisease(23).Subsequentlyan research in the 1990s when TG2 enzyme was identified DH, especiallywhendietarycomplianceispoor(22). constant, sinceitcanconvertfromclassicaldiseaseinto that the phenotype of coeliac disease is not invariably haplotypes inboth(19–21).Moreover, ithasbeenshown DQ8 haplotypes havebeenshown to bethepredisposing furthermore, predominantly HLA DQ2 and, more rarely, the samefamiliesandeveninmonozygotictwins, and coeliacdiseasehavebeenshowntooccuroftenin coeliac diseaseevenmoreconvincinglytogether:DH quent familyandgeneticstudieshavecoupledDH changes in DH, and to alleviate DH rash (17, 18). Subse 116 DH, however, hassomedistinctfeaturescompared A majorbreakthroughoccurredincoeliacdisease T. SalmiandK.Hervonen ------remained quiteunchangedduringrecentdecades(39). the clinical picture andthe severity ofDHrashhave common non-classicalsymptoms(36–38),itseemsthat become milderandmoreheterogenicwithincreasingly the clinicalpictureofcoeliacdiseasehasbeenshownto to one-thirdofpatients(34,35).Interestingly, although abdominal symptomshave,however, beenreportedinup signs ofmalabsorptionarerareinDH,butsomekind enteropathy, obviousgastrointestinalsymptomsand typical DHrash(31–33).Despitethegluten-sensitive either asasolepresentationorconcomitantlywiththe found be can and DH in finding rare, quite albeit one, mentation are consequently present. Acral purpura is hyperpig post-inflammatory and crusts erosions, only intense itchandscratching,theblistersarebroken rity oftherashandpruritus,butcommonlydueto also affected. There isindividualvariationintheseve sites, suchasthescalp,face,upperbackandneck,are buttocks (Fig.1a,bandTable I).Occasionallyother monly theextensorsurfacesofelbows,kneesand and inthedermis. (× blisters, papules and crusts on the elbow. (c) Direct immunofluorescence excoriated and Intact (b) knees. and elbows the on papules and blisters excoriated with (DH) herpetiformis dermatitis of picture clinical typical A of dermatitits 1. ClinicalFig. characteristics herpetiformis (DH). 40) finding in DH; granular IgA deposits in the basal membrane zone membrane basal the in deposits IgA granular DH; in finding 40) (a) - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV suggest that the pathogenesis of Japanese DHdiffers findings These patients. of proportion low in only seen are autoantibodies coeliac-disease-specific and rare, is lotypes, theoccurrenceofgluten-sensitive enteropathy carry thepredisposingHLA-DQ2 andHLA-DQ8hap Caucasian patients;theJapanesepatientswithDHdonot DH also show other distinct features that differ from of patientswithDH.However, Japanesepatientswith has beenreportedtooccurinapproximatelyone-third of IgA appearstobemorecommoninJapan,whereit pattern fibrillar The (45–47). presented been have DH IgA in fibrillary deposits of cases sporadic mostly IgA, this findingcanbeconsideredDH-specific. granular IgA innon-DHskin.For thetimebeing,atleast, before conclusionscanbedrawnabouttheexistenceof has beensmall,andfurtherresearchevidenceisneeded However, the number ofthe patients in these studies with inflammatory skin diseases other than DH (43, 44). skin ofcoeliacdiseasepatientswithhealthyor studies reporting that granular IgA also exists in the on astrictdiet(42). There areafewratherinteresting the disappearanceisprolonged,oftentakingyearseven patients withDHonaGFD,inparallelIgA,but demonstrated that TG3 disappearsfromthedermisof related, but not identical, to TG2 (1). It has recently been in DHskinisdirectedagainst TG3, anenzymeclosely found ingreateramounts(41). The immuneresponse is uninvolvedperilesionalskin,wherethedepositsare and thereforetheidealsitefordiagnosticskinbiopsy uniformly distributedintheskinofpatientswithDH, (Fig. 1c).IgA deposits are widespread, but not totally papillary dermisand/orat the dermoepidermaljunction shows thepathognomonicgranularIgA depositsinthe which examination, (IF) immunofluorescence direct is those ofDH(40). typical predilectionsitesofthesediseasesdiffer from to differentiate fromscratchedDHrash,althoughthe planus, urticaria and scabies may sometimes be difficult diseases, such as atopic and nummular dermatitis, lichen and bullouspemphigoid.Inaddition,otheritchyskin dermal blistering diseases, especially linear IgA disease Table I.Diagnosticproceduresindermatitisherpetiformis(DH)andrecommendationsregardingwhentheyshouldbeapplied HLA DQ2 and DQ8 typing Smallbowelbiopsyexamination Serum tissue transglutaminase orendomysial antibodies Histopathological analysis of lesionalskin biopsy Direct immunofluorescence examination ofperilesional skinbiopsy Diagnostic procedures Presenceof associated autoimmune diseases Family history of coeliac disease andDH Presenceof gastrointestinal andmalabsorptive symptomsandsigns Duration, severity andtype of skin symptoms Patient history and physical examination Procedure The differential diagnosis ofDHincludes other subepi In additiontothecharacteristicgranulardepositionof The gold-standardmethodtoverifyDHdiagnosis - - GFD adherence after the diagnosis. Circulating TG3 measurement canfurtherbe utilizedinthefollow-upof small bowelmucosaldamage. Ifelevated, TG2 antibody antibodies are suggestive of DH, and further, indicative of However, togetherwithacompatible clinicalpicture, TG2 and henceanegativeresultdoesnotexcludeDH(53). those patientswithsmallbowelmucosalvillousatrophy, disease, but in DH these antibodies are mostly confined to antibodies haveproventobehighlyaccurateincoeliac subjective andrequiresskilfullaboratorypersonnel. TG2 practice (Table I).However, theevaluationofEmA is IF-based EmA testscanequally beutilizedinclinical dies (EmA)(52),andELISA-based TG2- andindirect and TG3. TG2 isalsothetarget forendomysialantibo bodies againstbothtransglutaminaseisoenzymes, TG2 In DH, there are often circulating IgA-class autoanti FINDINGS INDERMATITIS HERPETIFORMIS SEROLOGICAL ANDSMALL BOWELMUCOSAL disease hasbecomeshorter(51). (39). Correspondingly, thediagnosticdelayin coeliac shortened duringrecentdecadesfrom12to8months same studyestablished that the diagnostic delay has associated withlongdiagnosticdelay. Fortunately, the a DH diagnosis prior to the year 2000 were significantly with DH.Femalesex,villousatrophyatdiagnosis,and diagnosis was 2 years or more in one-third of patients detected thatthedurationofskinsymptomsbefore the diagnostic delay ofDHduring the last 45years nosis ofDHisnotalwayseasy. The studyinvestigating of DHfromotherautoimmunebullousdisorders. mentioned findings alone do not allow the differentiation above- the However, (50). infiltrates eosinophil few a papillary microabscesses,togetherwithneutrophiland and blister subepidermal non-specific include findings an intactvesicleorerythematousskin,andthetypical Ideal areasforhistopathologicalbiopsyspecimenare compatible findings with DH support the diagnosis (40). is notrequiredfordiagnosisofDH,but,inobscurecases, on gluten(48,49). from that of Caucasian DH, andmaynotbe dependent A recentstudyfromFinlanddemonstratesthatdiag Histopathological examination of lesional skin biopsy Recommendation Only in obscure cases Only if gastrointestinalsymptomsnot compatible with coeliac diseaseexist Always In obscure cases Always Always Always Always Always Theme issue:Blistering skindisorders Dermatitis herpetiformis 117 - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Blistering skindisorders and anti-inflammatory properties,which relieves the DH with dapsone. with widespread,activerash needadditionaltreatment fore, atthebeginningofGFD treatmenttheindividuals several monthsorevenacoupleofyears(17,60). There symptoms, buttotalclearanceoftheDHrashmaytake the small bowel mucosaandalleviationoftheclinical with DH(59). Adherence toaGFDleadshealingof most countriesandtoleratedbythemajorityofpatients contaminated byothercereals)arecurrentlyallowedin from thedailydiet,butgluten-freeoats(i.e.not otherwise containingglutenarepermanentlyexcluded When adheringtoaGFD,wheat,rye,barleyandfoods The essentialtreatmentforDHisastrict,life-longGFD. IN DERMATITIS HERPETIFORMIS GLUTEN-FREE DIET AND DAPSONE TREATMENT bowel biopsieswhenDHisdiagnosed. behind thecurrentpolicyofnotobtainingroutinesmall DH (57,58),whichnaturallystrengthenstherationale does nothaveanyeffects onthelong-termprognosis of shown thattheseverityofmucosaldamageatdiagnosis to severevillousatrophyinDH,recentevidencehas bowel mucosal changes vary from inflammatory changes every diagnosticcentre.Importantly, eventhough small small bowel mucosal samples, which are not available in However, both of these investigations require frozen intestinal TG2-targeted autoantibodydeposits(25,26). of presence the is finding specific more even but (56), intraepithelial lymphocytesinthe small bowelmucosa both DH and coeliac disease is increased densities of γδ+ inflammation and/or immune response. Characteristic for bowel mucosaldamageevinceintestinalcoeliac-type However, virtually allsubjectswithoutevidentsmall of thepatientsevincenormalvillousarchitecture(53). bowel mucosal