Bolling, Maria C

Diercks, Gilles F H

Esajas, Martha

Horváth, Barbara

Oldhoff, J Marja

Pas, Hendri H

Rashid, Hanan

English

University of Groningen

   University of GroningenJuvenile and adult vulvar pemphigoid, an under recognized entityRashid, Hanan; Oldhoff, J Marja; Esajas, Martha; Diercks, Gilles F H; Pas, Hendri H; Bolling,Maria C; Horváth, BarbaraPublished in:JAAD case reportsDOI:10.1016/j.jdcr.2021.05.017IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2021Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Rashid, H., Oldhoff, J. M., Esajas, M., Diercks, G. F. H., Pas, H. H., Bolling, M. C., & Horváth, B. (2021).Juvenile and adult vulvar pemphigoid, an under recognized entity: Case series of fourteen patients. JAADcase reports, 13, 75-80. https://doi.org/10.1016/j.jdcr.2021.05.017CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 20-11-2022CASE SERIESFrom theDiseasesity MDepartgen, UnUniversFunding sCorresponDermat1, 9700Juvenile and adult vulvar pemphigoid, anunder recognized entity: Case series offourteen patientsHanan Rashid, MD,a J. Marja Oldhoff, MD, PhD,a Martha Esajas, MD,b Gilles F. H. Diercks, MD, PhD,cHendri H. Pas, PhD,a Maria C. Bolling, MD, PhD,a and Barbara Horvath, MD, PhDaGroningen, NetherlandsKey words: autoimmune blistering diseases; direct immunofluorescence microscopy; indirect immunofluo-rescence microscopy; mucous membrane pemphigoid; vulvar pemphigoid.Abbreviations used:DIF: direct immunofluorescence microscopyEBMZ: epidermal basement membrane zoneELPV: erosive lichen planus affecting the vulvaLS: lichen sclerosusMMP: mucous membrane pemphigoidVP: vulvar pemphigoidSSS: salt split skinIIF: indirect immunofluorescence microscopyELISA: enzyme-linked immunosorbent assayC3c: complement component 3Ig: immunoglobulinINTRODUCTIONVulvar pemphigoid (VP) is a rare subtype ofmucous membrane pemphigoid (MMP), which is aheterogeneous group of autoimmune subepidermalblistering diseases with predominantly mucosalinvolvement and characterized by autoantibodiesagainst structural proteins in the epidermal basementmembrane zone (EBMZ).1 In MMP, various mucosalsites can be simultaneously or separately affected.Mucosal lesions tend to heal with scar formation andmay result in loss of function of the affected area.In vulvar MMP, lesions are confined to theanogenital region but can also be a manifestationof a more extensive MMP with other mucosalinvolvement.2-5 Two variants can be distinguished:the juvenile form presenting in girls between 5 and10 years old, and the adult form, which occursmainly in postmenopausal women.6,7 However,symptoms may also occur in patients within thesetwo age categories. Overlapping with other chronicvulvar diseases, VP can present with variable clinicaland histopathologic features, including lichen scle-rosus (LS) and erosive lichen planus affectingthe vulva (ELPV).8,9 Careful examination of themucosa and skin is mandatory, which should befollowed by a biopsy for direct immunofluorescencemicroscopy (DIF) from perilesional skin or mucosa.Furthermore, indirect immunofluorescence micro-scopy (IIF) on salt split skin (SSS) and immunoser-ology can be performed for the detection ofcirculating autoantibodies in serum.Department of Dermatology, Center of Blisterings, European Reference Network-Skin Member, Univer-edical Center Groningen, University of Groningena;ment of Gynecology, University Medical Center Gronin-iversity of Groningenb; and Department of Pathology,ity Medical Center Groningen, University of Groningen.cources: None.dence to: Hanan Rashid, MD, Department ofology, University Medical Center Groningen, HanzepleinRB Groningen, Netherlands. E-mail: h.rashid@umcg.nl.In this study, we describe 14 patients diagnosedwith VP, demonstrating the wide clinical and immu-nologic variety of this disease.METHODSThis case series included patients diagnosed withVP from 2001 to 2018 at the Center for BlisteringDiseases in Groningen, which is the national referralcenter for autoimmune bullous diseases in theNetherlands. Diagnoses were made according toclinical features and immunologic criteria of linearn-serrated/u-serrated deposition of IgG, IgA, and/orcomplement component 3 along the EBMZ by DIFor detection of circulating autoantibodies. IIF onSSS was considered positive when immunoglobulin(Ig)G, IgA, and/or complement component 3 (C3c)staining at the epidermal and/or dermal side stainingwere observed. Immunoblot was used to detectJAAD Case Reports 2021;13:75-80.2352-5126 2021 by the American Academy of Dermatology, Inc. Publishedby Elsevier, Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).https://doi.org/10.1016/j.jdcr.2021.05.01775Table I. Clinical characteristics, diagnostic results, and treatment of patients with vulvar pemphigoidPatientno.Age inyearsSymptomdurationin months ScarringOthermucosalinvolvementSkininvolvement HistopathologyDIF onmucosaand/orskin Salt split skin ImmunoblotELISANC16ATopicaltherapySystemictherapy1 5 12 Yes - - Vacuolar degenerationbasal keratinocytes,homogenized collagenIgG & C3c Negative IgG BP180 Negative Clobetasol,TetracyclinePrednisone,Dapsone2 6 6 No - - Ulcerating inflammation,subepidermal splitIgG & C3c Negative Negative Negative Triamcinolone,Tetracycline-3 11 30 Yes Oral - Dermal mixed cellinflammation,subepidermal splitC3c IgGepidermalsideIgG BP180 Negative Tetracycline -4 11 72 No - - Dermal mixed cellinflammation,subepidermal splitIgG & IgA& C3cNegative Negative Positive Tetracycline,TriamcinoloneDapsone5 12 24 No - - Band-like lymphocyticinfiltrates, subepidermalsplitIgG & C3c Negative Negative Negative Tetracycline,Clobetasol-6 13 7 No - - Dermal mixed cellinflammation,subepidermal splitIgG & IgA& C3cNegative Negative Positive Tetracycline -7 48 9 Yes Oral - dermal lymphohistiocyticinflammation,subepidermal splitIgG & C3c Negative IgG BP180 Negative Tetracycline,Clobetasol,TriamcinoloneDoxycyline,Prednisone8 58 12 Yes - Submammary Dermal mixed cellinflammation,subepidermal splitIgG, IgA& C3cn-serratedIgG & IgAepidermalsideIgG BP180 Positive Triamcinolone Prednisone,Dapsone,Mycophenolicacid,Cyclophosphamide,Rituximab9 62 12 No - - Dermallymphoplasmacellularinflammation,subepidermalsplitC3cn-serratedNegative IgG BP180 Positive Triamcinolone,Fluticasone,Clobetason,TetracyclineDoxycycline10 65 60 Yes - - Dermal mixed cellinflammation,subepidermal splitIgG, IgA& C3cIgGepidermalsideIgG & IgABP180Positive ClobetasolTetracyclinePrednisone,Methotrexate,Mycophenolic acid,Azathioprine11 73 2 No Oral - - IgG Negative Negative Positive Tetracycline -JAADCASEREPORTSJULY202176Rashidetal12745NoOral-PerivascularlymphoplasmacellularinflammationIgAIgA epidermalsideIgABP180NegativeTetracycline,TriamcinoloneDapsone137414YesOral-SuperficialspongioticdermatitisIgG n-serratedIgG epidermalsideNegativeNegativeClobetasol-14917YesOral,nasal-SubepidermalsplitIgA,IgGn-serratedIgG epidermalsideIgGBP180PositiveClobetasolCyclophosphamideDIF,Directimmunofluorescencemicroscopy;ELISA,enzyme-linkedimmunosorbentassay;Igg,immunoglobulin;C3c,complementcomponent3.JAAD CASE REPORTSVOLUME 13Rashid et al 77circulating IgG or IgA against BP180. Autoantibodiesagainst the 16A domain of BP180 were detected withcommercially available enzyme-linked immunosor-bent assay (ELISA; cutoff index, $ 9 U/mL). Writtenconsent was provided.RESULTSFourteen patients diagnosed with VP wereincluded in this case series. One patient waspreviously described in the literature.10 Table Isummarizes the clinical, histopathologic, andimmunofluorescence findings, as well as the pre-scribed therapy of all patients. Six patients werediagnosed with juvenile VP, and the remaining 8were postmenopausal women. The age of onsetranged between 5 and 13 years in the juvenilegroup, and 48 and 91 years in the adult group. Themedian duration of symptoms before patients werereferred to the dermatologist at the Center forBlistering Diseases was 12 months (range, 2-72).Patients with extragenital involvement had ashorter median diagnostic delay compared withpatients with localized genital involvement (8 vs.12 months). The median follow-up time was22 months (range, 1-86). At the time of referral, 3patients had already received the diagnosis VP.One patient had previously been diagnosed withLS based on clinical and histologic features, and 1patient had been diagnosed with vulvar candidi-asis. The remaining patients were referred to ourclinic with no previous diagnosis.Clinical presentationFrequently reported symptoms included intermit-tent or continuous pain (10/14), followed by pruritus(5/14) and dysuria (5/14). Dyspareunia was reportedin 1 adult patient, and 2 patients experienced painduring defecation. One patient in the juvenile groupwas asymptomatic. Dermatologic examination re-vealed erosions (11/14), erythema (9/14), and su-perficial ulcerations (2/14) of the labia minora andmajora, periclitoreal area, vaginal introitus, andperineum (Fig 1, A, B and C). In one patient, anintact blister was seen. Structural architecture losswas observed in 5 adult patients, including fusion ofthe labia majora and minora and stenosis of thevaginal introitus, whereas only 2 patients in thejuvenile group developed fusion of the labia (Fig 1,B and C ). Examination of the vaginal mucosa wasnot performed. Extragenital mucosal involvementwas seen in 6/14 patients, of which 1 patient in thejuvenile group presented with erythematous swollengingiva and 5 adult patients with erythema, erosions,and blisters involving the gingiva, palatal surface,and buccal mucosa. One patient presented withFig 1. Lesions in juvenile and adult vulvar pemphigoid demonstrating erosions (A and C), scarformation (B and C), and complete fusion of the labia (B and C).JAAD CASE REPORTSJULY 202178 Rashid et alnasal crustae in addition to involvement of the oralmucosa. Furthermore, 1 adult patient had skininvolvement confined to the submammary region.Diagnostic findingsIn all patients (14/14), a biopsy for DIF wasperformed from perilesional mucosa and/or healthyskin, revealing linear deposition of IgG, IgA, and/orC3c complement component 3 along the EBMZ (Fig2,A). An n-serrated immunodeposition pattern alongthe EBMZwas identified in 4/14 biopsies for DIF, andin the remaining biopsies the serration pattern couldnot be identified. IIF on SSS revealed circulating IgGand/or IgA autoantibodies in 6/14 patients at theepidermal side of the split (Fig 2, B). Immunoblot forBP180 was positive for IgG and/or IgA in 8/14patients, and 7/14 patients showed positivity forIgG against the NC16A domain of BP180, as detectedby ELISA. A biopsy for histopathology was per-formed in 13/14 patients, revealing subepidermalblistering in 10 patients accompanied with a dermalinfiltrate consisting of lymphocytes, plasma cells,and eosinophils. One patient showed a band-likeinfiltrate of lymphocytes at the epidermal-dermaljunction; furthermore, in 1 patient, basal vacuolardegeneration and homogenization of the dermalcollagen was observed. Bacterial, fungal, and viralcultures were negative for all patients.TherapyAfter confirmation of the diagnosis, 8/14patients required systemic immunosuppressive orimmunomodulatory therapy in addition to localtherapy. In the juvenile group, 2/6 patients receiveddapsone in addition to local therapy, while 4/6patients received only topical corticosteroids. In 1patient, dapsone was discontinued after 1 year dueto hemolysis and replaced by prednisone followedby topical clobetasol propionate. Flare-ups werefrequently observed during treatment in this patient.The clinical outcome of the second patient is un-known, as follow-up took place in another hospitalafter the diagnosis was made. The remaining 4patients in the juvenile group responded well totopical triamcinolone acetonide and clobetasol onlyand did not experience flare-ups during treatment.The median duration until clinical response was2 months (range 0-28) in the juvenile group.Six out of 8 patients in the adult group requiredsystemic immunosuppressive therapy due to wors-ening of vulvar symptoms and poor response tolocal therapy. Systemic treatment included doxycy-cline, prednisone, dapsone, methotrexate, azathio-prine, cyclophosphamide, mycophenolic acid, andrituximab. The median duration until clinicalresponse was 1.5 months (range, 0-18). Flare-upswere seen in 5 out of 8 patients during treatment.These patients received several systemicFig 2. A, Direct immunofluorescence microscopyshowing linear C3c deposition along the epidermalbasement membrane zone in an n-serrated pattern. B,Indirect immunofluorescence on a substrate of salt splitskin, showing IgG bound to the epidermal basementmembrane zone (arrow) of the artificial split. Theepidermal side is depicted with * and the dermal side isdepicted with .̂JAAD CASE REPORTSVOLUME 13Rashid et al 79immunosuppressive agents during follow-up. Theremaining 2 patients who were treated with topicaltreatment only did not experience flare-ups duringtreatment.DISCUSSIONThis case series of 14 patients with juvenile andadult VP demonstrates the broad clinical spectrum ofthis disease. In the presence of vulvar erosions,ulcerations, blisters, and scarring, VP should beconsidered in the differential diagnosis. In addition,examining extragenital mucosal surfaces and per-forming immunofluorescence microscopy and im-munoserology is mandatory to differentiate betweenconditions with similar clinical findings.VP is often misdiagnosed for LS or ELPV, resultingin therapeutic delay.8,10 In children, VP may also bemistaken for sexual abuse.11 Differentiating betweenLS, ELPV, and VP is often challenging due to over-lapping clinical presentation and the presence ofchronic inflammation. The presence of Wickhamstriae, patchy hair loss, or nail abnormalities candistinguish lichen planus from pemphigoid. Vaginalinvolvement is common in ELVP but has not beenpreviously reported in VP.4,5,12 In this study, exam-ination of the vaginal mucosa was not performed.However, patients diagnosed with VP should beexamined by a gynecologist with expertise in ELVPfor evaluation of vaginal involvement. In contrast toLS, MMP and ELPV may affect other mucosal sites,such as the ocular, nasal, pharyngeal, and laryngealmucosa. In this study, the presence of extragenitalinvolvement might have led to a quicker diagnosis.Extragenital involvement, including the oral andnasal mucosa, was observed more often in the adultgroup. In addition, more patients in the adult grouppresented with scar formation.Histopathology can often be used to differentiateVP from ELVP and LS. However, in some cases,histologic differences are not that clear and mayoverlap. A lesional biopsy for histopathology inpemphigoid can show subepidermal splitting com-bined with a moderate to dense infiltrate composedof lymphocytes, neutrophils, and eosinophils. Thiscan also be seen in bullous LS, which is caused byeither increased vacuolar degeneration of the basalmembrane zone or edema in the papillarydermis.13,14 In this study, a subepidermal split wasseen in 10 patients. Moreover, histopathologic fea-tures mimicking lichen planus and LS wereobserved.Overall, VP of the juvenile form respondspromptly to potent topical therapy and generallydoes not require systemic therapy. In the juvenilegroup, 4 out of 6 patients had relatively milddisease and responded well to potent topicalsteroids, with the exception of 2 patients, whowere treated with systemic corticosteroids anddapsone. In contrast, the majority of the adultpatients required systemic therapy and oftenshowed flare-ups.In conclusion, VP presents a broad spectrum ofsymptoms and can be challenging to diagnose.Performing careful examination of other mucosaeand skin with additional immunofluorescence andimmunoserology is essential for an adequatediagnosis.Conflicts of interestDr Horvath reports fees from Janssen-Cilag (AdvisoryBoards, Educational grants, Consultations, InvestigatorJAAD CASE REPORTSJULY 202180 Rashid et alInitiative Studies), AbbVie (Advisory Boards, Educationalgrants, Consultations, Investigator Initiative Studies),Novartis Pharma (Advisory Boards, Consultations,Investigator Initiative Studies), UCB Pharma (AdvisoryBoards, Consultations), Leo Pharma (Consultations),Solenne B.V. (Investigator Initiative Studies), Celgene(Consultations, Investigator Initiative Studies), Akari ther-apeutics (Consultations, Investigator Initiative Studies),Philips (Consultation), Roche (Consultation), Regeneron(Consultation) and Sanofi (Consultation), which fees werepaid to the institution. The remaining authors declare noconflict of interest.REFERENCES1. Chan LS, Ahmed AR, Anhalt GJ, et al. The first internationalconsensus on mucous membrane pemphigoid: definition,diagnostic criteria, pathogenic factors, medical treatment,and prognostic indicators. Arch Dermatol. 2002;138(3):370-379.2. Goldstein AT, Anhalt GJ, Klingman D, Burrows LJ. Mucousmembrane pemphigoid of the vulva. Obstet Gynecol. 2005;105(5 Pt 2):1188-1190.3. Farrell AM, Kirtschig G, Dalziel KL, et al. Childhood vulvalpemphigoid: a clinical and immunopathological study of fivepatients. Br J Dermatol. 1999;140(2):308-312.4. Jolliffe DS, Sim-Davis D. Cicatricial pemphigoid in a young girl:report of a case. Clin Exp Dermatol. 1977;2(3):281-284.5. Stage AH, Humeniuk JM, Easley WK. Bullous pemphigoid of thevulva: a case report. Am J Obstet Gynecol. 1984;150(2):169-170.6. Belzile E, Funaro D, Powell J. Localized vulvar bullouspemphigoid of childhood: a rare cause of persistent vulvarerosions in children. Pediatr Dermatol. 2019;36(3):349-351.7. Venning VA, Frith PA, Bron AJ, Millard PR, Wojnarowska F.Mucosal involvement in bullous and cicatricial pemphigoid. Aclinical and immunopathological study. Br J Dermatol. 1988;118(1):7-15.8. Marren P, Walkden V, Mallon E, Wojnarowska F. Vulvalcicatricial pemphigoid may mimic lichen sclerosus. Br JDermatol. 1996;134(3):522-524.9. Loyal J, Rashtak S. Vulvar lichen planus pemphigoides. Int JWomens Dermatol. 2017;3(4):225-227.10. de Waard MM, Jonkman MF. Vulvair gelokaliseerd pemfigo€ıd.NTvDV. 2008;18(4):204-207.11. Levine V, Sanchez M, Nestor M. Localized vulvar pemphigoidin a child misdiagnosed as sexual abuse. Arch Dermatol. 1992;128(6):804-806.12. Rogers M, Painter D. Cicatricial pemphigoid in a four-year-oldchild: a case report. Australas J Dermatol. 1981;22(1):21-23.13. Kavak A, Erdogan B, Topkarc Z, S€onmezler H, Sakız D. Bullouslichen sclerosus: isolated vulvar involvement. Dermatol OnlineJ. 2018;24(2):13030/qt3mk9801x.14. Hallel-Halevy D, Grunwald MH, Yerushalmi J, Halevy S. Bullouslichen sclerosus et atrophicus. J Am Acad Dermatol. 1998;39(3):500-501.