villous atrophy, but at least one-quarter of theuntreatedDHpatientshavecoeliac-typesmall DH diagnosis.Itiswidelyrecognizedthatthemajority per gastrointestinalendoscopyarenotnecessaryfor used inresearchsettings. some extent obscure, these antibodies are currently mostly TG3 antibodiesinDHandcoeliac disease is, thus far, to strict GFD.However, sincetheexactroleandvalueof development ofDH,especiallyifnotcompliantwitha patients with TG3 reactivity are susceptible to future can bespeculated that skin symptom-free coeliac disease increases withageincoeliacdisease(55). Therefore, it TG3 islowerthaninDH(1)andthat TG3 reactivity to antibodies the of affinity the disease coeliac in that able skinlesions(1,54,55).Ithasbeenshown,however, the serumofcoeliacdiseasepatientswithoutanydetect surprisingly, theseantibodiesoccasionallyalsooccurin but DH-specific, be to suggested been have antibodies 118 Dapsone is a sulfone drug with potent antimicrobial Small bowel mucosal biopsies obtained during up T. SalmiandK.Hervonen - However, there are some reports suggesting that a pro GFD shouldbelife-longinDH,ascoeliacdisease. be excludedbydietaryconsultation. dietary lapsesareamorecommonreasonandhaveto cases ofnon-responsiveDH,intentionaloraccidental However, sincerefractoryDHseemstobeveryrare,in on aGFDandtheriskoflymphomaisincreased(62). disease, inwhichthesmallbowelmucosadoesnotheal probablydivergesrefractory DH fromrefractorycoeliac and none had developed lymphoma, which suggeststhat the smallbowelmucosahadrecoveredinallsubjects, Interestingly, despitetheongoingclinicalsymptoms, dapsone wasstillessentialduetotheactiveDHrash. had followedastrictGFDformeanof16years,but DH (61). The patientswithrefractoryDHinthatstudy DH, wasfoundtooccurinlessthan2%ofpatientswith to aGFD.Recently this condition, named refractory the rashcontinuesdespitelong-lasting,strict,adherence usually neededfor2–3years(57,60).InrarecasesofDH, treatment after being diagnosed, and when initiated, it is approximately 70% of patients with DHrequire dapsone monitoring duringtreatmentisnecessary. InFinland hepatitis lessfrequent.Hence,clinicalandlaboratory example, methaemoglobinaemia, agranulocytosis and dose-dependent haemolysisisthemostcommonand,for doses areused,butside-effects arepossible,ofwhich Dapsone isusuallywelltoleratedwhenrecommended discontinued astheGFDalonecontrolsrash(60). finally and tapered slowly be should dose the peared, up to 100 mg/day, and then, once the rash has disap mg/day. Ifneeded,thedosecanbeincreasedgradually pathy. doseofdapsoneshouldbe25–50The starting or inflammation. However, a long follow-up is needed is follow-up long a However, inflammation. or deposits, nordidhedevelop intestinalvillousatrophy patient, however, didnotshowanyskinsymptomsorIgA without skinsymptomsorcutaneous IgA deposits.One wed progression of small bowel mucosal villous atrophy showed smallbowelvillousatrophy, and3patientssho also 12ofwhom rash, 15(79%) developedDH 6 months; this study, 18(95%)ofthepatientsrelapsed inameanof long-term GFD-treatedDHpatientsinFinland(67).In a 12-monthgluten-challengestudywasperformedin19 during the prolonged gluten challenge (66). Very recently, manifest anytypeofrelapseintheskinorsmallbowel patients withgluten,theyreported7(18%)whodidnot when Bardella et al. later challenged 38GFD-treated DH (64%) ofthesealsowithvillousatrophy(65).However, of 12(92%)patientswithDHrelapsedrashand 7 gluten-challenge studybyLeonardetal.reported11 out first The DH. in tolerance gluten of redevelopment challenge studieshavealsoinvestigatedthepossible symptoms orsignsofDH(60,63,64). Three gluten- later re-introduce gluten to their diet without developing portion of patients with DH following a GFD could rash anditcheffectively, buthasnoeffect ontheentero Current recommendationsarethattreatmentwitha - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV DH hada22-foldriskforthe laterdevelopmentofbul (79). Inthatstudy, patients withpreviouslydiagnosed interesting associationofDH withbullouspemphigoid A recentFinnishregisterstudy demonstratedarather DH, butsubsequentdevelopment isalsoapossibility. have beenreportedtodeveloppriorthediagnosisof cumented. Mostoftheassociatedautoimmunediseases do arenotwell associations althoughthese DH, ate with vitiligo andalopeciaareatahavebeenreportedtoassoci diabetes 1–2%(75–78).Inaddition,Sjögren’s syndrome, has beenreportedtobeashigh4%andthatoftype 1 In DH,the frequency ofautoimmunethyroid disease have mostlybeenexplainedbycommongeneticfactors. with otherautoimmunediseases,andtheassociations patients (74). and slightly better than that of long-term treated coeliac GFD-treated DHpatientswasequaltothatofcontrols, ported byanotherstudy, inwhichtheQoloflong-term patients’ onDH impactofGFD positive QoL isalsosup year, theQoL increasestothelevelofcontrols(35). The but importantly, alreadyafteradherencetoaGFDfor1 ledge, theQoL ofpatientswithDHseemstobereduced, and QoL exist. However, according to current know been widelystudied,butonlylimitedevidenceofDH been veryrarelystudiedinDH(69,73). similar extentinDH,althoughbonecomplicationshave with coeliacdiseaseseemsnottobeacomplicationof 71, 72). Also, theincreasedbonefractureriskassociated to be increased, which is in contrast to coeliac disease (69, risk ofgastrointestinalcarcinomashasnotbeenreported increased inDHandcoeliacdisease(70–72).InDH,the in DH,therisk of which has been shownto be similarly that adherencetoaGFDreducestheriskoflymphoma one-third of patients (58, 69). Evidence clearly confirms absentfor dataaboutdietary adherencewas from theUK, explain theirexcellentprognosis,whereasinthestudy 98% of patients with DH adhered to a GFD, which may mortality rate(hazardratio0.93)(69).IntheFinnishstudy, reduced non-significantly, but slightly, a found UK the not thereafter(58).Similarly, apreviousDHstudyfrom was increased during the first 5 years after diagnosis, but dardized mortalityrate0.70),andthelymphoma rate in DH was, in contrast, significantly decreased (stan that, inarecentFinnishDHstudy, theall-causemortality lymphoma mortalityrisk(68). Therefore itisinteresting Coeliac diseaseisknownforincreasedall-causeand Long-term prognosis onagluten-free diet in allpatientswithDH. justified still is GFD a to adherence strict life-long and of glutentoleranceinDHisrareorevennon-existent, by thispatient,andatpresent,itseemsthatdevelopment before itcanbeconcludedthatglutenistrulytolerated Similar tocoeliacdisease,DHhasbeenassociated Quality oflife(QoL)aspectsincoeliacdiseasehave ------countries, such as Finland. countries, suchasFinland. year 2012(80),andisalsoutilizedinadultssome diagnosis has been recommended in children since the of IFexamination.Incoeliacdisease,serologically-based and enablediagnosticsincentreswithoutthepossibility the longrun,whichwouldfacilitatediagnosisofDH antibody-based diagnosisofDHcouldbeapossibilityin of developmentDH.Onefutureprospectisthat TG3 DH diagnostics or in the identification of subjects at risk measurement of TG3 antibodyhasadditionalvaluein revealwhether presumably will studies Future diagnosis. testing hasasupportive,butnotexclusive,roleinDH further valueinroutinediagnostics,and TG2 antibody I). Investigationofsmallbowelmucosalhistologyhasno biopsy remainthecornerstonesofDHdiagnosis(Table indicative ofDHandIFexaminationperilesionalskin ment ofDHdiagnostics.Recognizingthecutaneoussigns indicate thatthereisstillanecessityforfurtherimprove third ofpatientswithDHinahighprevalencearea(39) DH indifferent countries,anddelayed diagnosis inone- for figures prevalence variable However, (39). decades that the diagnostic delay has become shorter during recent decrease the QoL of patients (35).It is therefore fortunate 6). The cutaneoussymptomsofDHaretroublesomeand diagnostics has resulted in a declining incidence of DH (5, furthermore, that more accurate and active coeliac disease the developmentofDHand TG3 antibodyresponseand, directed immuneresponseservesasaprerequisitefor long-lasting andundetectedcoeliacdiseasewith TG2- manifestation ofcoeliacdisease.Itissuggestedthat DH isachronic,bullous skin disease,which is askin CONCLUSION could beanepitopespreadingphenomenon. speculated that a possible mechanism ofthis evolvement of DHtodiagnosisbullouspemphigoid. The authors lous pemphigoid,withameanof3yearsfromdiagnosis for futurestudies. patients adheringtothesame dietisaninterestingtopic trends currentlyexistingamong DHandcoeliacdisease tity morethoroughly. Inaddition,thediffering mortality en this to elaborate evidence isneededinorder research current knowledge of refractory DH is scarce and more compared with refractory coeliac disease (61).However, in general,refractoryDHseemstohavebetterprognosis Factual non-responsivenesstoGFDisrareinDH,but, effect on the above-mentioned outcomes of DH(57, 58). been shownthatthedegreeofvillousatrophyhasno sociated diseasesofDHandmortality. Instead,ithas as or complications of development the influence that adherence to a GFD, little is known about the factors with DHwhofollowthedietrigorously, butotherthan prognosis seems to be excellent in thoseindividuals herence to GFD is justified in all patients with DH. The According to current knowledge, strict life-long ad Theme issue:Blistering skindisorders Dermatitis herpetiformis 119 - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV 13. 