Juvenile and adult vulvar pemphigoid, an under recognized entity:Case series of fourteen patients

Proceedings - University of Groningen

   University of GroningenJuvenile and adult vulvar pemphigoid, an under recognized entityRashid, Hanan; Oldhoff, J Marja; Esajas, Martha; Diercks, Gilles F H; Pas, Hendri H; Bolling,Maria C; Horváth, BarbaraPublished in:JAAD case reportsDOI:10.1016/j.jdcr.2021.05.017IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2021Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Rashid, H., Oldhoff, J. M., Esajas, M., Diercks, G. F. H., Pas, H. H., Bolling, M. C., & Horváth, B. (2021).Juvenile and adult vulvar pemphigoid, an under recognized entity: Case series of fourteen patients. JAADcase reports, 13, 75-80. https://doi.org/10.1016/j.jdcr.2021.05.017CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 04-06-2022CASE SERIESFrom theDiseasesity MDepartgen, UnUniversFunding sCorresponDermat1, 9700Juvenile and adult vulvar pemphigoid, anunder recognized entity: Case series offourteen patientsHanan Rashid, MD,a J. Marja Oldhoff, MD, PhD,a Martha Esajas, MD,b Gilles F. H. Diercks, MD, PhD,cHendri H. Pas, PhD,a Maria C. Bolling, MD, PhD,a and Barbara Horvath, MD, PhDaGroningen, NetherlandsKey words: autoimmune blistering diseases; direct immunofluorescence microscopy; indirect immunofluo-rescence microscopy; mucous membrane pemphigoid; vulvar pemphigoid.Abbreviations used:DIF: direct immunofluorescence microscopyEBMZ: epidermal basement membrane zoneELPV: erosive lichen planus affecting the vulvaLS: lichen sclerosusMMP: mucous membrane pemphigoidVP: vulvar pemphigoidSSS: salt split skinIIF: indirect immunofluorescence microscopyELISA: enzyme-linked immunosorbent assayC3c: complement component 3Ig: immunoglobulinINTRODUCTIONVulvar pemphigoid (VP) is a rare subtype ofmucous membrane pemphigoid (MMP), which is aheterogeneous group of autoimmune subepidermalblistering diseases with predominantly mucosalinvolvement and characterized by autoantibodiesagainst structural proteins in the epidermal basementmembrane zone (EBMZ).1 In MMP, various mucosalsites can be simultaneously or separately affected.Mucosal lesions tend to heal with scar formation andmay result in loss of function of the affected area.In vulvar MMP, lesions are confined to theanogenital region but can also be a manifestationof a more extensive MMP with other mucosalinvolvement.2-5 Two variants can be distinguished:the juvenile form presenting in girls between 5 and10 years old, and the adult form, which occursmainly in postmenopausal women.6,7 However,symptoms may also occur in patients within thesetwo age categories. Overlapping with other chronicvulvar diseases, VP can present with variable clinicaland histopathologic features, including lichen scle-rosus (LS) and erosive lichen planus affectingthe vulva (ELPV).8,9 Careful examination of themucosa and skin is mandatory, which should befollowed by a biopsy for direct immunofluorescencemicroscopy (DIF) from perilesional skin or mucosa.Furthermore, indirect immunofluorescence micro-scopy (IIF) on salt split skin (SSS) and immunoser-ology can be performed for the detection ofcirculating autoantibodies in serum.Department of Dermatology, Center of Blisterings, European Reference Network-Skin Member, Univer-edical Center Groningen, University of Groningena;ment of Gynecology, University Medical Center Gronin-iversity of Groningenb; and Department of Pathology,ity Medical Center Groningen, University of Groningen.cources: None.dence to: Hanan Rashid, MD, Department ofology, University Medical Center Groningen, HanzepleinRB Groningen, Netherlands. E-mail: h.rashid@umcg.nl.In this study, we describe 14 patients diagnosedwith VP, demonstrating the wide clinical and immu-nologic variety of this disease.METHODSThis case series included patients diagnosed withVP from 2001 to 2018 at the Center for BlisteringDiseases in Groningen, which is the national referralcenter for autoimmune bullous diseases in theNetherlands. Diagnoses were made according toclinical features and immunologic criteria of linearn-serrated/u-serrated deposition of IgG, IgA, and/orcomplement component 3 along the EBMZ by DIFor detection of circulating autoantibodies. IIF onSSS was considered positive when immunoglobulin(Ig)G, IgA, and/or complement component 3 (C3c)staining at the epidermal and/or dermal side stainingwere observed. Immunoblot was used to detectJAAD Case Reports 2021;13:75-80.2352-5126 2021 by the American Academy of Dermatology, Inc. Publishedby Elsevier, Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).https://doi.org/10.1016/j.jdcr.2021.05.01775Table I. Clinical characteristics, diagnostic results, and treatment of patients with vulvar pemphigoidPatientno.Age inyearsSymptomdurationin months ScarringOthermucosalinvolvementSkininvolvement HistopathologyDIF onmucosaand/orskin Salt split skin ImmunoblotELISANC16ATopicaltherapySystemictherapy1 5 12 Yes - - Vacuolar degenerationbasal keratinocytes,homogenized collagenIgG & C3c Negative IgG BP180 Negative Clobetasol,TetracyclinePrednisone,Dapsone2 6 6 No - - Ulcerating inflammation,subepidermal splitIgG & C3c Negative Negative Negative Triamcinolone,Tetracycline-3 11 30 Yes Oral - Dermal mixed cellinflammation,subepidermal splitC3c IgGepidermalsideIgG BP180 Negative Tetracycline -4 11 72 No - - Dermal mixed cellinflammation,subepidermal splitIgG & IgA& C3cNegative Negative Positive Tetracycline,TriamcinoloneDapsone5 12 24 No - - Band-like lymphocyticinfiltrates, subepidermalsplitIgG & C3c Negative Negative Negative Tetracycline,Clobetasol-6 13 7 No - - Dermal mixed cellinflammation,subepidermal splitIgG & IgA& C3cNegative Negative Positive Tetracycline -7 48 9 Yes Oral - dermal lymphohistiocyticinflammation,subepidermal splitIgG & C3c Negative IgG BP180 Negative Tetracycline,Clobetasol,TriamcinoloneDoxycyline,Prednisone8 58 12 Yes - Submammary Dermal mixed cellinflammation,subepidermal splitIgG, IgA& C3cn-serratedIgG & IgAepidermalsideIgG BP180 Positive Triamcinolone Prednisone,Dapsone,Mycophenolicacid,Cyclophosphamide,Rituximab9 62 12 No - - Dermallymphoplasmacellularinflammation,subepidermalsplitC3cn-serratedNegative IgG BP180 Positive Triamcinolone,Fluticasone,Clobetason,TetracyclineDoxycycline10 65 60 Yes - - Dermal mixed cellinflammation,subepidermal splitIgG, IgA& C3cIgGepidermalsideIgG & IgABP180Positive ClobetasolTetracyclinePrednisone,Methotrexate,Mycophenolic acid,Azathioprine11 73 2 No Oral - - IgG Negative Negative Positive Tetracycline -JAADCASEREPORTSJULY202176Rashidetal12745NoOral-PerivascularlymphoplasmacellularinflammationIgAIgA epidermalsideIgABP180NegativeTetracycline,TriamcinoloneDapsone137414YesOral-SuperficialspongioticdermatitisIgG n-serratedIgG epidermalsideNegativeNegativeClobetasol-14917YesOral,nasal-SubepidermalsplitIgA,IgGn-serratedIgG epidermalsideIgGBP180PositiveClobetasolCyclophosphamideDIF,Directimmunofluorescencemicroscopy;ELISA,enzyme-linkedimmunosorbentassay;Igg,immunoglobulin;C3c,complementcomponent3.JAAD CASE REPORTSVOLUME 13Rashid et al 77circulating IgG or IgA against BP180. Autoantibodiesagainst the 16A domain of BP180 were detected withcommercially available enzyme-linked immunosor-bent assay (ELISA; cutoff index, $ 9 U/mL). Writtenconsent was provided.RESULTSFourteen patients diagnosed with VP wereincluded in this case series. One patient waspreviously described in the literature.10 Table Isummarizes the clinical, histopathologic, andimmunofluorescence findings, as well as the pre-scribed therapy of all patients. Six patients werediagnosed with juvenile VP, and the remaining 8were postmenopausal women. The age of onsetranged between 5 and 13 years in the juvenilegroup, and 48 and 91 years in the adult group. Themedian duration of symptoms before patients werereferred to the dermatologist at the Center forBlistering Diseases was 12 months (range, 2-72).Patients with extragenital involvement had ashorter median diagnostic delay compared withpatients with localized genital involvement (8 vs.12 months). The median follow-up time was22 months (range, 1-86). At the time of referral, 3patients had already received the diagnosis VP.One patient had previously been diagnosed withLS based on clinical and histologic features, and 1patient had been diagnosed with vulvar candidi-asis. The remaining patients were referred to ourclinic with no previous diagnosis.Clinical presentationFrequently reported symptoms included intermit-tent or continuous pain (10/14), followed by pruritus(5/14) and dysuria (5/14). Dyspareunia was reportedin 1 adult patient, and 2 patients experienced painduring defecation. One patient in the juvenile groupwas asymptomatic. Dermatologic examination re-vealed erosions (11/14), erythema (9/14), and su-perficial ulcerations (2/14) of the labia minora andmajora, periclitoreal area, vaginal introitus, andperineum (Fig 1, A, B and C). In one patient, anintact blister was seen. Structural architecture losswas observed in 5 adult patients, including fusion ofthe labia majora and minora and stenosis of thevaginal introitus, whereas only 2 patients in thejuvenile group developed fusion of the labia (Fig 1,B and C ). Examination of the vaginal mucosa wasnot performed. Extragenital mucosal involvementwas seen in 6/14 patients, of which 1 patient in thejuvenile group presented with erythematous swollengingiva and 5 adult patients with erythema, erosions,and blisters involving the gingiva, palatal surface,and buccal mucosa. One patient presented withFig 1. Lesions in juvenile and adult vulvar pemphigoid demonstrating erosions (A and C), scarformation (B and C), and complete fusion of the labia (B and C).JAAD CASE REPORTSJULY 202178 Rashid et alnasal crustae in addition to involvement of the oralmucosa. Furthermore, 1 adult patient had skininvolvement confined to the submammary region.Diagnostic findingsIn all patients (14/14), a biopsy for DIF wasperformed from perilesional mucosa and/or healthyskin, revealing linear deposition of IgG, IgA, and/orC3c complement component 3 along the EBMZ (Fig2,A). An n-serrated immunodeposition pattern alongthe EBMZwas identified in 4/14 biopsies for DIF, andin the remaining biopsies the serration pattern couldnot be identified. IIF on SSS revealed circulating IgGand/or IgA autoantibodies in 6/14 patients at theepidermal side of the split (Fig 2, B). Immunoblot forBP180 was positive for IgG and/or IgA in 8/14patients, and 7/14 patients showed positivity forIgG against the NC16A domain of BP180, as detectedby ELISA. A biopsy for histopathology was per-formed in 13/14 patients, revealing subepidermalblistering in 10 patients accompanied with a dermalinfiltrate consisting of lymphocytes, plasma cells,and eosinophils. One patient showed a band-likeinfiltrate of lymphocytes at the epidermal-dermaljunction; furthermore, in 1 patient, basal vacuolardegeneration and homogenization of the dermalcollagen was observed. Bacterial, fungal, and viralcultures were negative for all patients.TherapyAfter confirmation of the diagnosis, 8/14patients required systemic immunosuppressive orimmunomodulatory therapy in addition to localtherapy. In the juvenile group, 2/6 patients receiveddapsone in addition to local therapy, while 4/6patients received only topical corticosteroids. In 1patient, dapsone was discontinued after 1 year dueto hemolysis and replaced by prednisone followedby topical clobetasol propionate. Flare-ups werefrequently observed during treatment in this patient.The clinical outcome of the second patient is un-known, as follow-up took place in another hospitalafter the diagnosis was made. The remaining 4patients in the juvenile group responded well totopical triamcinolone acetonide and clobetasol onlyand did not experience flare-ups during treatment.The median duration until clinical response was2 months (range 0-28) in the juvenile group.Six out of 8 patients in the adult group requiredsystemic immunosuppressive therapy due to wors-ening of vulvar symptoms and poor response tolocal therapy. Systemic treatment included doxycy-cline, prednisone, dapsone, methotrexate, azathio-prine, cyclophosphamide, mycophenolic acid, andrituximab. The median duration until clinicalresponse was 1.5 months (range, 0-18). Flare-upswere seen in 5 out of 8 patients during treatment.These patients received several systemicFig 2. A, Direct immunofluorescence microscopyshowing linear C3c deposition along the epidermalbasement membrane zone in an n-serrated pattern. B,Indirect immunofluorescence on a substrate of salt splitskin, showing IgG bound to the epidermal basementmembrane zone (arrow) of the artificial split. Theepidermal side is depicted with * and the dermal side isdepicted with .̂JAAD CASE REPORTSVOLUME 13Rashid et al 79immunosuppressive agents during follow-up. Theremaining 2 patients who were treated with topicaltreatment only did not experience flare-ups duringtreatment.DISCUSSIONThis case series of 14 patients with juvenile andadult VP demonstrates the broad clinical spectrum ofthis disease. In the presence of vulvar erosions,ulcerations, blisters, and scarring, VP should beconsidered in the differential diagnosis. In addition,examining extragenital mucosal surfaces and per-forming immunofluorescence microscopy and im-munoserology is mandatory to differentiate betweenconditions with similar clinical findings.VP is often misdiagnosed for LS or ELPV, resultingin therapeutic delay.8,10 In children, VP may also bemistaken for sexual abuse.11 Differentiating betweenLS, ELPV, and VP is often challenging due to over-lapping clinical presentation and the presence ofchronic inflammation. The presence of Wickhamstriae, patchy hair loss, or nail abnormalities candistinguish lichen planus from pemphigoid. Vaginalinvolvement is common in ELVP but has not beenpreviously reported in VP.4,5,12 In this study, exam-ination of the vaginal mucosa was not performed.However, patients diagnosed with VP should beexamined by a gynecologist with expertise in ELVPfor evaluation of vaginal involvement. In contrast toLS, MMP and ELPV may affect other mucosal sites,such as the ocular, nasal, pharyngeal, and laryngealmucosa. In this study, the presence of extragenitalinvolvement might have led to a quicker diagnosis.Extragenital involvement, including the oral andnasal mucosa, was observed more often in the adultgroup. In addition, more patients in the adult grouppresented with scar formation.Histopathology can often be used to differentiateVP from ELVP and LS. However, in some cases,histologic differences are not that clear and mayoverlap. A lesional biopsy for histopathology inpemphigoid can show subepidermal splitting com-bined with a moderate to dense infiltrate composedof lymphocytes, neutrophils, and eosinophils. Thiscan also be seen in bullous LS, which is caused byeither increased vacuolar degeneration of the basalmembrane zone or edema in the papillarydermis.13,14 In this study, a subepidermal split wasseen in 10 patients. Moreover, histopathologic fea-tures mimicking lichen planus and LS wereobserved.Overall, VP of the juvenile form respondspromptly to potent topical therapy and generallydoes not require systemic therapy. In the juvenilegroup, 4 out of 6 patients had relatively milddisease and responded well to potent topicalsteroids, with the exception of 2 patients, whowere treated with systemic corticosteroids anddapsone. In contrast, the majority of the adultpatients required systemic therapy and oftenshowed flare-ups.In conclusion, VP presents a broad spectrum ofsymptoms and can be challenging to diagnose.Performing careful examination of other mucosaeand skin with additional immunofluorescence andimmunoserology is essential for an adequatediagnosis.Conflicts of interestDr Horvath reports fees from Janssen-Cilag (AdvisoryBoards, Educational grants, Consultations, InvestigatorJAAD CASE REPORTSJULY 202180 Rashid et alInitiative Studies), AbbVie (Advisory Boards, Educationalgrants, Consultations, Investigator Initiative Studies),Novartis Pharma (Advisory Boards, Consultations,Investigator Initiative Studies), UCB Pharma (AdvisoryBoards, Consultations), Leo Pharma (Consultations),Solenne B.V. (Investigator Initiative Studies), Celgene(Consultations, Investigator Initiative Studies), Akari ther-apeutics (Consultations, Investigator Initiative Studies),Philips (Consultation), Roche (Consultation), Regeneron(Consultation) and Sanofi (Consultation), which fees werepaid to the institution. The remaining authors declare noconflict of interest.REFERENCES1. Chan LS, Ahmed AR, Anhalt GJ, et al. The first internationalconsensus on mucous membrane pemphigoid: definition,diagnostic criteria, pathogenic factors, medical treatment,and prognostic indicators. Arch Dermatol. 2002;138(3):370-379.2. Goldstein AT, Anhalt GJ, Klingman D, Burrows LJ. Mucousmembrane pemphigoid of the vulva. Obstet Gynecol. 2005;105(5 Pt 2):1188-1190.3. Farrell AM, Kirtschig G, Dalziel KL, et al. Childhood vulvalpemphigoid: a clinical and immunopathological study of fivepatients. Br J Dermatol. 1999;140(2):308-312.4. Jolliffe DS, Sim-Davis D. Cicatricial pemphigoid in a young girl:report of a case. Clin Exp Dermatol. 1977;2(3):281-284.5. Stage AH, Humeniuk JM, Easley WK. Bullous pemphigoid of thevulva: a case report. Am J Obstet Gynecol. 1984;150(2):169-170.6. Belzile E, Funaro D, Powell J. Localized vulvar bullouspemphigoid of childhood: a rare cause of persistent vulvarerosions in children. Pediatr Dermatol. 2019;36(3):349-351.7. Venning VA, Frith PA, Bron AJ, Millard PR, Wojnarowska F.Mucosal involvement in bullous and cicatricial pemphigoid. Aclinical and immunopathological study. Br J Dermatol. 1988;118(1):7-15.8. Marren P, Walkden V, Mallon E, Wojnarowska F. Vulvalcicatricial pemphigoid may mimic lichen sclerosus. Br JDermatol. 1996;134(3):522-524.9. Loyal J, Rashtak S. Vulvar lichen planus pemphigoides. Int JWomens Dermatol. 2017;3(4):225-227.10. de Waard MM, Jonkman MF. Vulvair gelokaliseerd pemfigo€ıd.NTvDV. 2008;18(4):204-207.11. Levine V, Sanchez M, Nestor M. Localized vulvar pemphigoidin a child misdiagnosed as sexual abuse. Arch Dermatol. 1992;128(6):804-806.12. Rogers M, Painter D. Cicatricial pemphigoid in a four-year-oldchild: a case report. Australas J Dermatol. 1981;22(1):21-23.13. Kavak A, Erdogan B, Topkarc Z, S€onmezler H, Sakız D. Bullouslichen sclerosus: isolated vulvar involvement. Dermatol OnlineJ. 2018;24(2):13030/qt3mk9801x.14. Hallel-Halevy D, Grunwald MH, Yerushalmi J, Halevy S. Bullouslichen sclerosus et atrophicus. J Am Acad Dermatol. 1998;39(3):500-501.

Dissertations of the University of Groningen

   University of GroningenJuvenile and adult vulvar pemphigoid, an under recognized entityRashid, Hanan; Oldhoff, J Marja; Esajas, Martha; Diercks, Gilles F H; Pas, Hendri H; Bolling,Maria C; Horváth, BarbaraPublished in:JAAD case reportsDOI:10.1016/j.jdcr.2021.05.017IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2021Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Rashid, H., Oldhoff, J. M., Esajas, M., Diercks, G. F. H., Pas, H. H., Bolling, M. C., & Horváth, B. (2021).Juvenile and adult vulvar pemphigoid, an under recognized entity: Case series of fourteen patients. JAADcase reports, 13, 75-80. https://doi.org/10.1016/j.jdcr.2021.05.017CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 05-06-2022CASE SERIESFrom theDiseasesity MDepartgen, UnUniversFunding sCorresponDermat1, 9700Juvenile and adult vulvar pemphigoid, anunder recognized entity: Case series offourteen patientsHanan Rashid, MD,a J. Marja Oldhoff, MD, PhD,a Martha Esajas, MD,b Gilles F. H. Diercks, MD, PhD,cHendri H. Pas, PhD,a Maria C. Bolling, MD, PhD,a and Barbara Horvath, MD, PhDaGroningen, NetherlandsKey words: autoimmune blistering diseases; direct immunofluorescence microscopy; indirect immunofluo-rescence microscopy; mucous membrane pemphigoid; vulvar pemphigoid.Abbreviations used:DIF: direct immunofluorescence microscopyEBMZ: epidermal basement membrane zoneELPV: erosive lichen planus affecting the vulvaLS: lichen sclerosusMMP: mucous membrane pemphigoidVP: vulvar pemphigoidSSS: salt split skinIIF: indirect immunofluorescence microscopyELISA: enzyme-linked immunosorbent assayC3c: complement component 3Ig: immunoglobulinINTRODUCTIONVulvar pemphigoid (VP) is a rare subtype ofmucous membrane pemphigoid (MMP), which is aheterogeneous group of autoimmune subepidermalblistering diseases with predominantly mucosalinvolvement and characterized by autoantibodiesagainst structural proteins in the epidermal basementmembrane zone (EBMZ).1 In MMP, various mucosalsites can be simultaneously or separately affected.Mucosal lesions tend to heal with scar formation andmay result in loss of function of the affected area.In vulvar MMP, lesions are confined to theanogenital region but can also be a manifestationof a more extensive MMP with other mucosalinvolvement.2-5 Two variants can be distinguished:the juvenile form presenting in girls between 5 and10 years old, and the adult form, which occursmainly in postmenopausal women.6,7 However,symptoms may also occur in patients within thesetwo age categories. Overlapping with other chronicvulvar diseases, VP can present with variable clinicaland histopathologic features, including lichen scle-rosus (LS) and erosive lichen planus affectingthe vulva (ELPV).8,9 Careful examination of themucosa and skin is mandatory, which should befollowed by a biopsy for direct immunofluorescencemicroscopy (DIF) from perilesional skin or mucosa.Furthermore, indirect immunofluorescence micro-scopy (IIF) on salt split skin (SSS) and immunoser-ology can be performed for the detection ofcirculating autoantibodies in serum.Department of Dermatology, Center of Blisterings, European Reference Network-Skin Member, Univer-edical Center Groningen, University of Groningena;ment of Gynecology, University Medical Center Gronin-iversity of Groningenb; and Department of Pathology,ity Medical Center Groningen, University of Groningen.cources: None.dence to: Hanan Rashid, MD, Department ofology, University Medical Center Groningen, HanzepleinRB Groningen, Netherlands. E-mail: h.rashid@umcg.nl.In this study, we describe 14 patients diagnosedwith VP, demonstrating the wide clinical and immu-nologic variety of this disease.METHODSThis case series included patients diagnosed withVP from 2001 to 2018 at the Center for BlisteringDiseases in Groningen, which is the national referralcenter for autoimmune bullous diseases in theNetherlands. Diagnoses were made according toclinical features and immunologic criteria of linearn-serrated/u-serrated deposition of IgG, IgA, and/orcomplement component 3 along the EBMZ by DIFor detection of circulating autoantibodies. IIF onSSS was considered positive when immunoglobulin(Ig)G, IgA, and/or complement component 3 (C3c)staining at the epidermal and/or dermal side stainingwere observed. Immunoblot was used to detectJAAD Case Reports 2021;13:75-80.2352-5126 2021 by the American Academy of Dermatology, Inc. Publishedby Elsevier, Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).https://doi.org/10.1016/j.jdcr.2021.05.01775Table I. Clinical characteristics, diagnostic results, and treatment of patients with vulvar pemphigoidPatientno.Age inyearsSymptomdurationin months ScarringOthermucosalinvolvementSkininvolvement HistopathologyDIF onmucosaand/orskin Salt split skin ImmunoblotELISANC16ATopicaltherapySystemictherapy1 5 12 Yes - - Vacuolar degenerationbasal keratinocytes,homogenized collagenIgG & C3c Negative IgG BP180 Negative Clobetasol,TetracyclinePrednisone,Dapsone2 6 6 No - - Ulcerating inflammation,subepidermal splitIgG & C3c Negative Negative Negative Triamcinolone,Tetracycline-3 11 30 Yes Oral - Dermal mixed cellinflammation,subepidermal splitC3c IgGepidermalsideIgG BP180 Negative Tetracycline -4 11 72 No - - Dermal mixed cellinflammation,subepidermal splitIgG & IgA& C3cNegative Negative Positive Tetracycline,TriamcinoloneDapsone5 12 24 No - - Band-like lymphocyticinfiltrates, subepidermalsplitIgG & C3c Negative Negative Negative Tetracycline,Clobetasol-6 13 7 No - - Dermal mixed cellinflammation,subepidermal splitIgG & IgA& C3cNegative Negative Positive Tetracycline -7 48 9 Yes Oral - dermal lymphohistiocyticinflammation,subepidermal splitIgG & C3c Negative IgG BP180 Negative Tetracycline,Clobetasol,TriamcinoloneDoxycyline,Prednisone8 58 12 Yes - Submammary Dermal mixed cellinflammation,subepidermal splitIgG, IgA& C3cn-serratedIgG & IgAepidermalsideIgG BP180 Positive Triamcinolone Prednisone,Dapsone,Mycophenolicacid,Cyclophosphamide,Rituximab9 62 12 No - - Dermallymphoplasmacellularinflammation,subepidermalsplitC3cn-serratedNegative IgG BP180 Positive Triamcinolone,Fluticasone,Clobetason,TetracyclineDoxycycline10 65 60 Yes - - Dermal mixed cellinflammation,subepidermal splitIgG, IgA& C3cIgGepidermalsideIgG & IgABP180Positive ClobetasolTetracyclinePrednisone,Methotrexate,Mycophenolic acid,Azathioprine11 73 2 No Oral - - IgG Negative Negative Positive Tetracycline -JAADCASEREPORTSJULY202176Rashidetal12745NoOral-PerivascularlymphoplasmacellularinflammationIgAIgA epidermalsideIgABP180NegativeTetracycline,TriamcinoloneDapsone137414YesOral-SuperficialspongioticdermatitisIgG n-serratedIgG epidermalsideNegativeNegativeClobetasol-14917YesOral,nasal-SubepidermalsplitIgA,IgGn-serratedIgG epidermalsideIgGBP180PositiveClobetasolCyclophosphamideDIF,Directimmunofluorescencemicroscopy;ELISA,enzyme-linkedimmunosorbentassay;Igg,immunoglobulin;C3c,complementcomponent3.JAAD CASE REPORTSVOLUME 13Rashid et al 77circulating IgG or IgA against BP180. Autoantibodiesagainst the 16A domain of BP180 were detected withcommercially available enzyme-linked immunosor-bent assay (ELISA; cutoff index, $ 9 U/mL). Writtenconsent was provided.RESULTSFourteen patients diagnosed with VP wereincluded in this case series. One patient waspreviously described in the literature.10 Table Isummarizes the clinical, histopathologic, andimmunofluorescence findings, as well as the pre-scribed therapy of all patients. Six patients werediagnosed with juvenile VP, and the remaining 8were postmenopausal women. The age of onsetranged between 5 and 13 years in the juvenilegroup, and 48 and 91 years in the adult group. Themedian duration of symptoms before patients werereferred to the dermatologist at the Center forBlistering Diseases was 12 months (range, 2-72).Patients with extragenital involvement had ashorter median diagnostic delay compared withpatients with localized genital involvement (8 vs.12 months). The median follow-up time was22 months (range, 1-86). At the time of referral, 3patients had already received the diagnosis VP.One patient had previously been diagnosed withLS based on clinical and histologic features, and 1patient had been diagnosed with vulvar candidi-asis. The remaining patients were referred to ourclinic with no previous diagnosis.Clinical presentationFrequently reported symptoms included intermit-tent or continuous pain (10/14), followed by pruritus(5/14) and dysuria (5/14). Dyspareunia was reportedin 1 adult patient, and 2 patients experienced painduring defecation. One patient in the juvenile groupwas asymptomatic. Dermatologic examination re-vealed erosions (11/14), erythema (9/14), and su-perficial ulcerations (2/14) of the labia minora andmajora, periclitoreal area, vaginal introitus, andperineum (Fig 1, A, B and C). In one patient, anintact blister was seen. Structural architecture losswas observed in 5 adult patients, including fusion ofthe labia majora and minora and stenosis of thevaginal introitus, whereas only 2 patients in thejuvenile group developed fusion of the labia (Fig 1,B and C ). Examination of the vaginal mucosa wasnot performed. Extragenital mucosal involvementwas seen in 6/14 patients, of which 1 patient in thejuvenile group presented with erythematous swollengingiva and 5 adult patients with erythema, erosions,and blisters involving the gingiva, palatal surface,and buccal mucosa. One patient presented withFig 1. Lesions in juvenile and adult vulvar pemphigoid demonstrating erosions (A and C), scarformation (B and C), and complete fusion of the labia (B and C).JAAD CASE REPORTSJULY 202178 Rashid et alnasal crustae in addition to involvement of the oralmucosa. Furthermore, 1 adult patient had skininvolvement confined to the submammary region.Diagnostic findingsIn all patients (14/14), a biopsy for DIF wasperformed from perilesional mucosa and/or healthyskin, revealing linear deposition of IgG, IgA, and/orC3c complement component 3 along the EBMZ (Fig2,A). An n-serrated immunodeposition pattern alongthe EBMZwas identified in 4/14 biopsies for DIF, andin the remaining biopsies the serration pattern couldnot be identified. IIF on SSS revealed circulating IgGand/or IgA autoantibodies in 6/14 patients at theepidermal side of the split (Fig 2, B). Immunoblot forBP180 was positive for IgG and/or IgA in 8/14patients, and 7/14 patients showed positivity forIgG against the NC16A domain of BP180, as detectedby ELISA. A biopsy for histopathology was per-formed in 13/14 patients, revealing subepidermalblistering in 10 patients accompanied with a dermalinfiltrate consisting of lymphocytes, plasma cells,and eosinophils. One patient showed a band-likeinfiltrate of lymphocytes at the epidermal-dermaljunction; furthermore, in 1 patient, basal vacuolardegeneration and homogenization of the dermalcollagen was observed. Bacterial, fungal, and viralcultures were negative for all patients.TherapyAfter confirmation of the diagnosis, 8/14patients required systemic immunosuppressive orimmunomodulatory therapy in addition to localtherapy. In the juvenile group, 2/6 patients receiveddapsone in addition to local therapy, while 4/6patients received only topical corticosteroids. In 1patient, dapsone was discontinued after 1 year dueto hemolysis and replaced by prednisone followedby topical clobetasol propionate. Flare-ups werefrequently observed during treatment in this patient.The clinical outcome of the second patient is un-known, as follow-up took place in another hospitalafter the diagnosis was made. The remaining 4patients in the juvenile group responded well totopical triamcinolone acetonide and clobetasol onlyand did not experience flare-ups during treatment.The median duration until clinical response was2 months (range 0-28) in the juvenile group.Six out of 8 patients in the adult group requiredsystemic immunosuppressive therapy due to wors-ening of vulvar symptoms and poor response tolocal therapy. Systemic treatment included doxycy-cline, prednisone, dapsone, methotrexate, azathio-prine, cyclophosphamide, mycophenolic acid, andrituximab. The median duration until clinicalresponse was 1.5 months (range, 0-18). Flare-upswere seen in 5 out of 8 patients during treatment.These patients received several systemicFig 2. A, Direct immunofluorescence microscopyshowing linear C3c deposition along the epidermalbasement membrane zone in an n-serrated pattern. B,Indirect immunofluorescence on a substrate of salt splitskin, showing IgG bound to the epidermal basementmembrane zone (arrow) of the artificial split. Theepidermal side is depicted with * and the dermal side isdepicted with .̂JAAD CASE REPORTSVOLUME 13Rashid et al 79immunosuppressive agents during follow-up. Theremaining 2 patients who were treated with topicaltreatment only did not experience flare-ups duringtreatment.DISCUSSIONThis case series of 14 patients with juvenile andadult VP demonstrates the broad clinical spectrum ofthis disease. In the presence of vulvar erosions,ulcerations, blisters, and scarring, VP should beconsidered in the differential diagnosis. In addition,examining extragenital mucosal surfaces and per-forming immunofluorescence microscopy and im-munoserology is mandatory to differentiate betweenconditions with similar clinical findings.VP is often misdiagnosed for LS or ELPV, resultingin therapeutic delay.8,10 In children, VP may also bemistaken for sexual abuse.11 Differentiating betweenLS, ELPV, and VP is often challenging due to over-lapping clinical presentation and the presence ofchronic inflammation. The presence of Wickhamstriae, patchy hair loss, or nail abnormalities candistinguish lichen planus from pemphigoid. Vaginalinvolvement is common in ELVP but has not beenpreviously reported in VP.4,5,12 In this study, exam-ination of the vaginal mucosa was not performed.However, patients diagnosed with VP should beexamined by a gynecologist with expertise in ELVPfor evaluation of vaginal involvement. In contrast toLS, MMP and ELPV may affect other mucosal sites,such as the ocular, nasal, pharyngeal, and laryngealmucosa. In this study, the presence of extragenitalinvolvement might have led to a quicker diagnosis.Extragenital involvement, including the oral andnasal mucosa, was observed more often in the adultgroup. In addition, more patients in the adult grouppresented with scar formation.Histopathology can often be used to differentiateVP from ELVP and LS. However, in some cases,histologic differences are not that clear and mayoverlap. A lesional biopsy for histopathology inpemphigoid can show subepidermal splitting com-bined with a moderate to dense infiltrate composedof lymphocytes, neutrophils, and eosinophils. Thiscan also be seen in bullous LS, which is caused byeither increased vacuolar degeneration of the basalmembrane zone or edema in the papillarydermis.13,14 In this study, a subepidermal split wasseen in 10 patients. Moreover, histopathologic fea-tures mimicking lichen planus and LS wereobserved.Overall, VP of the juvenile form respondspromptly to potent topical therapy and generallydoes not require systemic therapy. In the juvenilegroup, 4 out of 6 patients had relatively milddisease and responded well to potent topicalsteroids, with the exception of 2 patients, whowere treated with systemic corticosteroids anddapsone. In contrast, the majority of the adultpatients required systemic therapy and oftenshowed flare-ups.In conclusion, VP presents a broad spectrum ofsymptoms and can be challenging to diagnose.Performing careful examination of other mucosaeand skin with additional immunofluorescence andimmunoserology is essential for an adequatediagnosis.Conflicts of interestDr Horvath reports fees from Janssen-Cilag (AdvisoryBoards, Educational grants, Consultations, InvestigatorJAAD CASE REPORTSJULY 202180 Rashid et alInitiative Studies), AbbVie (Advisory Boards, Educationalgrants, Consultations, Investigator Initiative Studies),Novartis Pharma (Advisory Boards, Consultations,Investigator Initiative Studies), UCB Pharma (AdvisoryBoards, Consultations), Leo Pharma (Consultations),Solenne B.V. (Investigator Initiative Studies), Celgene(Consultations, Investigator Initiative Studies), Akari ther-apeutics (Consultations, Investigator Initiative Studies),Philips (Consultation), Roche (Consultation), Regeneron(Consultation) and Sanofi (Consultation), which fees werepaid to the institution. The remaining authors declare noconflict of interest.REFERENCES1. Chan LS, Ahmed AR, Anhalt GJ, et al. The first internationalconsensus on mucous membrane pemphigoid: definition,diagnostic criteria, pathogenic factors, medical treatment,and prognostic indicators. Arch Dermatol. 2002;138(3):370-379.2. Goldstein AT, Anhalt GJ, Klingman D, Burrows LJ. Mucousmembrane pemphigoid of the vulva. Obstet Gynecol. 2005;105(5 Pt 2):1188-1190.3. Farrell AM, Kirtschig G, Dalziel KL, et al. Childhood vulvalpemphigoid: a clinical and immunopathological study of fivepatients. Br J Dermatol. 1999;140(2):308-312.4. Jolliffe DS, Sim-Davis D. Cicatricial pemphigoid in a young girl:report of a case. Clin Exp Dermatol. 1977;2(3):281-284.5. Stage AH, Humeniuk JM, Easley WK. Bullous pemphigoid of thevulva: a case report. Am J Obstet Gynecol. 1984;150(2):169-170.6. Belzile E, Funaro D, Powell J. Localized vulvar bullouspemphigoid of childhood: a rare cause of persistent vulvarerosions in children. Pediatr Dermatol. 2019;36(3):349-351.7. Venning VA, Frith PA, Bron AJ, Millard PR, Wojnarowska F.Mucosal involvement in bullous and cicatricial pemphigoid. Aclinical and immunopathological study. Br J Dermatol. 1988;118(1):7-15.8. Marren P, Walkden V, Mallon E, Wojnarowska F. Vulvalcicatricial pemphigoid may mimic lichen sclerosus. Br JDermatol. 1996;134(3):522-524.9. Loyal J, Rashtak S. Vulvar lichen planus pemphigoides. Int JWomens Dermatol. 2017;3(4):225-227.10. de Waard MM, Jonkman MF. Vulvair gelokaliseerd pemfigo€ıd.NTvDV. 2008;18(4):204-207.11. Levine V, Sanchez M, Nestor M. Localized vulvar pemphigoidin a child misdiagnosed as sexual abuse. Arch Dermatol. 1992;128(6):804-806.12. Rogers M, Painter D. Cicatricial pemphigoid in a four-year-oldchild: a case report. Australas J Dermatol. 1981;22(1):21-23.13. Kavak A, Erdogan B, Topkarc Z, S€onmezler H, Sakız D. Bullouslichen sclerosus: isolated vulvar involvement. Dermatol OnlineJ. 2018;24(2):13030/qt3mk9801x.14. Hallel-Halevy D, Grunwald MH, Yerushalmi J, Halevy S. Bullouslichen sclerosus et atrophicus. J Am Acad Dermatol. 1998;39(3):500-501.