12. 19. 16. 11. 18. 15. 10. 20. 17. 14. 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------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV stage whetherthereactionwillbesevereandlife-threa One ofthemajorchallengesistoidentifyataveryearly doi: 10.2340/00015555-3408 (1) reported2casesofadisseminated cutaneouseruption In 1922, the American paediatricians Stevens & Johnson HISTORICAL CONSIDERATIONS and treatmentmodalitiesdiffer substantially. mimic SJS/TEN.Differentiation isimportantasprognosis conditions suchasGBFDEorIgA-lineardermatosiscan toimmune disease,isalsochallenging,since,forexample, fixed drug eruption (GBFDE) and, sometimes, bullous au and toxicepidermalnecrolysis(TEN),generalizedbullous types ofreaction,suchasStevens-Johnsonsyndrome(SJS) tening. Onceblistersarepresent,differentiation between B E-mail: [email protected] Faculty, University of Freiburg, Hauptstr. 7, DE-79104 Freiburg, Germany. tionen (dZh), Department of Dermatology, Medical Center and Medical Hautreak schwerer Dokumentationszentrum Mockenhaupt, Maja Corr: Acta DermVenereol 2020;100:adv00057. Accepted Jan24,2020;EpubaheadofprintFeb 6,2020 fixed drugeruption. son syndrome; toxic epidermal necrolysis; generalized bullous Key words: severe cutaneous adverse reaction; Stevens-John munomodulating therapy maybeconsidered. appropriately. Inaddition to care,im bestsupportive underlying condition, aninfection, e.g. mustbetreated be withdrawn, while within cases other aetiology the with drugcausality the potentially agentmust culprit cases of bullous eruptions Incases aredrug-induced. although it should be taken into account that not all drug, inducing potentially the of identification cludes quate managementmustbeinitiated. Thelatter in spected, appropriate diagnostic andade procedures membranes become obvious. Oncethe diagnosis is su before blisters anderosions oftheskinandmucous toms that indicate a severe bullous drug eruption even blister formation. Theremaybeearlysignsandsymp ferentiate themfrom other clinicalentities involving Freiburg, Germany Dokumentationszentrum schwerer Hautreaktionen (dZh), Department of Dermatology, Medical Center and Medical Faculty, University of Maja MOCKENHAUPT Bullous DrugReactions Centenary theme section:BLISTERING SKIN DISORDERS is important to recognize theseconditions andto dif most adversereactions It severecutaneous (SCAR). to treating physicianstheyareconsideredto bethe they pose a bothchallenge to patients and affected Bullous drugeruptions areinfrequent, butbecause Acta DermVenereol 2020;100: adv00057 medication use, but there are also other possible causes. ullous drugreactionsgenerallyoccurasaresultof This isan open access article under the CC BY-NC license. www.medicaljournals.se/acta REVIEW ARTICLE ------associated with erosive stomatitisandsevereocularinvolve erosive with associated considered asseverityvariants ofasinglediseaseentity findings, aetiology, risk factors, and mechanisms, they are SJS and TEN shareaclinicalpattern, histopathological definition that separates these conditions from EM. Because developedaconsensus international groupofdermatologists and theobservationthatSJS mayprogressinto TEN, an necrolysis” forSJS/TEN.Basedontheoriginaldescriptions EM, whereas Lyell (8) suggested the name “exanthematic TEN and“transmissionofforms”,butdidnotseparate the term“acutedisseminatedepidermalnecrosis”forSJS, the reactions.Ruiz-Maldonado(7),forexample,proposed tempts have been made to disentangle, regroupand rename described byvonHebrain1860(6).However, severalat the spectrum of erythema multiforme (EM), which was first pathological features,SJSand TEN havebeenincludedin clinical featuresandbehaviourinallergological testing. rated amultilocularorGBFDEfromSJSand TEN through Around the same time Kauppinen (5)fromFinlandsepa the causeofthisreactionandtonameitaccordingly(4). it tookuntil1971toidentifyastaphylococcalexotoxinas case had already been described in his first publication, but between anintraepidermalsubcornealseparationinone eruption (GBFDE) (3). The histopathological difference drug fixed bullous generalized and (SSSS) syndrome skin cases inhispublicationasSJS/TEN,staphylococcalscalded that time,butinalaterreappraisalevaluatedtheoriginal4 Lyell did not refer to the findings of Stevens & Johnson at introduced theterm“toxicepidermalnecrolysis”.However, patients with epidermal loss secondary to necrosis, and ment. In 1956, the Scottish dermatologist Lyell (2) described tive care, immunomodulating therapy may be considered. e.g. infection, must be treated. In addition to best suppor while in cases with other aetiology, the underlying condition, withdrawn, be must agent culprit potentially the causality, drug with cases In crucial. is infections, and use drug toms, must beinitiated. Adetailedhistory, includingclinical symp pected, appropriate diagnosticandtherapeutic procedures sus is diagnosis the appear.Once mucosa and skin the of picion of a bullous drug reaction before blisters and erosions re are early signs and symptoms that may lead to the sus tions) are challenging for reac patients and physicians. drug Often the bullous as (known blisters with reactions Drug SIGNIFICANCE Over theyears,duetosimilaritiesinclinicalandhisto Journal Compilation ©2020ActaDermato-Venereologica. ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV so-called typicaltarget lesionsseeninEM)and/ormacules (these lackthetypical3-zone, target-like constellation of hematous exanthema consists of atypical flat target lesions detachment anderosionsofmucous membranes. The eryt EN ischaracterizedbyerythematous skin,epidermal CLINICAL FEATURES ANDCLASSIFICATION due toadvancedageanddiseaseseverity(21). older than70yearsandapproximately22%ofpatientsdie frequently affects women.Oftheaffected patients70%are most typesofcutaneousadversereactions,GBFDEmore since therearecurrentlynopopulation-baseddata. As with curring morefrequently(15,20). involvement orcaseswithonlymucosalinvolvement)oc (SJS-TEN), with milder cases (EM minus with only skin approximately thesameorderofmagnitudeasthatEN of casessevereEMMleadingtohospitalizationis years) andmale(approximately 75%)(9,20). The incidence young (80%areyoungerthan40years,45%under18 and underlyingconditions. The majorityofpatientsare vement) isverylow, affecting fewindividualsofolderage multiforme majus(E(E)MM;i.e.EMwithmucosalinvol age, andunderlyingcomorbidity. prognosis, suchaslarger extentofskindetachment, older 50% for TEN (17–19).Severalfactorscontributetopoor 22–25%, varying from approximately 10% for SJSto almost risk (11, 16). The overallmortalityassociatedwithENis and sometypesofvasculitis)cancerareatincreased disease mixedconnectivetissue scleroderma, polymyositis, lupus erythematosus,Sjögrensyndrome,dermatomyositis, tive tissuedisease,includingrheumatoidarthritis,systemic patients with collagen vasculardisease (also called connec man immunodeficiency virus (HIV) and, to a lesser degree, affected, withasexratioof0.6.Patientsinfected withhu more than2,200patients(15). Women aremorefrequently patients was53.4years(range1–94years)inacohortof elderly personsover65yearsofage(14). The meanageof increases with age and the highest incidence is seen in rare diseases(13).ENcanoccuratanyage,buttherisk not primarilydesignedforepidemiologicalanalysisof cases permillionyearderivefrommedicaldatabases based registry (11, 12).However, incidences as high as 5–6 using strictlyvalidatedcasesofaprospectivepopulation- all incidence Epidermal necrolysis (EN) is a rare condition with an over EPIDEMIOLOGY for both(10). or “epithelial necrolysis” (referringto skin and mucosa) more appropriatetousetheterm“epidermalnecrolysis” to thebodysurfacearea(BSA)(9). Therefore, itseems that differs onlyintheextent ofskindetachmentrelated To date, estimates ofthe incidence ofGBFDE are lacking, In contrast,themortalityforerythema(exsudativum) of 1–2casespermillionpersons,estimated ------cranial to caudal. Blisters develop on the erythema and coa from spread and confluent become to tend frequently that necrolysis. EM: erythema multiforme; SJS: Stevens-Johnson syndrome; TEN: toxic epidermal disease entityofdifferent severity(9). aetiology andpathogenesis,theyareconsideredasasingle TEN, andduetothefactthatSJS TEN share thesame progresses, turningacaseinitiallythoughtofasSJSinto present (Fig. 2). Due to the fact that the skin detachment and sometimesalsotrachea,bronchi,urethraanus,are branes, includingeyes,lips,mouth,vulva,glanspenis, mem ofmucous haemorrhagicerosions 95% ofcases, SJS/TEN-overlap (Table I, as defined is values these between detachment Skin TEN. the BSA referstoSJS,andmorethan30%of theBSA to of 10% than less of detachment skin definition: consensus the to according classified is condition (10). The common erosion inadditiontotheskin.Feverandmalaisearevery lesce. Usually, at least one mucous membrane is affected by Table I.Consensusdefinitionofepidermalnecrolysis(EN)(22) areas ofskindetachmentinepidermal necrolysis(patient’s back). blisters, leading to large confluent with macules Confluent 1. Fig. Distribution Maculae Atypical targetlesions Typical target lesions Skin detachment, % Criteria limbs Mainly – Raised + < 10 majus EM Theme issue:Blistering skindisorders SJS spread Wide + Flat – < 10 Fig. 1)(22).Inapproximately spread Wide + Flat – 10–30 overlap SJS/TEN Bullous drugreactions maculae with TEN spread Wide + Flat – > 30 (without spots) erythema TEN onlarge Widespread – – – >10 123 - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV multiforme majus(ontheleg). Fig. 3.Typical target lesions with centralblisters in erythema distinction fromSJS(23).Moreover, duetotheirdemarca helps tobetterclassifythevariouspatternsofEMandtheir The description ofa typical andatypical type ofEMM and adolescents,sincetheselesionssometimescoalesce. distribution oftypicaltarget lesions,especiallyinchildren This alsoaccountsforthemainlytruncalandgeneralized case ofatypicalEMMinvolving“gianttargets”. ( especially when typical targets on the limbsare present cases), of 90% than more (in definition consensus the on of health(20). severely illwithhighfeverandoverallpoorgeneralstate 10, 20).Furthermore,youngerpatientswithEMMmaybe medications andinEMMalmostexclusivelyinfections(9, of causal factors, which in SJS/TEN are predominantly assessment false to lead may classification incorrect this was assumedtobealesssevereformofSJS.However, mucosal involvement(erythemamultiformemajus;EMM) Theme issue:Blistering skindisorders may alsopresentwithdiffuse erythemaandblisters,which more than10%oftheBSA (Fig.4).However, the reaction blistering and,inmostcases,skin detachmentdoesnotaffect patches, buttheskinremains intactbetweentheareasof laceous or brownish colour. Blisters may develop on these well-defined round or oval, egg-sized patches of dusky vio agnosis ofEN. This reaction istypicallycharacterizedby resolving patchesinGBFDE(18). tion towardsintactskin,older“gianttargets” mayresemble of lipsandoral mucosa,genitalerosions in (c)amaleand(d)femalepatient. orerythemamultiformemajus in epidermalnecrolysis membranes 2. Haemorrhagicerosionsofmucous Fig. 124 Fig. 3).However, differentiation may be challenging in the EMM andSJScangenerallybewelldifferentiated based Due tothesametypeofmucosalinvolvement,EMwith Besides EMM,GBFDEisanimportantdifferential di M. Mockenhaupt - - - malaise, buttheremaybemildmucousmembraneinvol erythema arepotentiallysevereformsofGBFDE(10,24). among expertsastowhethertherarecasesof TEN onlarge will showdemarcationduringthecourse. There isadebate are no specific laboratory parameters to differentiate bet differentiate to parameters laboratory specific no are the validationphaseandhasnotyetbeenpublished. There diagnostic differentiation ofGBFDE,whichis currentlyin above (22),the RegiSCAR-group developed a score forthe patient’s medicalhistory(18,21,24). not theocular surface. Milder eruptions are frequent in the vement, withthegenitaland/ororalmucosaaffected, but generalized bullousfixeddrug eruption Fig. 4.Well-demarcatederythematous patches with blisters in containing infiltrate perivascular deep a stage, later a at possible inthecourseofdisease.Ifabiopsyistaken histology ofGBFDE,inwhichadistinctionissometimes proof the specific clinical form. The same accounts for the condition within the spectrum of disease but is unable to clinical the confirm only can histopathology Therefore, in thedermis,oftenaperivascularlocation(25,26). visible, as well as a sparse superficial lymphocytic infiltrate an EMMtarget, completeepidermalnecrosismayalsobe important: ifthebiopsyistakenfromcentralblisterof formation. Localizationandtimingofsamplecollectionare or ascompleteepidermalnecrosiswithsubepidermalblister ptotic) keratinocytes, either in a disseminated distribution The histologyofEN HISTOPATHOLOGY ween thevarioustypesofblisteringreactions. Patients withGBFDEusuallydonotdevelopfeverand To supplement the consensus definition for EN described reveals necrotic(dyskeratoticorapo : (a)blepharitis,(b)erosions (ontheback). - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV symptoms occurinchildren (10, 18,33). are important differential diagnoses when the first signs and patients (Table II ) (32). Varicella and other viralexanthems and conjunctivitis,mustbeconsidered, especiallyinelderly drug eruptions, which can also present with oral lesions of thedisease,maculo-papular, multiforme-ortarget-like tern and during the course of the reaction. In the early stage sometimes mistakenforskindetachmentinEN(18,31). post-inflammatory desquamation is frequently observed and normal values. When theskineruptionheals,widespread days mayoccur when eosinophilia has already turned to at leasta2-foldincreaseintransaminases,on2different kidney parameters,etc.Liverinvolvement,indicatedby for adiagnosisofDRESS,e.g.eosinophilia,liverenzymes, it is important to monitor specific laboratory values relevant Therefore, DRESS. to point skin the of infiltration matory inflam with erythema and oedema facial as such features erosions ofthelipsmayraisesuspicionEN,although cells (18).Inaddition,atypicaltarget lesionsonthelimbsand epidermal of necrosis secondary by followed first occurs epidermal detachmentandthatthesubepidermalseparation will showthatthereisnofull-thicknessnecrosisleadingto (DRESS), ENmightbesuspected,butearlyhistopathology in drugreactionwitheosinophiliaandsystemicsymptoms blister roof (30). If tension blisters appear due to oedema epidermal blisterformationandsecondarynecrosisofthe in body areas with oedema, leading to widespread intra rapid healing of the subcorneal lesions. Bullae may occur since thereisnoprimaryepidermalnecrosis,but Nikolsky’s sign.However, AGEP doesnotturnintoEN, EN, when confluence of pustules appears to reveal a positive generalized exanthematous pustulosis (AGEP)may mimic subacute cutaneous lupus erythematosus (10,18). Acute drug eruptions,erythroderma,exfoliativedermatitis,and considered inthedifferential diagnosisincludewidespread being afrequentcause(29).Otherdisordersthatshouldbe tachment incasesthatweredrug-induced,withvancomycin reported amoreseverepatternwithlarger areasofskinde several casereportsandseries(28,29).Someauthors (LABD) can imitate SJS/TEN, as has been described in should beperformed(10).LinearIgA bullous dermatosis parameters (e.g.anti-BP 180-,230-,desmogleinantibodies) immunofluorescence test as well as serological autoimmune (10). adirect suspected, is diseases Therefore, ifoneofthese pemphigus, should be included in the differential diagnosis IgA dermatosis, pemphigus vulgaris, and paraneoplastic autoimmune dermatoses, such as bullous pemphigoid, linear shows intraepidermal,subcornealseparation(4).Bullous cal scaldedskinsyndrome(SSSS),whichhistologically EN andGBFDEmustbedifferentiated fromstaphylococ FURTHER DIFFERENTIAL DIAGNOSES also pigmentdeposits(26,27). neutrophils andeosinophilsmaybeseen,potentially Other differential diagnosesvarywiththeclinicalpat - - - - - These symptomsarefollowedbytheappearanceoferythe malaise, precedingmucocutaneouslesionsby1–3days. such assorethroat,runnynose,cough,headache,fever, and EN typically begins with unspecific prodromal symptoms, CLINICAL COURSE OFEPIDERMAL NECROLYSIS erythematous, dusky-red,irregularly-shaped,purpuricma couple ofhours. The initialskinlesionsarecharacterizedby rapidly to the entire body within a few days or even within a arms andlegsareoftenspared,buttheeruptionmayextend and theproximalpartsoflimbs. The distalpartsofthe a symmetricaldistributionontheface,uppertrunk, of aseveredisease(10,33). patient’s general state ofhealth should prompt the suspicion addition ofnew signs, severe pain, and rapid decline in the membranes. The rapid progression of such symptoms, the begin directly with specific lesions of the skin and mucous either bycutaneous ormucosal involvement, but some may Most reactions start with non-specific symptoms, followed progressively, heraldingmucousmembraneinvolvement. of the eyes, and pain whenswallowingorurinating,develop confluent and on which blisters occur. Burning or stinging matous macules andatypical targets oftheskinthat may be (10) (EN) of epidermalnecrolysis diagnoses Table II.Differential that thesurfaceareacan becoveredbyonehand(the small blisters. Therefore, itmaybehelpfultoremember ment is difficult, especially in areas with spotty lesions and Nikolsky’s sign). Correctevaluationoftheextentdetach in whichtheepidermisisdetached ordetachable(positive area total the on based I) (Table definition consensus the (10, 15,18,33). dermis, whereas the epidermis may remain in other areas revealing large areasofexposed,red,sometimesoozing orbyfrictionaltrauma, points detachedatpressure easily is easily arepresentatthisstage,andthenecroticepidermis positive onerythematousareas.Flaccidblistersthatburst sign (dislodgementoftheepidermisbylateralpressure)is necrotic lesions leads to extensive erythema, and Nikolsky’s lesions with dark centres are often observed. Confluence of cules, whichcoalesceprogressively(Fig.1). Atypical target  Most likely   Consider         