   University of GroningenJuvenile and adult vulvar pemphigoid, an under recognized entityRashid, Hanan; Oldhoff, J Marja; Esajas, Martha; Diercks, Gilles F H; Pas, Hendri H; Bolling,Maria C; Horváth, BarbaraPublished in:JAAD case reportsDOI:10.1016/j.jdcr.2021.05.017IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2021Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Rashid, H., Oldhoff, J. M., Esajas, M., Diercks, G. F. H., Pas, H. H., Bolling, M. C., & Horváth, B. (2021).Juvenile and adult vulvar pemphigoid, an under recognized entity: Case series of fourteen patients. JAADcase reports, 13, 75-80. https://doi.org/10.1016/j.jdcr.2021.05.017CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 10-09-2023CASE SERIESFrom theDiseasesity MDepartgen, UnUniversFunding sCorresponDermat1, 9700Juvenile and adult vulvar pemphigoid, anunder recognized entity: Case series offourteen patientsHanan Rashid, MD,a J. Marja Oldhoff, MD, PhD,a Martha Esajas, MD,b Gilles F. H. Diercks, MD, PhD,cHendri H. Pas, PhD,a Maria C. Bolling, MD, PhD,a and Barbara Horvath, MD, PhDaGroningen, NetherlandsKey words: autoimmune blistering diseases; direct immunofluorescence microscopy; indirect immunofluo-rescence microscopy; mucous membrane pemphigoid; vulvar pemphigoid.Abbreviations used:DIF: direct immunofluorescence microscopyEBMZ: epidermal basement membrane zoneELPV: erosive lichen planus affecting the vulvaLS: lichen sclerosusMMP: mucous membrane pemphigoidVP: vulvar pemphigoidSSS: salt split skinIIF: indirect immunofluorescence microscopyELISA: enzyme-linked immunosorbent assayC3c: complement component 3Ig: immunoglobulinINTRODUCTIONVulvar pemphigoid (VP) is a rare subtype ofmucous membrane pemphigoid (MMP), which is aheterogeneous group of autoimmune subepidermalblistering diseases with predominantly mucosalinvolvement and characterized by autoantibodiesagainst structural proteins in the epidermal basementmembrane zone (EBMZ).1 In MMP, various mucosalsites can be simultaneously or separately affected.Mucosal lesions tend to heal with scar formation andmay result in loss of function of the affected area.In vulvar MMP, lesions are confined to theanogenital region but can also be a manifestationof a more extensive MMP with other mucosalinvolvement.2-5 Two variants can be distinguished:the juvenile form presenting in girls between 5 and10 years old, and the adult form, which occursmainly in postmenopausal women.6,7 However,symptoms may also occur in patients within thesetwo age categories. Overlapping with other chronicvulvar diseases, VP can present with variable clinicaland histopathologic features, including lichen scle-rosus (LS) and erosive lichen planus affectingthe vulva (ELPV).8,9 Careful examination of themucosa and skin is mandatory, which should befollowed by a biopsy for direct immunofluorescencemicroscopy (DIF) from perilesional skin or mucosa.Furthermore, indirect immunofluorescence micro-scopy (IIF) on salt split skin (SSS) and immunoser-ology can be performed for the detection ofcirculating autoantibodies in serum.Department of Dermatology, Center of Blisterings, European Reference Network-Skin Member, Univer-edical Center Groningen, University of Groningena;ment of Gynecology, University Medical Center Gronin-iversity of Groningenb; and Department of Pathology,ity Medical Center Groningen, University of Groningen.cources: None.dence to: Hanan Rashid, MD, Department ofology, University Medical Center Groningen, HanzepleinRB Groningen, Netherlands. E-mail: h.rashid@umcg.nl.In this study, we describe 14 patients diagnosedwith VP, demonstrating the wide clinical and immu-nologic variety of this disease.METHODSThis case series included patients diagnosed withVP from 2001 to 2018 at the Center for BlisteringDiseases in Groningen, which is the national referralcenter for autoimmune bullous diseases in theNetherlands. Diagnoses were made according toclinical features and immunologic criteria of linearn-serrated/u-serrated deposition of IgG, IgA, and/orcomplement component 3 along the EBMZ by DIFor detection of circulating autoantibodies. IIF onSSS was considered positive when immunoglobulin(Ig)G, IgA, and/or complement component 3 (C3c)staining at the epidermal and/or dermal side stainingwere observed. Immunoblot was used to detectJAAD Case Reports 2021;13:75-80.2352-5126 2021 by the American Academy of Dermatology, Inc. Publishedby Elsevier, Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).https://doi.org/10.1016/j.jdcr.2021.05.01775Table I. Clinical characteristics, diagnostic results, and treatment of patients with vulvar pemphigoidPatientno.Age inyearsSymptomdurationin months ScarringOthermucosalinvolvementSkininvolvement HistopathologyDIF onmucosaand/orskin Salt split skin ImmunoblotELISANC16ATopicaltherapySystemictherapy1 5 12 Yes - - Vacuolar degenerationbasal keratinocytes,homogenized collagenIgG & C3c Negative IgG BP180 Negative Clobetasol,TetracyclinePrednisone,Dapsone2 6 6 No - - Ulcerating inflammation,subepidermal splitIgG & C3c Negative Negative Negative Triamcinolone,Tetracycline-3 11 30 Yes Oral - Dermal mixed cellinflammation,subepidermal splitC3c IgGepidermalsideIgG BP180 Negative Tetracycline -4 11 72 No - - Dermal mixed cellinflammation,subepidermal splitIgG & IgA& C3cNegative Negative Positive Tetracycline,TriamcinoloneDapsone5 12 24 No - - Band-like lymphocyticinfiltrates, subepidermalsplitIgG & C3c Negative Negative Negative Tetracycline,Clobetasol-6 13 7 No - - Dermal mixed cellinflammation,subepidermal splitIgG & IgA& C3cNegative Negative Positive Tetracycline -7 48 9 Yes Oral - dermal lymphohistiocyticinflammation,subepidermal splitIgG & C3c Negative IgG BP180 Negative Tetracycline,Clobetasol,TriamcinoloneDoxycyline,Prednisone8 58 12 Yes - Submammary Dermal mixed cellinflammation,subepidermal splitIgG, IgA& C3cn-serratedIgG & IgAepidermalsideIgG BP180 Positive Triamcinolone Prednisone,Dapsone,Mycophenolicacid,Cyclophosphamide,Rituximab9 62 12 No - - Dermallymphoplasmacellularinflammation,subepidermalsplitC3cn-serratedNegative IgG BP180 Positive Triamcinolone,Fluticasone,Clobetason,TetracyclineDoxycycline10 65 60 Yes - - Dermal mixed cellinflammation,subepidermal splitIgG, IgA& C3cIgGepidermalsideIgG & IgABP180Positive ClobetasolTetracyclinePrednisone,Methotrexate,Mycophenolic acid,Azathioprine11 73 2 No Oral - - IgG Negative Negative Positive Tetracycline -JAADCASEREPORTSJULY202176Rashidetal12745NoOral-PerivascularlymphoplasmacellularinflammationIgAIgA epidermalsideIgABP180NegativeTetracycline,TriamcinoloneDapsone137414YesOral-SuperficialspongioticdermatitisIgG n-serratedIgG epidermalsideNegativeNegativeClobetasol-14917YesOral,nasal-SubepidermalsplitIgA,IgGn-serratedIgG epidermalsideIgGBP180PositiveClobetasolCyclophosphamideDIF,Directimmunofluorescencemicroscopy;ELISA,enzyme-linkedimmunosorbentassay;Igg,immunoglobulin;C3c,complementcomponent3.JAAD CASE REPORTSVOLUME 13Rashid et al 77circulating IgG or IgA against BP180. Autoantibodiesagainst the 16A domain of BP180 were detected withcommercially available enzyme-linked immunosor-bent assay (ELISA; cutoff index, $ 9 U/mL). Writtenconsent was provided.RESULTSFourteen patients diagnosed with VP wereincluded in this case series. One patient waspreviously described in the literature.10 Table Isummarizes the clinical, histopathologic, andimmunofluorescence findings, as well as the pre-scribed therapy of all patients. Six patients werediagnosed with juvenile VP, and the remaining 8were postmenopausal women. The age of onsetranged between 5 and 13 years in the juvenilegroup, and 48 and 91 years in the adult group. Themedian duration of symptoms before patients werereferred to the dermatologist at the Center forBlistering Diseases was 12 months (range, 2-72).Patients with extragenital involvement had ashorter median diagnostic delay compared withpatients with localized genital involvement (8 vs.12 months). The median follow-up time was22 months (range, 1-86). At the time of referral, 3patients had already received the diagnosis VP.One patient had previously been diagnosed withLS based on clinical and histologic features, and 1patient had been diagnosed with vulvar candidi-asis. The remaining patients were referred to ourclinic with no previous diagnosis.Clinical presentationFrequently reported symptoms included intermit-tent or continuous pain (10/14), followed by pruritus(5/14) and dysuria (5/14). Dyspareunia was reportedin 1 adult patient, and 2 patients experienced painduring defecation. One patient in the juvenile groupwas asymptomatic. Dermatologic examination re-vealed erosions (11/14), erythema (9/14), and su-perficial ulcerations (2/14) of the labia minora andmajora, periclitoreal area, vaginal introitus, andperineum (Fig 1, A, B and C). In one patient, anintact blister was seen. Structural architecture losswas observed in 5 adult patients, including fusion ofthe labia majora and minora and stenosis of thevaginal introitus, whereas only 2 patients in thejuvenile group developed fusion of the labia (Fig 1,B and C ). Examination of the vaginal mucosa wasnot performed. Extragenital mucosal involvementwas seen in 6/14 patients, of which 1 patient in thejuvenile group presented with erythematous swollengingiva and 5 adult patients with erythema, erosions,and blisters involving the gingiva, palatal surface,and buccal mucosa. One patient presented withFig 1. Lesions in juvenile and adult vulvar pemphigoid demonstrating erosions (A and C), scarformation (B and C), and complete fusion of the labia (B and C).JAAD CASE REPORTSJULY 202178 Rashid et alnasal crustae in addition to involvement of the oralmucosa. Furthermore, 1 adult patient had skininvolvement confined to the submammary region.Diagnostic findingsIn all patients (14/14), a biopsy for DIF wasperformed from perilesional mucosa and/or healthyskin, revealing linear deposition of IgG, IgA, and/orC3c complement component 3 along the EBMZ (Fig2,A). An n-serrated immunodeposition pattern alongthe EBMZwas identified in 4/14 biopsies for DIF, andin the remaining biopsies the serration pattern couldnot be identified. IIF on SSS revealed circulating IgGand/or IgA autoantibodies in 6/14 patients at theepidermal side of the split (Fig 2, B). Immunoblot forBP180 was positive for IgG and/or IgA in 8/14patients, and 7/14 patients showed positivity forIgG against the NC16A domain of BP180, as detectedby ELISA. A biopsy for histopathology was per-formed in 13/14 patients, revealing subepidermalblistering in 10 patients accompanied with a dermalinfiltrate consisting of lymphocytes, plasma cells,and eosinophils. One patient showed a band-likeinfiltrate of lymphocytes at the epidermal-dermaljunction; furthermore, in 1 patient, basal vacuolardegeneration and homogenization of the dermalcollagen was observed. Bacterial, fungal, and viralcultures were negative for all patients.TherapyAfter confirmation of the diagnosis, 8/14patients required systemic immunosuppressive orimmunomodulatory therapy in addition to localtherapy. In the juvenile group, 2/6 patients receiveddapsone in addition to local therapy, while 4/6patients received only topical corticosteroids. In 1patient, dapsone was discontinued after 1 year dueto hemolysis and replaced by prednisone followedby topical clobetasol propionate. Flare-ups werefrequently observed during treatment in this patient.The clinical outcome of the second patient is un-known, as follow-up took place in another hospitalafter the diagnosis was made. The remaining 4patients in the juvenile group responded well totopical triamcinolone acetonide and clobetasol onlyand did not experience flare-ups during treatment.The median duration until clinical response was2 months (range 0-28) in the juvenile group.Six out of 8 patients in the adult group requiredsystemic immunosuppressive therapy due to wors-ening of vulvar symptoms and poor response tolocal therapy. Systemic treatment included doxycy-cline, prednisone, dapsone, methotrexate, azathio-prine, cyclophosphamide, mycophenolic acid, andrituximab. The median duration until clinicalresponse was 1.5 months (range, 0-18). Flare-upswere seen in 5 out of 8 patients during treatment.These patients received several systemicFig 2. A, Direct immunofluorescence microscopyshowing linear C3c deposition along the epidermalbasement membrane zone in an n-serrated pattern. B,Indirect immunofluorescence on a substrate of salt splitskin, showing IgG bound to the epidermal basementmembrane zone (arrow) of the artificial split. Theepidermal side is depicted with * and the dermal side isdepicted with .̂JAAD CASE REPORTSVOLUME 13Rashid et al 79immunosuppressive agents during follow-up. Theremaining 2 patients who were treated with topicaltreatment only did not experience flare-ups duringtreatment.DISCUSSIONThis case series of 14 patients with juvenile andadult VP demonstrates the broad clinical spectrum ofthis disease. In the presence of vulvar erosions,ulcerations, blisters, and scarring, VP should beconsidered in the differential diagnosis. In addition,examining extragenital mucosal surfaces and per-forming immunofluorescence microscopy and im-munoserology is mandatory to differentiate betweenconditions with similar clinical findings.VP is often misdiagnosed for LS or ELPV, resultingin therapeutic delay.8,10 In children, VP may also bemistaken for sexual abuse.11 Differentiating betweenLS, ELPV, and VP is often challenging due to over-lapping clinical presentation and the presence ofchronic inflammation. The presence of Wickhamstriae, patchy hair loss, or nail abnormalities candistinguish lichen planus from pemphigoid. Vaginalinvolvement is common in ELVP but has not beenpreviously reported in VP.4,5,12 In this study, exam-ination of the vaginal mucosa was not performed.However, patients diagnosed with VP should beexamined by a gynecologist with expertise in ELVPfor evaluation of vaginal involvement. In contrast toLS, MMP and ELPV may affect other mucosal sites,such as the ocular, nasal, pharyngeal, and laryngealmucosa. In this study, the presence of extragenitalinvolvement might have led to a quicker diagnosis.Extragenital involvement, including the oral andnasal mucosa, was observed more often in the adultgroup. In addition, more patients in the adult grouppresented with scar formation.Histopathology can often be used to differentiateVP from ELVP and LS. However, in some cases,histologic differences are not that clear and mayoverlap. A lesional biopsy for histopathology inpemphigoid can show subepidermal splitting com-bined with a moderate to dense infiltrate composedof lymphocytes, neutrophils, and eosinophils. Thiscan also be seen in bullous LS, which is caused byeither increased vacuolar degeneration of the basalmembrane zone or edema in the papillarydermis.13,14 In this study, a subepidermal split wasseen in 10 patients. Moreover, histopathologic fea-tures mimicking lichen planus and LS wereobserved.Overall, VP of the juvenile form respondspromptly to potent topical therapy and generallydoes not require systemic therapy. In the juvenilegroup, 4 out of 6 patients had relatively milddisease and responded well to potent topicalsteroids, with the exception of 2 patients, whowere treated with systemic corticosteroids anddapsone. In contrast, the majority of the adultpatients required systemic therapy and oftenshowed flare-ups.In conclusion, VP presents a broad spectrum ofsymptoms and can be challenging to diagnose.Performing careful examination of other mucosaeand skin with additional immunofluorescence andimmunoserology is essential for an adequatediagnosis.Conflicts of interestDr Horvath reports fees from Janssen-Cilag (AdvisoryBoards, Educational grants, Consultations, InvestigatorJAAD CASE REPORTSJULY 202180 Rashid et alInitiative Studies), AbbVie (Advisory Boards, Educationalgrants, Consultations, Investigator Initiative Studies),Novartis Pharma (Advisory Boards, Consultations,Investigator Initiative Studies), UCB Pharma (AdvisoryBoards, Consultations), Leo Pharma (Consultations),Solenne B.V. (Investigator Initiative Studies), Celgene(Consultations, Investigator Initiative Studies), Akari ther-apeutics (Consultations, Investigator Initiative Studies),Philips (Consultation), Roche (Consultation), Regeneron(Consultation) and Sanofi (Consultation), which fees werepaid to the institution. The remaining authors declare noconflict of interest.REFERENCES1. Chan LS, Ahmed AR, Anhalt GJ, et al. The first internationalconsensus on mucous membrane pemphigoid: definition,diagnostic criteria, pathogenic factors, medical treatment,and prognostic indicators. Arch Dermatol. 2002;138(3):370-379.2. Goldstein AT, Anhalt GJ, Klingman D, Burrows LJ. Mucousmembrane pemphigoid of the vulva. Obstet Gynecol. 2005;105(5 Pt 2):1188-1190.3. Farrell AM, Kirtschig G, Dalziel KL, et al. Childhood vulvalpemphigoid: a clinical and immunopathological study of fivepatients. Br J Dermatol. 1999;140(2):308-312.4. Jolliffe DS, Sim-Davis D. Cicatricial pemphigoid in a young girl:report of a case. Clin Exp Dermatol. 1977;2(3):281-284.5. Stage AH, Humeniuk JM, Easley WK. Bullous pemphigoid of thevulva: a case report. Am J Obstet Gynecol. 1984;150(2):169-170.6. Belzile E, Funaro D, Powell J. Localized vulvar bullouspemphigoid of childhood: a rare cause of persistent vulvarerosions in children. Pediatr Dermatol. 2019;36(3):349-351.7. Venning VA, Frith PA, Bron AJ, Millard PR, Wojnarowska F.Mucosal involvement in bullous and cicatricial pemphigoid. Aclinical and immunopathological study. Br J Dermatol. 1988;118(1):7-15.8. Marren P, Walkden V, Mallon E, Wojnarowska F. Vulvalcicatricial pemphigoid may mimic lichen sclerosus. Br JDermatol. 1996;134(3):522-524.9. Loyal J, Rashtak S. Vulvar lichen planus pemphigoides. Int JWomens Dermatol. 2017;3(4):225-227.10. de Waard MM, Jonkman MF. Vulvair gelokaliseerd pemfigo€ıd.NTvDV. 2008;18(4):204-207.11. Levine V, Sanchez M, Nestor M. Localized vulvar pemphigoidin a child misdiagnosed as sexual abuse. Arch Dermatol. 1992;128(6):804-806.12. Rogers M, Painter D. Cicatricial pemphigoid in a four-year-oldchild: a case report. Australas J Dermatol. 1981;22(1):21-23.13. Kavak A, Erdogan B, Topkarc Z, S€onmezler H, Sakız D. Bullouslichen sclerosus: isolated vulvar involvement. Dermatol OnlineJ. 2018;24(2):13030/qt3mk9801x.14. Hallel-Halevy D, Grunwald MH, Yerushalmi J, Halevy S. Bullouslichen sclerosus et atrophicus. J Am Acad Dermatol. 1998;39(3):500-501.