– Varicella – Erythemamultiforme majus Limited EN (SJS) – Drug reaction with eosinophilia and systemic symptoms – Drug reaction with eosinophilia and systemic symptoms – Generalized bullous fixed drugeruption – Acutegeneralized exanthematous pustulosis Widespread EN(SJS/TENoverlap and TEN) Paraneoplastic pemphigus Linear IgA bullous dermatosis Pressure blistersafter coma Tension blistersduetooedema Phototoxic reaction Graft-versus-host disease Staphylococcal scalded skin syndrome Thermal burns Skin necrosisfrom disseminated intravascular coagulation or Chemical toxicity (e.g. colchicineintoxication, methotrexate overdose) In the majority ofEN-casestheeruption initially shows In terms of severity, cases are classified according to according classified are cases severity, of terms In Theme issue:Blistering skindisorders Bullous drugreactions 125 - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV NSAIDs: non-steroidal anti-inflammatory drugs;ACEinhibitors:angiotensin-converting-enzyme inhibitors. Theme issue:Blistering skindisorders Table III.Drugsandrecommendationsinepidermalnecrolysis(EN)(34) more thanhalfofthecasesoccurringinEuropeaccording for account these and risk, high a carry to identified been in theliteratureasinducersofEN,lessthanadozenhave Although more than 100 different drugs have been reported AETIOLOGY ANDMEDICATION RISK complications andlong-lastingsequelae(10,15,18,33). tation, inparticular, isanurgent requirementtoprevent and genitalmucosainwomen.Ophthalmologicalconsul further specialistsintheexaminationofeyes,deepthroat clinical examinationofthepatient’s entirebody, involving in younggirls. but maybemoreeasilyoverlookedinfemales,especially be shed.Genitalerosionsarefrequentinmenandwomen, occur between eyelids and conjunctiva, andeyelashes may and purulentconjunctivitisblepharitis.Synechiaeoften to epithelialdefectandcornealulceration,anterioruveitis, lacrimation, rednessand discharge. Severe forms may lead have conjunctival lesions accompanied bypain, photophobia, with haemorrhagiccrusts. Approximately 80%ofpatients with greyishwhitepseudomembranes. The lipsarecovered affected and reveals painful haemorrhagic erosions, often and painfulurination. The oralcavityisalmostinvariably lead toimpairedalimentation,photophobia,conjunctivitis mes, trachealorbronchialmucosa. These symptomsusually erosions oftheoral,ocular, genital,nasal,analand,someti 2). Ittypicallybeginswitherythema,followedbypainful 2 sites)isobservedinapproximately90%ofpatients(Fig. the patient’s BSA (10,15). patient’s handinchildren)representsapproximately1%of 126 • • • • • • • • C. Drugs with no increased risk of EN • • • • • B. Drugswith a moderate(significant butsubstantially lower)riskof EN The risksof various antibioticstoinduce EN are within thesameorderof magnitude, but substantially lower than the riskof anti-infective sulphonamides. and if some may becontinuedor re-introduced. stopped be must one(s) which determine to important is administration of timing the benefits, expected high with severalmedications to exposed are patients When An interval of 4–28 days between start of drug use andonsetof adverse reaction is most suggestive of an association between themedicationandSJS/TEN. • • • • • • • • Use of these drugsshould be evaluated carefullyand they should besuspected promptly. A. Drugs with a high risk of inducing EN Valproic acid NSAIDs (propionicacid type, e.g. ibuprofen) Insulin Sulfonylurea anti-diabetics (with sulphonamide structure) Thiazide diuretics(with sulphonamide structure) Calcium channel blockers ACE inhibitors Beta-blockers NSAIDs (aceticacid type, e.g. diclofenac) Tetracyclines Quinolones Macrolides Cephalosporins Phenytoin Phenobarbital NSAIDs (oxicam type, e.g. meloxicam) Nevirapine Lamotrigine Co-trimoxazole (and other anti-infective sulphonamides and sulfasalazine) Carbamazepine Allopurinol To detectsuchdistinctfeatures requiresathorough Mucous membraneinvolvement(inmostcasesonatleast M. Mockenhaupt - - high-risk drugsareallopurinol,antibacterialsulphonami to 2 multinational case-control studies (16, 34). These shown fordifferent groupsofantibiotics,suchascepha lower, riskthanforantibacterial sulphonamideshasbeen III) (34,36). acid derivatives(e.g.ibuprofen)noincreasedrisk(Table derivatives (e.g. diclofenac) moderate risk, and propionic groups: oxicam derivatives carry the highest risk, acetic acid EN, butthereisahugedifference inriskamongthevarious more thanadecadeagoandremainsassuchtodate(40,41). was identified as the major cause of EN in Europe and Israel is widelybelievedtobeaverysafemedication;however, it lopurinol, an old drug used to treat hyperuricaemia and gout, revealing alower, butsubstantial,riskofcausingEN. Al a far lower risk,seemsto cross-react with carbamazepine, derivative ofcarbamazepine,whichwasconsideredtohave decreasing riskofEN(37–39).Oxcarbazepine,a10-keto rate ofmilderuptions.However, thereisnoevidencefora since slowdoseescalationhadbeenshowntodecreasethe of thedosagecouldpreventsuchsevereadversereactions, HIV-drug nevirapine,itwasthoughtthataslowtitration and 28days(16,34,35,36).Forlamotriginetheanti- 4 between medication the of use continuous first the after 8 weeksoftreatmentand most reported EN cases started and nevirapine. The risk appears to be confined to the first oxicam-type, the of (NSAIDs) drugs anti-inflammatory lamotrigine, phenobarbitalandphenytoin,non-steroidal des, certainantiepilepticdrugs,suchascarbamazepine, pump inhibitors ortramadol, thecalculated riskwas For other medications, such as corticosteroids, proton losporins, quinolones,tetracyclinesandaminopenicillins. Among anti-infective agents, a significant, but much but significant, a agents, anti-infective Among Often the entiregroupof NSAIDs is suspectedtoinduce - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV use. Furthermore,information onprioruseisveryim of day last and first their with listed be should index-day 34). All medicationstakenwithinamonthprecedingthe (so-called index-day)isofmajorimportance(10,15,33, the correctdeterminationofdayreactiononset as forcausalityassessmentinanindividualcaseofEN, the causeofENifitwastaken andtoleratedinthepast. A portant, since it is rather unlikely foramedication to be eliciting factorsmustbesaught: children andadolescentswithEN.Inthesecasesother drug cause, whereas this proportion reaches 50% among EN, at least 25% of all cases remain without a plausible nations ofolddrugsaretakenintoaccountastriggers epidemiological methods.Evenifnewdrugsorcombi different completely 2 using by identified be could cause For approximatelyone-thirdofcasesEN,nopatentdrug “unlikely”, “possible”,“probable”to“veryprobable(43). taken orwasadministered,rangingfrom“veryunlikely”, causality assessment for each individual drug a patient has and alternativecauses.Numericalscorevaluesleadtoa notoriety (based on drug lists that require a regular update) rechallenge anddechallenge(ifavailable),typeofdrug/ liver andkidneyfunction),informationonprechallenge/ into accountthedrug’s half-lifeaswellthepatient’s reaction), drugpresentinthebodybeforeindex-day(taking start ofdruguseandindex-day(i.e.onsettheadverse is basedonthefollowingcriteria:timelatencybetween tured helpforidentifyingthemostlikelyculpritdrugand more than2decades(16,34,42). ALDEN providesstruc and moderate)riskwasstable(65–68%)overaperiodof could be explained by medications with a significant (high demonstrated thattheproportionofvalidatedcases ALDEN (algorithmforcausalityassessmentinEN)(42) of systematicallyascertainedregistrydataonENusing with theresultsof2case-controlstudies,recentanalysis strongly affected byconfounding (16,34).Incomparison that mustbeconsideredasadifferential diagnosisofEN(45). skin detachment may be an extreme phenotype of cutaneous LE doubtful in such cases and keratinocyte necrosis and subsequent sociated withanincreasedriskofEN.Oftendrugcausalityis erythematosus (systemic LE or subacute cutaneous LE) is as of GVHD,thisdiagnosisseemstobemorelikely(44).Lupus transplantation andthepresenceofnon-cutaneoussymptoms often indistinguishable,butdependingonreactiononsetafter and histological findings in EN and extensive acute GVHD are acute graft-versus-hostdisease(GVHD).However, clinical by medicationuse,othersareratheramaximalvariantof transplantation, someeruptionsofwhichmaybeinduced EN hasalsobeenreportedinthecontextofbonemarrow and mustbelabelledas“idiopathic”(10,24). the reactionoccurssuddenlywithnopriorsignsorsymptoms distinguished fromtheprodromalsymptomsofEN;inothers niae, are rare. In some cases a preceding infection cannot be virus, cytomegalovirus,adenovirusorMycoplasmapneumo certain well-knowninfectiousagents,suchasEpstein-Barr diagnosed by clinical means, but positive serology related to month before reaction onset. Mostoften these infections are An importantnon-drugriskfactorisinfectionswithinone For druganalysisinepidemiologicalstudies,aswell - - - - - differs fromtheclassicalsensitization inallergic condi weeks, withoutpriorexposure(34). Thus, themechanism use, mostoftenfor drug inducing EN is typically taken as the first continuous patient numbers. The rangeoftriggersincludeantimicro (47–50); however, no analyses have been conducted on large literature providinginformationonpossibledrugtriggers risk ofcausingEN(33). bacterial infectionsalonedonotseemtohaveanincreased but ithelpstoconsiderthetypeofinfection,sinceclassic tics usedtotreatinfections(“confoundingbyindication”), triggering agentcanbechallenginginthecaseofantibio (34, 35). Differentiation between infection and drugs as the an increased risk was estimated in epidemiological studies these substances do not belong to the drug groups for which weeks toatleast4daysbeforereactiononset.Furthermore, 4 started that use continuous first the represents exposure cations causingENhavenotbeenusedpreviouslyandtheir drug exposurecausingEN(15,33,46).Incontrast,medi (“protopathic bias”).Neitherofthesepatternsistypicalfor were started after the onset of prodromal symptoms of EN they haveusuallybeentakenandtoleratedpreviouslyand/or When lookingmorecloselyattheuseofthesemedications, as“coughandcoldmedicines.” summarized sometimes mainly concernsantipyretics,analgesics,andsecretolytics, toms aresuspectedofhavinginducedthereaction. This identifiable, medications taken to treat the prodromal symp tions (10,15,37,38,39). there has been a previous, often less severe, event, but cases there hasbeenaprevious,often lesssevere,event,butcases T cellsremainingintheaffected skin(51).Inmanycases high riskofrecurrence,which maybeexplainedbymemory repeatedly intheliterature. was verysimilarandnotnecessarilyshorter, asreported latency betweenthestartofdruguseandreactiononset to the same drug that had induced the first event. The time experienced asecondeventofENafteraccidentalexposure multinational RegiSCAR study, few individual patients Kirsti Kauppinenhadalreadyobservedin1972(5).Inthe The risk of recurrence in EN appears to be rather low, as RISK OFRECURRENCE must bedifferentiated fromEN. of the drug. Thus, GBFDE is a classic allergic reaction that with a fixed drug eruption occurs rapidly upon renewed use tion happensovertime,meaningthatareactionconsistent has oftenbeenusedandtoleratedinthepast(18).Sensitiza hours toafewdays.IncontrastEN,thetriggeringagent the startofdruguseandreactiononsetrangesfromafew (especially carbamazepine) (47–50). The latency between frequently, antibiotics, allopurinol, andantiepilepticdrugs (especially metamizole,butalsoparacetamol),and,less bial sulphonamides(especiallycotrimoxazole),analgesics For GBFDE,therearenumerouscasereportsinthe Frequently, andespeciallywhennoobviousdrugcauseis In contrast, fixed drug eruption, including GBFDE, hasa 1–4 weeks,butsometimesforupto8 Theme issue:Blistering skindisorders Bullous drugreactions 127 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV in thedermisandCD8 Theme issue:Blistering skindisorders this alleleanassociationof55% wasfoundinallopurinol- disease, notonlyforEN,but alsoforDRESS(65).For observed inHanChinesepatients withallopurinol-induced (52). A secondstrongassociation withHLA-B*5801was symptoms differentpulmonary and DRESS SJS/TEN from by fever, rash and constitutional, gastrointestinal, and/or ciated withabacavirhypersensitivity, whichischaracterized HLA-B*5701 hadpreviouslybeendemonstratedtobeasso to carbamazepine-inducedSJS/TEN(64).Interestingly, HLA-B*5701 was identified to confer genetic susceptibility sociation couldnotbedetectedinEuropeanpatients,where with ENwhowereofHanChinesedescent(63). This as HLA-B*1502 andcarbamazepinewasobservedinpatients (62). Almost 20 years later, a strong association between associated with sulphonamides or with oxicam-NSAIDs human leukocyte antigen (HLA) loci were found for TEN predisposition todevelopEN. As earlyas1987,different as welltheriskofmortality(61). that IL-15is associated with the severity ofthe reaction immunomodulating treatments.Ithasalsobeenshown is a severity marker in EN and provides a target for possible reaction (60). Therefore, it wasconcludedthatgranulysin concentration correlatingwiththeseverityofclinical with ENcomparedotherblisteringdiseases,its patients of fluids blister the in cytotoxicity strongest the but ratherthecationicproteingranulysin(60).Itshowed the mostimportantcytokinesinacutephaseofEN, ver, itwasdemonstratedthatFasandligandarenot CD4 primarily identified investigations chemical the pathogeneticmechanisminEN,sinceimmunohisto A T-cell reactioncomparabletoGVHDisbelievedbe PATHOGENESIS ANDGENETICS rapidly that they are notrecognized again asan antigen (52). and itmaybeassumedthattheviraltriggerschangeso restingly, infection-inducedENcasesdonotseemtorecur, even severaltimes,beforethereactionresolves(20).Inte been observed,inupto10%ofcases,andsomepatients escents, andherpessimplexvirusinadults.Recurrencehas infections, especiallyM.pneumoniaeinchildrenandadol and re-occurwiththesameamountofinvolvement(49). with extensiveskindetachmentmayalsooccurdenovo 128 receptor enhanceapoptosisinkeratinocytes(59).Howe proteins such as Fas antigen (CD 95) and the P55 TNF-α as TNF-α or granzyme B (57, 58). It is also assumed that enhanced bythereleaseofperforinandcytokines,such (54, 56).Cytotoxic T-cells areabletoinitiateapoptosis, in ENisattributedtoanextensiveprocessofapoptosis metabolites (55). The acutenecrosisofkeratinocytes the nativeformofdrugratherthanagainstreactive cytotoxic T against directed specifically are usually cells In contrasttowhatwaspostulatedinearlieryears,these It hasbeenknownformanyyearsthatthereisagenetic EMM appearstobealmostexclusivelytriggeredby M. Mockenhaupt + cellsintheepidermis(53,54). + cells ------predisposition isnottheonlyimportantfactorfordevelo induced ENcasesofEuropeandescent(66).Clearly, genetic the reaction,mostlikelyculpritdrugshouldbeiden Assuming amedicationratherthananinfectiontriggered Taking a detailed and thoroughmedication historyiscrucial. THERAPY compared withEN(27). concentration ofgranulysinismuchlowerinGBFDE B, areequallyexpressedinGBFDEandEN,whereasthe FAS/FAS-L, as such cytokines, perforinandgranzyme reaction mayexpandifitrecurs(51).Furthermore,several drug eruption”takesthisfactintoaccount,althoughthe “fixed term site. The same the at re-occurs reaction a why affected areasofskinas“memorycells”,which explains cells play an important role here, since they remain in the analyses on the T-cell population in fixed drug eruption. T genesis ofGBFDEhaveyetbeenundertaken,thereare EN cases(68). test has led to a marked reduction in carbamazepine-induced least inthecaseofcarbamazepine,forwhichpredictive successfully demonstratedinSoutheast Asian subjects,at predictive test to prevent EN (67). In contrast, this has been medication-specific a deploy to large too be to appears chromosome 6,thevariabilityinEuropeanpopulation alleles/genetic variantsarealllocatedintheHLA locus on European patientswithENdemonstratedthattherelevant (46). Although alarge genome-wideassociationstudyin be ultimatelyassociatedwithinfection-inducedreactions to betriggeredbyantipyreticsandsecretolyticsappear ver, some reports on specific HLA alleles in cases thought the geneticpatternofinfection-inducedENcases.Howe African descent(52). was shownforpatientsofsoutheast Asian, Europeanand as ethnicity, patient’s the also but drug, specific a to due ping acertaintypeofseverecutaneousadversereaction antimicrobial treatment;reluctance toprovidemedication reaction, patientsshouldreceive adequateantibioticor as triggers.Ifaninfectionis thoughttohaveinducedthe often suspectedasthecause ofEN,canalsobeexcluded administered totreatprodromal symptomsandthatare vital forlife,needtobewithdrawn.Medicationsthatwere becomes obviousthatnotalldrugs,someofwhichmaybe narrow downorevenidentifytheinducingagent.Itthen on durationofuse(startandenduse),itispossibleto y-axis (Fig.5).Basedonthediagramandinformation and themedicationstakenorappliedareenteredon of sequence entered is clinical on symptoms the x-axis to createatimelinediagram,intowhichthechronological risk ofthetypereactioninquestion.Itmaybehelpful reaction, aswellthedrugsthathaveahigh-to-moderate time latencybetweenthestartofdruguseandonset the know to essential is it Thus, discontinued. and tified Although nosystematicinvestigationsintothepatho To date, there have been nosystematic investigations into - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV necrolysis) toassessapatient’sprognosis Table IV. SCORTEN (69) (severity-of-illnessscorefor epidermal topical treatmentisrecommended: detrimental (15,33). The followingsupportivecareand in amedicalconditionfrequentlycausedbydrugsmaybe Fig. 5.Timelinediagramwithchronologicsequenceofclinicalsymptoms(x-axis)andmedicationuse(y-axis). Possible score Serum bicarbonate, mmol/l Serum glucose, mmol/l Serum urea, mmol/l Tachycardia, /min Body surfaceareadetached (day 1), % Malignancy Age, years Factor cornerstone oftreatmentandincludesmaintaininghaemodyna care facilitiesor burn units (72, 73). Supportive care is still the European countries),othersshouldbetransferredtointensive care mayremainindermatologyunitsorhospitals(inmany local ornationalfacilities,patientswhodonotneedintensive can be treated in non-specialized wards. Depending on the value of0or1,andadiseasethatisnotrapidlyprogressing (69–71) (Table IV). higher istheriskofdeathandlowerchancesurvival positive scorepointsare added andthehigher the value, the (< stitial oedemaisabsent.Inordertoselectthecorrectamount imately 1/3–/4oftheinfusionvolumeinburns)becauseinter than for burns of a similar extent of skin detachment (approx adjusted onadailybasis.Infusionvolumesareusuallylower detachment, hypovolaemia and electrolyteimbalancemustbe Due to significant fluid loss in patients with large amount of skin mic equilibrium and preventing life-threatening complications. 