NARCIS 

Juvenile and adult vulvar pemphigoid, an under recognized entity: Case series of fourteen patients

   University of GroningenJuvenile and adult vulvar pemphigoid, an under recognized entityRashid, Hanan; Oldhoff, J Marja; Esajas, Martha; Diercks, Gilles F H; Pas, Hendri H; Bolling,Maria C; Horváth, BarbaraPublished in:JAAD case reportsDOI:10.1016/j.jdcr.2021.05.017IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2021Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Rashid, H., Oldhoff, J. M., Esajas, M., Diercks, G. F. H., Pas, H. H., Bolling, M. C., & Horváth, B. (2021).Juvenile and adult vulvar pemphigoid, an under recognized entity: Case series of fourteen patients. JAADcase reports, 13, 75-80. https://doi.org/10.1016/j.jdcr.2021.05.017CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 29-04-2023CASE SERIESFrom theDiseasesity MDepartgen, UnUniversFunding sCorresponDermat1, 9700Juvenile and adult vulvar pemphigoid, anunder recognized entity: Case series offourteen patientsHanan Rashid, MD,a J. Marja Oldhoff, MD, PhD,a Martha Esajas, MD,b Gilles F. H. Diercks, MD, PhD,cHendri H. Pas, PhD,a Maria C. Bolling, MD, PhD,a and Barbara Horvath, MD, PhDaGroningen, NetherlandsKey words: autoimmune blistering diseases; direct immunofluorescence microscopy; indirect immunofluo-rescence microscopy; mucous membrane pemphigoid; vulvar pemphigoid.Abbreviations used:DIF: direct immunofluorescence microscopyEBMZ: epidermal basement membrane zoneELPV: erosive lichen planus affecting the vulvaLS: lichen sclerosusMMP: mucous membrane pemphigoidVP: vulvar pemphigoidSSS: salt split skinIIF: indirect immunofluorescence microscopyELISA: enzyme-linked immunosorbent assayC3c: complement component 3Ig: immunoglobulinINTRODUCTIONVulvar pemphigoid (VP) is a rare subtype ofmucous membrane pemphigoid (MMP), which is aheterogeneous group of autoimmune subepidermalblistering diseases with predominantly mucosalinvolvement and characterized by autoantibodiesagainst structural proteins in the epidermal basementmembrane zone (EBMZ).1 In MMP, various mucosalsites can be simultaneously or separately affected.Mucosal lesions tend to heal with scar formation andmay result in loss of function of the affected area.In vulvar MMP, lesions are confined to theanogenital region but can also be a manifestationof a more extensive MMP with other mucosalinvolvement.2-5 Two variants can be distinguished:the juvenile form presenting in girls between 5 and10 years old, and the adult form, which occursmainly in postmenopausal women.6,7 However,symptoms may also occur in patients within thesetwo age categories. Overlapping with other chronicvulvar diseases, VP can present with variable clinicaland histopathologic features, including lichen scle-rosus (LS) and erosive lichen planus affectingthe vulva (ELPV).8,9 Careful examination of themucosa and skin is mandatory, which should befollowed by a biopsy for direct immunofluorescencemicroscopy (DIF) from perilesional skin or mucosa.Furthermore, indirect immunofluorescence micro-scopy (IIF) on salt split skin (SSS) and immunoser-ology can be performed for the detection ofcirculating autoantibodies in serum.Department of Dermatology, Center of Blisterings, European Reference Network-Skin Member, Univer-edical Center Groningen, University of Groningena;ment of Gynecology, University Medical Center Gronin-iversity of Groningenb; and Department of Pathology,ity Medical Center Groningen, University of Groningen.cources: None.dence to: Hanan Rashid, MD, Department ofology, University Medical Center Groningen, HanzepleinRB Groningen, Netherlands. E-mail: h.rashid@umcg.nl.In this study, we describe 14 patients diagnosedwith VP, demonstrating the wide clinical and immu-nologic variety of this disease.METHODSThis case series included patients diagnosed withVP from 2001 to 2018 at the Center for BlisteringDiseases in Groningen, which is the national referralcenter for autoimmune bullous diseases in theNetherlands. Diagnoses were made according toclinical features and immunologic criteria of linearn-serrated/u-serrated deposition of IgG, IgA, and/orcomplement component 3 along the EBMZ by DIFor detection of circulating autoantibodies. IIF onSSS was considered positive when immunoglobulin(Ig)G, IgA, and/or complement component 3 (C3c)staining at the epidermal and/or dermal side stainingwere observed. Immunoblot was used to detectJAAD Case Reports 2021;13:75-80.2352-5126 2021 by the American Academy of Dermatology, Inc. Publishedby Elsevier, Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).https://doi.org/10.1016/j.jdcr.2021.05.01775Table I. Clinical characteristics, diagnostic results, and treatment of patients with vulvar pemphigoidPatientno.Age inyearsSymptomdurationin months ScarringOthermucosalinvolvementSkininvolvement HistopathologyDIF onmucosaand/orskin Salt split skin ImmunoblotELISANC16ATopicaltherapySystemictherapy1 5 12 Yes - - Vacuolar degenerationbasal keratinocytes,homogenized collagenIgG & C3c Negative IgG BP180 Negative Clobetasol,TetracyclinePrednisone,Dapsone2 6 6 No - - Ulcerating inflammation,subepidermal splitIgG & C3c Negative Negative Negative Triamcinolone,Tetracycline-3 11 30 Yes Oral - Dermal mixed cellinflammation,subepidermal splitC3c IgGepidermalsideIgG BP180 Negative Tetracycline -4 11 72 No - - Dermal mixed cellinflammation,subepidermal splitIgG & IgA& C3cNegative Negative Positive Tetracycline,TriamcinoloneDapsone5 12 24 No - - Band-like lymphocyticinfiltrates, subepidermalsplitIgG & C3c Negative Negative Negative Tetracycline,Clobetasol-6 13 7 No - - Dermal mixed cellinflammation,subepidermal splitIgG & IgA& C3cNegative Negative Positive Tetracycline -7 48 9 Yes Oral - dermal lymphohistiocyticinflammation,subepidermal splitIgG & C3c Negative IgG BP180 Negative Tetracycline,Clobetasol,TriamcinoloneDoxycyline,Prednisone8 58 12 Yes - Submammary Dermal mixed cellinflammation,subepidermal splitIgG, IgA& C3cn-serratedIgG & IgAepidermalsideIgG BP180 Positive Triamcinolone Prednisone,Dapsone,Mycophenolicacid,Cyclophosphamide,Rituximab9 62 12 No - - Dermallymphoplasmacellularinflammation,subepidermalsplitC3cn-serratedNegative IgG BP180 Positive Triamcinolone,Fluticasone,Clobetason,TetracyclineDoxycycline10 65 60 Yes - - Dermal mixed cellinflammation,subepidermal splitIgG, IgA& C3cIgGepidermalsideIgG & IgABP180Positive ClobetasolTetracyclinePrednisone,Methotrexate,Mycophenolic acid,Azathioprine11 73 2 No Oral - - IgG Negative Negative Positive Tetracycline -JAADCASEREPORTSJULY202176Rashidetal12745NoOral-PerivascularlymphoplasmacellularinflammationIgAIgA epidermalsideIgABP180NegativeTetracycline,TriamcinoloneDapsone137414YesOral-SuperficialspongioticdermatitisIgG n-serratedIgG epidermalsideNegativeNegativeClobetasol-14917YesOral,nasal-SubepidermalsplitIgA,IgGn-serratedIgG epidermalsideIgGBP180PositiveClobetasolCyclophosphamideDIF,Directimmunofluorescencemicroscopy;ELISA,enzyme-linkedimmunosorbentassay;Igg,immunoglobulin;C3c,complementcomponent3.JAAD CASE REPORTSVOLUME 13Rashid et al 77circulating IgG or IgA against BP180. Autoantibodiesagainst the 16A domain of BP180 were detected withcommercially available enzyme-linked immunosor-bent assay (ELISA; cutoff index, $ 9 U/mL). Writtenconsent was provided.RESULTSFourteen patients diagnosed with VP wereincluded in this case series. One patient waspreviously described in the literature.10 Table Isummarizes the clinical, histopathologic, andimmunofluorescence findings, as well as the pre-scribed therapy of all patients. Six patients werediagnosed with juvenile VP, and the remaining 8were postmenopausal women. The age of onsetranged between 5 and 13 years in the juvenilegroup, and 48 and 91 years in the adult group. Themedian duration of symptoms before patients werereferred to the dermatologist at the Center forBlistering Diseases was 12 months (range, 2-72).Patients with extragenital involvement had ashorter median diagnostic delay compared withpatients with localized genital involvement (8 vs.12 months). The median follow-up time was22 months (range, 1-86). At the time of referral, 3patients had already received the diagnosis VP.One patient had previously been diagnosed withLS based on clinical and histologic features, and 1patient had been diagnosed with vulvar candidi-asis. The remaining patients were referred to ourclinic with no previous diagnosis.Clinical presentationFrequently reported symptoms included intermit-tent or continuous pain (10/14), followed by pruritus(5/14) and dysuria (5/14). Dyspareunia was reportedin 1 adult patient, and 2 patients experienced painduring defecation. One patient in the juvenile groupwas asymptomatic. Dermatologic examination re-vealed erosions (11/14), erythema (9/14), and su-perficial ulcerations (2/14) of the labia minora andmajora, periclitoreal area, vaginal introitus, andperineum (Fig 1, A, B and C). In one patient, anintact blister was seen. Structural architecture losswas observed in 5 adult patients, including fusion ofthe labia majora and minora and stenosis of thevaginal introitus, whereas only 2 patients in thejuvenile group developed fusion of the labia (Fig 1,B and C ). Examination of the vaginal mucosa wasnot performed. Extragenital mucosal involvementwas seen in 6/14 patients, of which 1 patient in thejuvenile group presented with erythematous swollengingiva and 5 adult patients with erythema, erosions,and blisters involving the gingiva, palatal surface,and buccal mucosa. One patient presented withFig 1. Lesions in juvenile and adult vulvar pemphigoid demonstrating erosions (A and C), scarformation (B and C), and complete fusion of the labia (B and C).JAAD CASE REPORTSJULY 202178 Rashid et alnasal crustae in addition to involvement of the oralmucosa. Furthermore, 1 adult patient had skininvolvement confined to the submammary region.Diagnostic findingsIn all patients (14/14), a biopsy for DIF wasperformed from perilesional mucosa and/or healthyskin, revealing linear deposition of IgG, IgA, and/orC3c complement component 3 along the EBMZ (Fig2,A). An n-serrated immunodeposition pattern alongthe EBMZwas identified in 4/14 biopsies for DIF, andin the remaining biopsies the serration pattern couldnot be identified. IIF on SSS revealed circulating IgGand/or IgA autoantibodies in 6/14 patients at theepidermal side of the split (Fig 2, B). Immunoblot forBP180 was positive for IgG and/or IgA in 8/14patients, and 7/14 patients showed positivity forIgG against the NC16A domain of BP180, as detectedby ELISA. A biopsy for histopathology was per-formed in 13/14 patients, revealing subepidermalblistering in 10 patients accompanied with a dermalinfiltrate consisting of lymphocytes, plasma cells,and eosinophils. One patient showed a band-likeinfiltrate of lymphocytes at the epidermal-dermaljunction; furthermore, in 1 patient, basal vacuolardegeneration and homogenization of the dermalcollagen was observed. Bacterial, fungal, and viralcultures were negative for all patients.TherapyAfter confirmation of the diagnosis, 8/14patients required systemic immunosuppressive orimmunomodulatory therapy in addition to localtherapy. In the juvenile group, 2/6 patients receiveddapsone in addition to local therapy, while 4/6patients received only topical corticosteroids. In 1patient, dapsone was discontinued after 1 year dueto hemolysis and replaced by prednisone followedby topical clobetasol propionate. Flare-ups werefrequently observed during treatment in this patient.The clinical outcome of the second patient is un-known, as follow-up took place in another hospitalafter the diagnosis was made. The remaining 4patients in the juvenile group responded well totopical triamcinolone acetonide and clobetasol onlyand did not experience flare-ups during treatment.The median duration until clinical response was2 months (range 0-28) in the juvenile group.Six out of 8 patients in the adult group requiredsystemic immunosuppressive therapy due to wors-ening of vulvar symptoms and poor response tolocal therapy. Systemic treatment included doxycy-cline, prednisone, dapsone, methotrexate, azathio-prine, cyclophosphamide, mycophenolic acid, andrituximab. The median duration until clinicalresponse was 1.5 months (range, 0-18). Flare-upswere seen in 5 out of 8 patients during treatment.These patients received several systemicFig 2. A, Direct immunofluorescence microscopyshowing linear C3c deposition along the epidermalbasement membrane zone in an n-serrated pattern. B,Indirect immunofluorescence on a substrate of salt splitskin, showing IgG bound to the epidermal basementmembrane zone (arrow) of the artificial split. Theepidermal side is depicted with * and the dermal side isdepicted with .̂JAAD CASE REPORTSVOLUME 13Rashid et al 79immunosuppressive agents during follow-up. Theremaining 2 patients who were treated with topicaltreatment only did not experience flare-ups duringtreatment.DISCUSSIONThis case series of 14 patients with juvenile andadult VP demonstrates the broad clinical spectrum ofthis disease. In the presence of vulvar erosions,ulcerations, blisters, and scarring, VP should beconsidered in the differential diagnosis. In addition,examining extragenital mucosal surfaces and per-forming immunofluorescence microscopy and im-munoserology is mandatory to differentiate betweenconditions with similar clinical findings.VP is often misdiagnosed for LS or ELPV, resultingin therapeutic delay.8,10 In children, VP may also bemistaken for sexual abuse.11 Differentiating betweenLS, ELPV, and VP is often challenging due to over-lapping clinical presentation and the presence ofchronic inflammation. The presence of Wickhamstriae, patchy hair loss, or nail abnormalities candistinguish lichen planus from pemphigoid. Vaginalinvolvement is common in ELVP but has not beenpreviously reported in VP.4,5,12 In this study, exam-ination of the vaginal mucosa was not performed.However, patients diagnosed with VP should beexamined by a gynecologist with expertise in ELVPfor evaluation of vaginal involvement. In contrast toLS, MMP and ELPV may affect other mucosal sites,such as the ocular, nasal, pharyngeal, and laryngealmucosa. In this study, the presence of extragenitalinvolvement might have led to a quicker diagnosis.Extragenital involvement, including the oral andnasal mucosa, was observed more often in the adultgroup. In addition, more patients in the adult grouppresented with scar formation.Histopathology can often be used to differentiateVP from ELVP and LS. However, in some cases,histologic differences are not that clear and mayoverlap. A lesional biopsy for histopathology inpemphigoid can show subepidermal splitting com-bined with a moderate to dense infiltrate composedof lymphocytes, neutrophils, and eosinophils. Thiscan also be seen in bullous LS, which is caused byeither increased vacuolar degeneration of the basalmembrane zone or edema in the papillarydermis.13,14 In this study, a subepidermal split wasseen in 10 patients. Moreover, histopathologic fea-tures mimicking lichen planus and LS wereobserved.Overall, VP of the juvenile form respondspromptly to potent topical therapy and generallydoes not require systemic therapy. In the juvenilegroup, 4 out of 6 patients had relatively milddisease and responded well to potent topicalsteroids, with the exception of 2 patients, whowere treated with systemic corticosteroids anddapsone. In contrast, the majority of the adultpatients required systemic therapy and oftenshowed flare-ups.In conclusion, VP presents a broad spectrum ofsymptoms and can be challenging to diagnose.Performing careful examination of other mucosaeand skin with additional immunofluorescence andimmunoserology is essential for an adequatediagnosis.Conflicts of interestDr Horvath reports fees from Janssen-Cilag (AdvisoryBoards, Educational grants, Consultations, InvestigatorJAAD CASE REPORTSJULY 202180 Rashid et alInitiative Studies), AbbVie (Advisory Boards, Educationalgrants, Consultations, Investigator Initiative Studies),Novartis Pharma (Advisory Boards, Consultations,Investigator Initiative Studies), UCB Pharma (AdvisoryBoards, Consultations), Leo Pharma (Consultations),Solenne B.V. (Investigator Initiative Studies), Celgene(Consultations, Investigator Initiative Studies), Akari ther-apeutics (Consultations, Investigator Initiative Studies),Philips (Consultation), Roche (Consultation), Regeneron(Consultation) and Sanofi (Consultation), which fees werepaid to the institution. The remaining authors declare noconflict of interest.REFERENCES1. Chan LS, Ahmed AR, Anhalt GJ, et al. The first internationalconsensus on mucous membrane pemphigoid: definition,diagnostic criteria, pathogenic factors, medical treatment,and prognostic indicators. Arch Dermatol. 2002;138(3):370-379.2. Goldstein AT, Anhalt GJ, Klingman D, Burrows LJ. Mucousmembrane pemphigoid of the vulva. Obstet Gynecol. 2005;105(5 Pt 2):1188-1190.3. Farrell AM, Kirtschig G, Dalziel KL, et al. Childhood vulvalpemphigoid: a clinical and immunopathological study of fivepatients. Br J Dermatol. 1999;140(2):308-312.4. Jolliffe DS, Sim-Davis D. Cicatricial pemphigoid in a young girl:report of a case. Clin Exp Dermatol. 1977;2(3):281-284.5. Stage AH, Humeniuk JM, Easley WK. Bullous pemphigoid of thevulva: a case report. Am J Obstet Gynecol. 1984;150(2):169-170.6. Belzile E, Funaro D, Powell J. Localized vulvar bullouspemphigoid of childhood: a rare cause of persistent vulvarerosions in children. Pediatr Dermatol. 2019;36(3):349-351.7. Venning VA, Frith PA, Bron AJ, Millard PR, Wojnarowska F.Mucosal involvement in bullous and cicatricial pemphigoid. Aclinical and immunopathological study. Br J Dermatol. 1988;118(1):7-15.8. Marren P, Walkden V, Mallon E, Wojnarowska F. Vulvalcicatricial pemphigoid may mimic lichen sclerosus. Br JDermatol. 1996;134(3):522-524.9. Loyal J, Rashtak S. Vulvar lichen planus pemphigoides. Int JWomens Dermatol. 2017;3(4):225-227.10. de Waard MM, Jonkman MF. Vulvair gelokaliseerd pemfigo€ıd.NTvDV. 2008;18(4):204-207.11. Levine V, Sanchez M, Nestor M. Localized vulvar pemphigoidin a child misdiagnosed as sexual abuse. Arch Dermatol. 1992;128(6):804-806.12. Rogers M, Painter D. Cicatricial pemphigoid in a four-year-oldchild: a case report. Australas J Dermatol. 1981;22(1):21-23.13. Kavak A, Erdogan B, Topkarc Z, S€onmezler H, Sakız D. Bullouslichen sclerosus: isolated vulvar involvement. Dermatol OnlineJ. 2018;24(2):13030/qt3mk9801x.14. Hallel-Halevy D, Grunwald MH, Yerushalmi J, Halevy S. Bullouslichen sclerosus et atrophicus. J Am Acad Dermatol. 1998;39(3):500-501.