1 (≥ lignancy, (iv)percentageofdetachmentrelativetoBSA onday points: (i) age (≥ equally significant, factors are used for the calculation of score score forEN)hasbeendeveloped(69).Sevenindependent,but ropriate therapeuticoptions,theSCORTEN (severity-of-illness In ordertoassessapatient’s prognosisandtodecideontheapp Only patients with limited skin involvement, limitedskin and a with SCORTEN patients Only 20 mmol/l),and(vii)serumglucose(>

10 %), (v ------M M M M M edic edic edic edic edic M edi ) serum urea (> a a a a a t t t t t c i i i i i o o o o on a n n n n t 40 years), (ii) heart rate (≥ i o 5 4 3 2 1 F n i r s h t 01. i ons s t - - o 07. r e y t 1 o 9 10 mmol/l), (vi f b lis t e r s

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e 14 14 10 120 10 40 r o s 14 mmol/l)(69). The 08. i ons ) serum bicarbonate ) serum bicarbonate 120/min), (iii) ma 07. 1 0–7 1 1 1 1 1 1 1 Weight/score value 9 C D lin r ug - - - - - 15. i c a e 07. l x

c pos our 1 9 u s r inflammatory (e.g. corticosteroid) eye drops are recommen are drops eye corticosteroid) (e.g. inflammatory antibiotic orantisepticeyedrops, oftenalternatingwithanti- immediately afteradmission. Preservative-free emollients, an experienced ophthalmologist should examine the patient cal specialist should be consulted. In terms of eye involvement, antiseptic treatment isrecommended and the appropriate medi proliferation of stem cells due to inflammatory cytokines (76). an obstacletore-epithelializationandmightevenacceleratethe superficial burns nor in EN, because superficial necrosis is not suggested thataggressivedebridementisneithernecessaryin tion. Although thisremainsatopicofdebate,itwasrecently use of biosynthetic dressingsinordertoprotectagainstinfec mend completeremovalofdetachedskinandtheconsecutive as anatural cover toprotect the dermis, while othersrecom dition toadequatepainmanagement,areessential(10,72,73). and skilful wound care, performed by experiences nurses, in ad remains a matter ofexperience in each centre. Careful handling concerning theuseofantisepticsandwounddressings,which adhesive gauzedressingsareused. There isnostandardpolicy Antiseptic solutionsorgels,aswellnon-medicatedandnon- should befollowed(75). nutrition, intensivecareguidelines(e.g.ESPENguidelines) the gastrointestinal tract (10, 18, 72, 73). For adequate enteral healing anddecreasetheriskofbacterialtranslocationfrom be providedthroughnasogastrictubesinordertopromote anticoagulation is needed and early nutritional support should based onclinicalfeaturesandlaboratoryresults.Prophylactic EN shouldreceiveantibioticswhenaninfectionissuspected of antibioticsshouldbeavoided,andinsteadpatientswith for bacteriaandfungiatfrequentintervals.Prophylacticuse required. Skin,blood,andurinespecimensshouldbecultured To reducetheriskofinfection,asepticandcarefulhandlingis patient’s the comfort. increase to help may beds Air-fluidized regulation inpatientswithextensiveskindetachment(72). to 25–30°Cisimportantcompensateforlossofthermo prone toinfection.Increasingtheenvironmentaltemperature sible, sincethesitesofinsertioncentrallinesarefarmore important (74). Peripheral venous lines should be used, if pos of fluid replacement, correct estimation of the denuded BSA is e e In thecaseoferosivemucousmembraneinvolvement,local Some expertsrecommendleavingtheblisterroofinplace Topical treatmentplaysaspecialroleinbullousreactions. 22. Sor r ed 07. e e t y 1 h e 9 r s oat, e F S x e k ant v i

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o o e i n n ssi c a t o i o n n 129 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Blistering skindisorders 130 • be evaluatedwithcare: ment efficacy. Therefore, existing data on treatment of EN must challenge toconductacontrolledrandomizedstudyontreat onset and rapid progression of the reaction, it remains a huge the resultinglowpatientnumbers,aswellunexpected case seriesandreports.DuetotherarityofSJS/TEN Data ontherapeuticapproacheslargely derivefromuncontrolled treatments havebeentriedtohalt theprogressionofdisease. of cytokines, several immunosuppressive and anti-inflammatory mechanisms withinvolvementofcytotoxic T-cells andrelease Immunomodulating treatment. Becauseoftheimmunological datory, butcanbehelpfulinsomecases(24,48). often unaffected, interdisciplinaryconsultationsarenotman is thesameasinEN.Sincemucousmembranesaremost and patients with extensive skin detachment. Topical treatment requiring intensivecare can occur, especially in older patients drug, supportive carealone is adequate.However, complications ceases toprogressshortlyafterdiscontinuationofthetriggering dilators coveredwithointmentcanbeapplied(78). early adhesionsmustbecarefullydisrupted. To avoidthese, gynaecological examinationshouldalsobeperformed,since If deepervaginalinvolvementissuspectedinyounggirls,a such complicationswetdressingsorasitzbatharehelpful. female patients may lead to adhesions or strictures. To avoid bland ointment,e.g.dexpanthenol.Genitalerosionsinmaleand erosions, whereaserosionsofthelipsshouldbetreatedwith requires dailyconsultationwithanophthalmologist(73,77). severe ocularsequelae.Inanycase,involvement amniotic membranehasbeenproposedtodecreasetherateof mechanical disruptionisindicatedandgraftofcryopreserved ded every 2 h in theacutephase.In case of early synechiae, • Glucocorticosteroids arethemostfrequentlyusedimmuno problems werefoundinthe studies showingapositiveeffect 88). However, anumberofmethodological weaknessesand 87, 84, (80, benefit any show to unable were others whereas given that somereports described a positive effect (85, 86), human IVIG(85). Their use remains a subject ofcontroversy, keratinocyte apoptosisisblocked byantibodiespresentin as therapyoptionbasedon the assumptionthat Fas-induced Intravenous immunoglobulins(IVIG)havebeensuggested skin detachment(80,84). mucous membranes,butlittleimpactontheprogressionof effect apositive treatment optionwith andpainful onswollen (50–250 mg)foronlyafewdays,glucocorticosteroidsare Nevertheless, ifadministeredshort-termatamediumdose reports andsmallcaseseriesshouldbeviewedwithcaution. in larger observationalstudies(82,83). Thus, individualcase confirmed be not could effect this sequelae; ocular of ment day for 3 days) in massive eye involvement on the develop positive effect of methylprednisolone pulse therapy (500 mg/ death rate(81,82). A caseseriesof5patientsreportedonthe number ofdeathsbySCORTEN withtheactuallyobserved expected the comparing when benefit a demonstrated days) methylprednisolone ordexamethasone(100mg/dayfor3 administration ofglucocorticosteroidpulsetherapywith CI) 0.29–1.01)(80). A numberofsmallercaseseriesonthe (95% interval confidence 95% 0.54; (OR) ratio (odds alone care supportive with compared benefit survival a conferred ted thattheadministrationofsystemicglucocorticosteroids investigated publications in the period 1990–2012 demonstra recently publishedmeta-analysisonthetreatmentofENthat and septicaemiadelaywoundhealing(79).However, a is controversial,sincetheymayincreasetheriskofinfection modulating treatmentinpatientswithEN(18),buttheiruse Since GBFDEisconsideredtobeaself-limitingdiseasethat Disinfectant mouthwashcanbeusedfortreatmentoforal M. Mockenhaupt - - - - - • • observed mortalitywaslowerthanexpectedbyapplica (IVIG, glucocorticosteroids,supportivecareonly),andthe epithelialization began earlier than in the comparison group approaches toassesstheeffect ofcyclosporine A. Again, re- larger studywasconductedinMadrid andused3different values and/orothersystemictherapies(93–95). A recent tients treatedwithcyclosporine A comparedwithSCORTEN pa in benefit survival a showing all published, were series (92). Inthefollowingyears,individualcasereportsand which receivedcyclophosphamideandglucocorticosteroids receiving cyclosporine A comparedwiththecontrolgroup, stopped andwoundhealingwasfasterinthepatientgroup hed as early as2000(92). The progression in skin detachment 11 patientsweretreatedwith2×3mg/kgBW/day, waspublis cytokines. The first larger retrospective case series, in which mechanisms followedbyananti-apoptoticeffect ofseveral tokines, and, on the other hand, inhibition of CD8+ cytotoxic healing startedearlierandtheinhibitor reducedthelevelsof with theachievedSCORTEN values was observed. Wound mortality in patients with EN treated with etanercept compared domized treatmentstudythatwas publishedrecentlyalower treatment successhave been published(101,102).Inaran etanercept, forthetreatmentof EN, butonlyscantreportsof and infliximab e.g. inhibitors, TNF-α other used studies of patientsinthetreatment arm of the study. However, later Paradoxical high levels of TNF-α were detected in the serum in the thalidomide group died than in the placebo group (100). EN was terminated early, because significantly more patients controlled treatment study using thalidomide in patients with approach in EN. In1998,a randomized double-blind placebo- the use of TNF-α inhibitors appeared as a potential treatment related withtheseverityofreaction(99,100). Therefore, rum, andskinsamplesofpatientswithEN,thelevelcor se fluids, blister in found were levels elevated TNF-α since EN, of treatment for tried been also have inhibitors TNF-α years) withEN(98). only afewreportsonthetreatmentofelderlypatients(> cyclosporine A at the suggested doses are rare, but there are cases. Strictcontraindicationstoshort-termtreatmentwith and renal insufficiency, but not necessarily mandatory in other of creatininelevelsisadvisableinthecasehigherdoses monitor creatininelevelsduringtreatment.Closesurveillance with impaired renalfunction(98). Therefore, itis necessary to days, but adjustment of the dose may be needed in patients recommended dose is 3–5 mg/kg BW/day for a total of 10 the observedmortalityislowerthanexpected(80,91). The second and, earlier begins re-epithelialization first, because concluded thatcyclosporine A isaverypromisingtreatment, ler caseseries(97). The 2meta-analysesmentionedabove A hasbeenusedsuccessfullyinchildrenwithENsmal were notincludedinmanyofthesestudies,butcyclosporine patients thanestimateddied(96).Childrenandadolescents tion ofSCORTEN, whereasinthecomparisongroupmore may, on the one hand, be activation of T-helper cells and cy thus hasbeenusedinthetreatmentofEN.Itsmechanism Cyclosporine A hasstrongimmunomodulatingcapacityand compared withsupportivetherapy(80,91). benefit for patients with EN who received treatment with IVIG dose (90). Two extensivemeta-analysesalsofoundnosurvival did nothaveapositiveeffect onsurvival,notevenatahigher study of64patientsrevealedthattheadministrationIVIG SCORTENusing amorerecentretrospective forcomparison, at least2.8g/kgBW inpositivestudies(88).Nevertheless, was BW,it g/kg whereas ≤2 mostly was dose the IVIG, for focus ofthediscussion. Instudies thatshowedadisadvantage for IVIG(89).Furthermore,theeffect ofIVIGdoseisoftenthe 70 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV reactions. Inthelatter, initialuseofthesubstance iswell no classicsensitizationasinother delayed hypersensitivity EN isnotanallergic reactioninthestrict sense,sincethereis ALLERGY WORK-UP in thelongterm(107). about theirreaction,itssequelae,andhowtodealwiththese many patients andtheir relatives are inadequately informed A large survey, performed5yearsafterEN,revealedthat disorders, andnightmares,tofearofusinganymedications. may rangefromsymptomsofpost-traumaticstress,sleep logical sequelaeyearsaftertheirreaction. These sequelae (10, 15,77,106,107). entropium sequelae affect theeyesbysymblepharonformationwith far the most hazardous and, for the patient, mostdramatic, the urethraoroesophagus,representagreaterproblem.By Mucosal adhesionsthatmaycausestricturesin,forexample, as wellnailgrowthdisordersarefrequentlyobserved. persist for months to years.Reversible loss of hair and nails, often reaction inflammatory the of result a as skin the of rally healwithoutscarring,hyper- andhypo-pigmentation mucous membranes(106,107). Whereas skinlesions gene quelae of varying severity, affecting primarily the skin and are advised,e.g.reverseisolation,etc.(72,73). preferred wherever possible and specific hygiene measures venous catheters. Therefore, peripheralcathetersshouldbe mial infection and septicaemia, frequently caused by central (10, 73). The mostcommoncomplicationsincludenosoco ratherquickly resolve usually involvement,which mucosal panied by hepatitis, tubular nephritis, or tracheobronchial During theacutestageofdisease,ENmaybeaccom COMPLICATIONS ANDSEQUELAE and doesnotresultinfasterhealing(18,49). patients, butitappearsthattheirshort-termusedoesnoharm GBFDE. Systemicglucocorticosteroidsarealsousedinsome benefit of systemicimmunomodulatingtherapyinthetreatment the on trials clinical from data no are there date, To • Many patients still experience somatic as well aspsycho The majorityofENsurvivorsexperiencelong-termse able todemonstrateverifiablepositiveresults(104,105). involved inapoptosis,arestillused,althoughtheywerenot plasmapheresis, whichisbasedontheremovalofcytokines the case of cyclophosphamide (80). Other treatments, such as cases, theseoptionsarenolonger, oronlyrarely, used,asin very lowduetothesmallnumberofpatientstreated.Insome have been used to treat EN, but the reliability of the findings is Other immunomodulatorytreatment options.Othertherapies group couldbeduetotheprolongeduseofcorticosteroids. cal problems. The delayedre-epithelializationinthecontrol significant and this study also had a number of methodologi area ofsevereskinreactions.However, mostresultsarenot tively, sincetreatmentstudiesofthatkindarelackinginthe prospective randomizedstudydesigncanberegardedposi with theglucocorticosteroid-treatedcontrolgroup(103). The compared fluids blister and serum in granulysin and TNF-α and trichiasis,whichcanevencauseblindness ------most often are not helpful for confirming the suspected trig exposure (5). reaction, ENwasrarelyobservedfollowingsimilarre- rapid onset,andpossiblyevenmoreextensive,repeated drug inpatientswithGBFDEcanbeexpectedtocausea eruptions. While renewed administration of a triggering occurred, and repeated use often causes localized fixed drug since previousexposuretothetriggeringdrughasusually first courseoftreatmentwithadrug(34). exposure. ENdiffers inthat ittypicallyoccursduringthe tolerated, withareactiondevelopingonlyuponrenewed specificity of the various tests, e.g. the lymphocyte proli lymphocyte the e.g. tests, various the of specificity experimental. This may, in part, be due to the fact that the use isyetnotpartofroutinediagnosticsandremainsrather the inducing agent in bullous drug reactions; however, their (108, 109). testing duetothelackoflipophilicityandskinpenetration nol, averycommontriggerofEN,isnotsuitableforskin with EN(108).Oneshouldalsobearinmindthatallopuri was confirmed by patch testing in less than 25% of patients few yearsagoinFrance,forexample,thetriggeringagent as wellonthedrugtobetested.Inastudyperformed on the type of reaction and the T-cell populations involved, ger inEN. The successoftestingdepends,toagreatextent, REFERENCES (Deutsche Forschungsgemeinschaft;FOR534). derations were partly supported by German Research Foundation through ElseKröner-Fresenius-Foundation. Methodologicalconsi Else KrönerMemorialStipendiumforsupportofclinicalresearch Tibotec-Janssen) 2003and2012. between The authorreceivedthe Servier, Sanofi-Aventis, Pfizer, Novartis, Merck, Dome, and Ingelheim, Cephalon, GlaxoSmithKline, Grünenthal, MSDSharp by severalpharmaceuticalcompanies(Bayervital,Boehringer- provided was support financial of 1020.0355.01c). part Aminor senschaftlicher Arbeit auf dem Gebiet der Dermatologie; grant no. Dermatology Foundation(DeutscheStiftungzurFörderungwis (grant no.1020.0355.01b)andagrant/donationbytheGerman a private donation (C.H.R., Nailsea, UK) for SCAR-research Foundation forclinicalresearch(grantno.1020.0355.01a), also receivedagrant/donationbyErika-and Werner Messmer- Bildung und Forschung (BMBF); grant no. 01KG1018). The dZh Ministry forEducationandResearch(Bundesministeriumfür (QLRT-2002-01738)Commission andbyagrantfromtheFederal 2003, wasmainlyfundedbyaresearchgrantfromtheEuropean ting theGermanpartofmultinationalRegiSCAR-studysince The GermanRegistryofSevereSkinReactions(dZh),represen ACKNOWLEDGEMENT assays, is high, while their sensitivity is much lower (109). feration test,thelymphocytestimulationandcytokine Skin tests, such as the patch test, are generally safe,but GBFDE, ontheotherhand,isatrueallergic reaction, In vitro testswerethemostsuitableinstrumenttoidentify 2. 1. scalding of the skin. Br JDermatol 1956; 68: 355–361. Lyell A. Toxic epidermal necrolysis: an eruption resembling in children. Am J Dis Child 1922;24:526–533. cases two of report ophthalmia: and stomatitis with Stevens AM, Johnson FC. 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