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   University of GroningenJuvenile and adult vulvar pemphigoid, an under recognized entityRashid, Hanan; Oldhoff, J Marja; Esajas, Martha; Diercks, Gilles F H; Pas, Hendri H; Bolling,Maria C; Horváth, BarbaraPublished in:JAAD case reportsDOI:10.1016/j.jdcr.2021.05.017IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2021Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Rashid, H., Oldhoff, J. M., Esajas, M., Diercks, G. F. H., Pas, H. H., Bolling, M. C., & Horváth, B. (2021).Juvenile and adult vulvar pemphigoid, an under recognized entity: Case series of fourteen patients. JAADcase reports, 13, 75-80. https://doi.org/10.1016/j.jdcr.2021.05.017CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 31-10-2023CASE SERIESFrom theDiseasesity MDepartgen, UnUniversFunding sCorresponDermat1, 9700Juvenile and adult vulvar pemphigoid, anunder recognized entity: Case series offourteen patientsHanan Rashid, MD,a J. Marja Oldhoff, MD, PhD,a Martha Esajas, MD,b Gilles F. H. Diercks, MD, PhD,cHendri H. Pas, PhD,a Maria C. Bolling, MD, PhD,a and Barbara Horvath, MD, PhDaGroningen, NetherlandsKey words: autoimmune blistering diseases; direct immunofluorescence microscopy; indirect immunofluo-rescence microscopy; mucous membrane pemphigoid; vulvar pemphigoid.Abbreviations used:DIF: direct immunofluorescence microscopyEBMZ: epidermal basement membrane zoneELPV: erosive lichen planus affecting the vulvaLS: lichen sclerosusMMP: mucous membrane pemphigoidVP: vulvar pemphigoidSSS: salt split skinIIF: indirect immunofluorescence microscopyELISA: enzyme-linked immunosorbent assayC3c: complement component 3Ig: immunoglobulinINTRODUCTIONVulvar pemphigoid (VP) is a rare subtype ofmucous membrane pemphigoid (MMP), which is aheterogeneous group of autoimmune subepidermalblistering diseases with predominantly mucosalinvolvement and characterized by autoantibodiesagainst structural proteins in the epidermal basementmembrane zone (EBMZ).1 In MMP, various mucosalsites can be simultaneously or separately affected.Mucosal lesions tend to heal with scar formation andmay result in loss of function of the affected area.In vulvar MMP, lesions are confined to theanogenital region but can also be a manifestationof a more extensive MMP with other mucosalinvolvement.2-5 Two variants can be distinguished:the juvenile form presenting in girls between 5 and10 years old, and the adult form, which occursmainly in postmenopausal women.6,7 However,symptoms may also occur in patients within thesetwo age categories. Overlapping with other chronicvulvar diseases, VP can present with variable clinicaland histopathologic features, including lichen scle-rosus (LS) and erosive lichen planus affectingthe vulva (ELPV).8,9 Careful examination of themucosa and skin is mandatory, which should befollowed by a biopsy for direct immunofluorescencemicroscopy (DIF) from perilesional skin or mucosa.Furthermore, indirect immunofluorescence micro-scopy (IIF) on salt split skin (SSS) and immunoser-ology can be performed for the detection ofcirculating autoantibodies in serum.Department of Dermatology, Center of Blisterings, European Reference Network-Skin Member, Univer-edical Center Groningen, University of Groningena;ment of Gynecology, University Medical Center Gronin-iversity of Groningenb; and Department of Pathology,ity Medical Center Groningen, University of Groningen.cources: None.dence to: Hanan Rashid, MD, Department ofology, University Medical Center Groningen, HanzepleinRB Groningen, Netherlands. E-mail: h.rashid@umcg.nl.In this study, we describe 14 patients diagnosedwith VP, demonstrating the wide clinical and immu-nologic variety of this disease.METHODSThis case series included patients diagnosed withVP from 2001 to 2018 at the Center for BlisteringDiseases in Groningen, which is the national referralcenter for autoimmune bullous diseases in theNetherlands. Diagnoses were made according toclinical features and immunologic criteria of linearn-serrated/u-serrated deposition of IgG, IgA, and/orcomplement component 3 along the EBMZ by DIFor detection of circulating autoantibodies. IIF onSSS was considered positive when immunoglobulin(Ig)G, IgA, and/or complement component 3 (C3c)staining at the epidermal and/or dermal side stainingwere observed. Immunoblot was used to detectJAAD Case Reports 2021;13:75-80.2352-5126 2021 by the American Academy of Dermatology, Inc. Publishedby Elsevier, Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).https://doi.org/10.1016/j.jdcr.2021.05.01775Table I. Clinical characteristics, diagnostic results, and treatment of patients with vulvar pemphigoidPatientno.Age inyearsSymptomdurationin months ScarringOthermucosalinvolvementSkininvolvement HistopathologyDIF onmucosaand/orskin Salt split skin ImmunoblotELISANC16ATopicaltherapySystemictherapy1 5 12 Yes - - Vacuolar degenerationbasal keratinocytes,homogenized collagenIgG & C3c Negative IgG BP180 Negative Clobetasol,TetracyclinePrednisone,Dapsone2 6 6 No - - Ulcerating inflammation,subepidermal splitIgG & C3c Negative Negative Negative Triamcinolone,Tetracycline-3 11 30 Yes Oral - Dermal mixed cellinflammation,subepidermal splitC3c IgGepidermalsideIgG BP180 Negative Tetracycline -4 11 72 No - - Dermal mixed cellinflammation,subepidermal splitIgG & IgA& C3cNegative Negative Positive Tetracycline,TriamcinoloneDapsone5 12 24 No - - Band-like lymphocyticinfiltrates, subepidermalsplitIgG & C3c Negative Negative Negative Tetracycline,Clobetasol-6 13 7 No - - Dermal mixed cellinflammation,subepidermal splitIgG & IgA& C3cNegative Negative Positive Tetracycline -7 48 9 Yes Oral - dermal lymphohistiocyticinflammation,subepidermal splitIgG & C3c Negative IgG BP180 Negative Tetracycline,Clobetasol,TriamcinoloneDoxycyline,Prednisone8 58 12 Yes - Submammary Dermal mixed cellinflammation,subepidermal splitIgG, IgA& C3cn-serratedIgG & IgAepidermalsideIgG BP180 Positive Triamcinolone Prednisone,Dapsone,Mycophenolicacid,Cyclophosphamide,Rituximab9 62 12 No - - Dermallymphoplasmacellularinflammation,subepidermalsplitC3cn-serratedNegative IgG BP180 Positive Triamcinolone,Fluticasone,Clobetason,TetracyclineDoxycycline10 65 60 Yes - - Dermal mixed cellinflammation,subepidermal splitIgG, IgA& C3cIgGepidermalsideIgG & IgABP180Positive ClobetasolTetracyclinePrednisone,Methotrexate,Mycophenolic acid,Azathioprine11 73 2 No Oral - - IgG Negative Negative Positive Tetracycline -JAADCASEREPORTSJULY202176Rashidetal12745NoOral-PerivascularlymphoplasmacellularinflammationIgAIgA epidermalsideIgABP180NegativeTetracycline,TriamcinoloneDapsone137414YesOral-SuperficialspongioticdermatitisIgG n-serratedIgG epidermalsideNegativeNegativeClobetasol-14917YesOral,nasal-SubepidermalsplitIgA,IgGn-serratedIgG epidermalsideIgGBP180PositiveClobetasolCyclophosphamideDIF,Directimmunofluorescencemicroscopy;ELISA,enzyme-linkedimmunosorbentassay;Igg,immunoglobulin;C3c,complementcomponent3.JAAD CASE REPORTSVOLUME 13Rashid et al 77circulating IgG or IgA against BP180. Autoantibodiesagainst the 16A domain of BP180 were detected withcommercially available enzyme-linked immunosor-bent assay (ELISA; cutoff index, $ 9 U/mL). Writtenconsent was provided.RESULTSFourteen patients diagnosed with VP wereincluded in this case series. One patient waspreviously described in the literature.10 Table Isummarizes the clinical, histopathologic, andimmunofluorescence findings, as well as the pre-scribed therapy of all patients. Six patients werediagnosed with juvenile VP, and the remaining 8were postmenopausal women. The age of onsetranged between 5 and 13 years in the juvenilegroup, and 48 and 91 years in the adult group. Themedian duration of symptoms before patients werereferred to the dermatologist at the Center forBlistering Diseases was 12 months (range, 2-72).Patients with extragenital involvement had ashorter median diagnostic delay compared withpatients with localized genital involvement (8 vs.12 months). The median follow-up time was22 months (range, 1-86). At the time of referral, 3patients had already received the diagnosis VP.One patient had previously been diagnosed withLS based on clinical and histologic features, and 1patient had been diagnosed with vulvar candidi-asis. The remaining patients were referred to ourclinic with no previous diagnosis.Clinical presentationFrequently reported symptoms included intermit-tent or continuous pain (10/14), followed by pruritus(5/14) and dysuria (5/14). Dyspareunia was reportedin 1 adult patient, and 2 patients experienced painduring defecation. One patient in the juvenile groupwas asymptomatic. Dermatologic examination re-vealed erosions (11/14), erythema (9/14), and su-perficial ulcerations (2/14) of the labia minora andmajora, periclitoreal area, vaginal introitus, andperineum (Fig 1, A, B and C). In one patient, anintact blister was seen. Structural architecture losswas observed in 5 adult patients, including fusion ofthe labia majora and minora and stenosis of thevaginal introitus, whereas only 2 patients in thejuvenile group developed fusion of the labia (Fig 1,B and C ). Examination of the vaginal mucosa wasnot performed. Extragenital mucosal involvementwas seen in 6/14 patients, of which 1 patient in thejuvenile group presented with erythematous swollengingiva and 5 adult patients with erythema, erosions,and blisters involving the gingiva, palatal surface,and buccal mucosa. One patient presented withFig 1. Lesions in juvenile and adult vulvar pemphigoid demonstrating erosions (A and C), scarformation (B and C), and complete fusion of the labia (B and C).JAAD CASE REPORTSJULY 202178 Rashid et alnasal crustae in addition to involvement of the oralmucosa. Furthermore, 1 adult patient had skininvolvement confined to the submammary region.Diagnostic findingsIn all patients (14/14), a biopsy for DIF wasperformed from perilesional mucosa and/or healthyskin, revealing linear deposition of IgG, IgA, and/orC3c complement component 3 along the EBMZ (Fig2,A). An n-serrated immunodeposition pattern alongthe EBMZwas identified in 4/14 biopsies for DIF, andin the remaining biopsies the serration pattern couldnot be identified. IIF on SSS revealed circulating IgGand/or IgA autoantibodies in 6/14 patients at theepidermal side of the split (Fig 2, B). Immunoblot forBP180 was positive for IgG and/or IgA in 8/14patients, and 7/14 patients showed positivity forIgG against the NC16A domain of BP180, as detectedby ELISA. A biopsy for histopathology was per-formed in 13/14 patients, revealing subepidermalblistering in 10 patients accompanied with a dermalinfiltrate consisting of lymphocytes, plasma cells,and eosinophils. One patient showed a band-likeinfiltrate of lymphocytes at the epidermal-dermaljunction; furthermore, in 1 patient, basal vacuolardegeneration and homogenization of the dermalcollagen was observed. Bacterial, fungal, and viralcultures were negative for all patients.TherapyAfter confirmation of the diagnosis, 8/14patients required systemic immunosuppressive orimmunomodulatory therapy in addition to localtherapy. In the juvenile group, 2/6 patients receiveddapsone in addition to local therapy, while 4/6patients received only topical corticosteroids. In 1patient, dapsone was discontinued after 1 year dueto hemolysis and replaced by prednisone followedby topical clobetasol propionate. Flare-ups werefrequently observed during treatment in this patient.The clinical outcome of the second patient is un-known, as follow-up took place in another hospitalafter the diagnosis was made. The remaining 4patients in the juvenile group responded well totopical triamcinolone acetonide and clobetasol onlyand did not experience flare-ups during treatment.The median duration until clinical response was2 months (range 0-28) in the juvenile group.Six out of 8 patients in the adult group requiredsystemic immunosuppressive therapy due to wors-ening of vulvar symptoms and poor response tolocal therapy. Systemic treatment included doxycy-cline, prednisone, dapsone, methotrexate, azathio-prine, cyclophosphamide, mycophenolic acid, andrituximab. The median duration until clinicalresponse was 1.5 months (range, 0-18). Flare-upswere seen in 5 out of 8 patients during treatment.These patients received several systemicFig 2. A, Direct immunofluorescence microscopyshowing linear C3c deposition along the epidermalbasement membrane zone in an n-serrated pattern. B,Indirect immunofluorescence on a substrate of salt splitskin, showing IgG bound to the epidermal basementmembrane zone (arrow) of the artificial split. Theepidermal side is depicted with * and the dermal side isdepicted with .̂JAAD CASE REPORTSVOLUME 13Rashid et al 79immunosuppressive agents during follow-up. Theremaining 2 patients who were treated with topicaltreatment only did not experience flare-ups duringtreatment.DISCUSSIONThis case series of 14 patients with juvenile andadult VP demonstrates the broad clinical spectrum ofthis disease. In the presence of vulvar erosions,ulcerations, blisters, and scarring, VP should beconsidered in the differential diagnosis. In addition,examining extragenital mucosal surfaces and per-forming immunofluorescence microscopy and im-munoserology is mandatory to differentiate betweenconditions with similar clinical findings.VP is often misdiagnosed for LS or ELPV, resultingin therapeutic delay.8,10 In children, VP may also bemistaken for sexual abuse.11 Differentiating betweenLS, ELPV, and VP is often challenging due to over-lapping clinical presentation and the presence ofchronic inflammation. The presence of Wickhamstriae, patchy hair loss, or nail abnormalities candistinguish lichen planus from pemphigoid. Vaginalinvolvement is common in ELVP but has not beenpreviously reported in VP.4,5,12 In this study, exam-ination of the vaginal mucosa was not performed.However, patients diagnosed with VP should beexamined by a gynecologist with expertise in ELVPfor evaluation of vaginal involvement. In contrast toLS, MMP and ELPV may affect other mucosal sites,such as the ocular, nasal, pharyngeal, and laryngealmucosa. In this study, the presence of extragenitalinvolvement might have led to a quicker diagnosis.Extragenital involvement, including the oral andnasal mucosa, was observed more often in the adultgroup. In addition, more patients in the adult grouppresented with scar formation.Histopathology can often be used to differentiateVP from ELVP and LS. However, in some cases,histologic differences are not that clear and mayoverlap. A lesional biopsy for histopathology inpemphigoid can show subepidermal splitting com-bined with a moderate to dense infiltrate composedof lymphocytes, neutrophils, and eosinophils. Thiscan also be seen in bullous LS, which is caused byeither increased vacuolar degeneration of the basalmembrane zone or edema in the papillarydermis.13,14 In this study, a subepidermal split wasseen in 10 patients. Moreover, histopathologic fea-tures mimicking lichen planus and LS wereobserved.Overall, VP of the juvenile form respondspromptly to potent topical therapy and generallydoes not require systemic therapy. In the juvenilegroup, 4 out of 6 patients had relatively milddisease and responded well to potent topicalsteroids, with the exception of 2 patients, whowere treated with systemic corticosteroids anddapsone. In contrast, the majority of the adultpatients required systemic therapy and oftenshowed flare-ups.In conclusion, VP presents a broad spectrum ofsymptoms and can be challenging to diagnose.Performing careful examination of other mucosaeand skin with additional immunofluorescence andimmunoserology is essential for an adequatediagnosis.Conflicts of interestDr Horvath reports fees from Janssen-Cilag (AdvisoryBoards, Educational grants, Consultations, InvestigatorJAAD CASE REPORTSJULY 202180 Rashid et alInitiative Studies), AbbVie (Advisory Boards, Educationalgrants, Consultations, Investigator Initiative Studies),Novartis Pharma (Advisory Boards, Consultations,Investigator Initiative Studies), UCB Pharma (AdvisoryBoards, Consultations), Leo Pharma (Consultations),Solenne B.V. (Investigator Initiative Studies), Celgene(Consultations, Investigator Initiative Studies), Akari ther-apeutics (Consultations, Investigator Initiative Studies),Philips (Consultation), Roche (Consultation), Regeneron(Consultation) and Sanofi (Consultation), which fees werepaid to the institution. The remaining authors declare noconflict of interest.REFERENCES1. Chan LS, Ahmed AR, Anhalt GJ, et al. The first internationalconsensus on mucous membrane pemphigoid: definition,diagnostic criteria, pathogenic factors, medical treatment,and prognostic indicators. Arch Dermatol. 2002;138(3):370-379.2. Goldstein AT, Anhalt GJ, Klingman D, Burrows LJ. Mucousmembrane pemphigoid of the vulva. Obstet Gynecol. 2005;105(5 Pt 2):1188-1190.3. Farrell AM, Kirtschig G, Dalziel KL, et al. Childhood vulvalpemphigoid: a clinical and immunopathological study of fivepatients. Br J Dermatol. 1999;140(2):308-312.4. Jolliffe DS, Sim-Davis D. Cicatricial pemphigoid in a young girl:report of a case. Clin Exp Dermatol. 1977;2(3):281-284.5. Stage AH, Humeniuk JM, Easley WK. Bullous pemphigoid of thevulva: a case report. Am J Obstet Gynecol. 1984;150(2):169-170.6. Belzile E, Funaro D, Powell J. Localized vulvar bullouspemphigoid of childhood: a rare cause of persistent vulvarerosions in children. Pediatr Dermatol. 2019;36(3):349-351.7. Venning VA, Frith PA, Bron AJ, Millard PR, Wojnarowska F.Mucosal involvement in bullous and cicatricial pemphigoid. Aclinical and immunopathological study. Br J Dermatol. 1988;118(1):7-15.8. Marren P, Walkden V, Mallon E, Wojnarowska F. Vulvalcicatricial pemphigoid may mimic lichen sclerosus. Br JDermatol. 1996;134(3):522-524.9. Loyal J, Rashtak S. Vulvar lichen planus pemphigoides. Int JWomens Dermatol. 2017;3(4):225-227.10. de Waard MM, Jonkman MF. Vulvair gelokaliseerd pemfigo€ıd.NTvDV. 2008;18(4):204-207.11. Levine V, Sanchez M, Nestor M. Localized vulvar pemphigoidin a child misdiagnosed as sexual abuse. Arch Dermatol. 1992;128(6):804-806.12. Rogers M, Painter D. Cicatricial pemphigoid in a four-year-oldchild: a case report. Australas J Dermatol. 1981;22(1):21-23.13. Kavak A, Erdogan B, Topkarc Z, S€onmezler H, Sakız D. Bullouslichen sclerosus: isolated vulvar involvement. Dermatol OnlineJ. 2018;24(2):13030/qt3mk9801x.14. Hallel-Halevy D, Grunwald MH, Yerushalmi J, Halevy S. Bullouslichen sclerosus et atrophicus. J Am Acad Dermatol. 1998;39(3):500-501.

   University of GroningenJuvenile and adult vulvar pemphigoid, an under recognized entityRashid, Hanan; Oldhoff, J Marja; Esajas, Martha; Diercks, Gilles F H; Pas, Hendri H; Bolling,Maria C; Horváth, BarbaraPublished in:JAAD case reportsDOI:10.1016/j.jdcr.2021.05.017IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2021Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Rashid, H., Oldhoff, J. M., Esajas, M., Diercks, G. F. H., Pas, H. H., Bolling, M. C., & Horváth, B. (2021).Juvenile and adult vulvar pemphigoid, an under recognized entity: Case series of fourteen patients. JAADcase reports, 13, 75-80. https://doi.org/10.1016/j.jdcr.2021.05.017CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 21-06-2022CASE SERIESFrom theDiseasesity MDepartgen, UnUniversFunding sCorresponDermat1, 9700Juvenile and adult vulvar pemphigoid, anunder recognized entity: Case series offourteen patientsHanan Rashid, MD,a J. Marja Oldhoff, MD, PhD,a Martha Esajas, MD,b Gilles F. H. Diercks, MD, PhD,cHendri H. Pas, PhD,a Maria C. Bolling, MD, PhD,a and Barbara Horvath, MD, PhDaGroningen, NetherlandsKey words: autoimmune blistering diseases; direct immunofluorescence microscopy; indirect immunofluo-rescence microscopy; mucous membrane pemphigoid; vulvar pemphigoid.Abbreviations used:DIF: direct immunofluorescence microscopyEBMZ: epidermal basement membrane zoneELPV: erosive lichen planus affecting the vulvaLS: lichen sclerosusMMP: mucous membrane pemphigoidVP: vulvar pemphigoidSSS: salt split skinIIF: indirect immunofluorescence microscopyELISA: enzyme-linked immunosorbent assayC3c: complement component 3Ig: immunoglobulinINTRODUCTIONVulvar pemphigoid (VP) is a rare subtype ofmucous membrane pemphigoid (MMP), which is aheterogeneous group of autoimmune subepidermalblistering diseases with predominantly mucosalinvolvement and characterized by autoantibodiesagainst structural proteins in the epidermal basementmembrane zone (EBMZ).1 In MMP, various mucosalsites can be simultaneously or separately affected.Mucosal lesions tend to heal with scar formation andmay result in loss of function of the affected area.In vulvar MMP, lesions are confined to theanogenital region but can also be a manifestationof a more extensive MMP with other mucosalinvolvement.2-5 Two variants can be distinguished:the juvenile form presenting in girls between 5 and10 years old, and the adult form, which occursmainly in postmenopausal women.6,7 However,symptoms may also occur in patients within thesetwo age categories. Overlapping with other chronicvulvar diseases, VP can present with variable clinicaland histopathologic features, including lichen scle-rosus (LS) and erosive lichen planus affectingthe vulva (ELPV).8,9 Careful examination of themucosa and skin is mandatory, which should befollowed by a biopsy for direct immunofluorescencemicroscopy (DIF) from perilesional skin or mucosa.Furthermore, indirect immunofluorescence micro-scopy (IIF) on salt split skin (SSS) and immunoser-ology can be performed for the detection ofcirculating autoantibodies in serum.Department of Dermatology, Center of Blisterings, European Reference Network-Skin Member, Univer-edical Center Groningen, University of Groningena;ment of Gynecology, University Medical Center Gronin-iversity of Groningenb; and Department of Pathology,ity Medical Center Groningen, University of Groningen.cources: None.dence to: Hanan Rashid, MD, Department ofology, University Medical Center Groningen, HanzepleinRB Groningen, Netherlands. E-mail: h.rashid@umcg.nl.In this study, we describe 14 patients diagnosedwith VP, demonstrating the wide clinical and immu-nologic variety of this disease.METHODSThis case series included patients diagnosed withVP from 2001 to 2018 at the Center for BlisteringDiseases in Groningen, which is the national referralcenter for autoimmune bullous diseases in theNetherlands. Diagnoses were made according toclinical features and immunologic criteria of linearn-serrated/u-serrated deposition of IgG, IgA, and/orcomplement component 3 along the EBMZ by DIFor detection of circulating autoantibodies. IIF onSSS was considered positive when immunoglobulin(Ig)G, IgA, and/or complement component 3 (C3c)staining at the epidermal and/or dermal side stainingwere observed. Immunoblot was used to detectJAAD Case Reports 2021;13:75-80.2352-5126 2021 by the American Academy of Dermatology, Inc. Publishedby Elsevier, Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).https://doi.org/10.1016/j.jdcr.2021.05.01775Table I. Clinical characteristics, diagnostic results, and treatment of patients with vulvar pemphigoidPatientno.Age inyearsSymptomdurationin months ScarringOthermucosalinvolvementSkininvolvement HistopathologyDIF onmucosaand/orskin Salt split skin ImmunoblotELISANC16ATopicaltherapySystemictherapy1 5 12 Yes - - Vacuolar degenerationbasal keratinocytes,homogenized collagenIgG & C3c Negative IgG BP180 Negative Clobetasol,TetracyclinePrednisone,Dapsone2 6 6 No - - Ulcerating inflammation,subepidermal splitIgG & C3c Negative Negative Negative Triamcinolone,Tetracycline-3 11 30 Yes Oral - Dermal mixed cellinflammation,subepidermal splitC3c IgGepidermalsideIgG BP180 Negative Tetracycline -4 11 72 No - - Dermal mixed cellinflammation,subepidermal splitIgG & IgA& C3cNegative Negative Positive Tetracycline,TriamcinoloneDapsone5 12 24 No - - Band-like lymphocyticinfiltrates, subepidermalsplitIgG & C3c Negative Negative Negative Tetracycline,Clobetasol-6 13 7 No - - Dermal mixed cellinflammation,subepidermal splitIgG & IgA& C3cNegative Negative Positive Tetracycline -7 48 9 Yes Oral - dermal lymphohistiocyticinflammation,subepidermal splitIgG & C3c Negative IgG BP180 Negative Tetracycline,Clobetasol,TriamcinoloneDoxycyline,Prednisone8 58 12 Yes - Submammary Dermal mixed cellinflammation,subepidermal splitIgG, IgA& C3cn-serratedIgG & IgAepidermalsideIgG BP180 Positive Triamcinolone Prednisone,Dapsone,Mycophenolicacid,Cyclophosphamide,Rituximab9 62 12 No - - Dermallymphoplasmacellularinflammation,subepidermalsplitC3cn-serratedNegative IgG BP180 Positive Triamcinolone,Fluticasone,Clobetason,TetracyclineDoxycycline10 65 60 Yes - - Dermal mixed cellinflammation,subepidermal splitIgG, IgA& C3cIgGepidermalsideIgG & IgABP180Positive ClobetasolTetracyclinePrednisone,Methotrexate,Mycophenolic acid,Azathioprine11 73 2 No Oral - - IgG Negative Negative Positive Tetracycline -JAADCASEREPORTSJULY202176Rashidetal12745NoOral-PerivascularlymphoplasmacellularinflammationIgAIgA epidermalsideIgABP180NegativeTetracycline,TriamcinoloneDapsone137414YesOral-SuperficialspongioticdermatitisIgG n-serratedIgG epidermalsideNegativeNegativeClobetasol-14917YesOral,nasal-SubepidermalsplitIgA,IgGn-serratedIgG epidermalsideIgGBP180PositiveClobetasolCyclophosphamideDIF,Directimmunofluorescencemicroscopy;ELISA,enzyme-linkedimmunosorbentassay;Igg,immunoglobulin;C3c,complementcomponent3.JAAD CASE REPORTSVOLUME 13Rashid et al 77circulating IgG or IgA against BP180. Autoantibodiesagainst the 16A domain of BP180 were detected withcommercially available enzyme-linked immunosor-bent assay (ELISA; cutoff index, $ 9 U/mL). Writtenconsent was provided.RESULTSFourteen patients diagnosed with VP wereincluded in this case series. One patient waspreviously described in the literature.10 Table Isummarizes the clinical, histopathologic, andimmunofluorescence findings, as well as the pre-scribed therapy of all patients. Six patients werediagnosed with juvenile VP, and the remaining 8were postmenopausal women. The age of onsetranged between 5 and 13 years in the juvenilegroup, and 48 and 91 years in the adult group. Themedian duration of symptoms before patients werereferred to the dermatologist at the Center forBlistering Diseases was 12 months (range, 2-72).Patients with extragenital involvement had ashorter median diagnostic delay compared withpatients with localized genital involvement (8 vs.12 months). The median follow-up time was22 months (range, 1-86). At the time of referral, 3patients had already received the diagnosis VP.One patient had previously been diagnosed withLS based on clinical and histologic features, and 1patient had been diagnosed with vulvar candidi-asis. The remaining patients were referred to ourclinic with no previous diagnosis.Clinical presentationFrequently reported symptoms included intermit-tent or continuous pain (10/14), followed by pruritus(5/14) and dysuria (5/14). Dyspareunia was reportedin 1 adult patient, and 2 patients experienced painduring defecation. One patient in the juvenile groupwas asymptomatic. Dermatologic examination re-vealed erosions (11/14), erythema (9/14), and su-perficial ulcerations (2/14) of the labia minora andmajora, periclitoreal area, vaginal introitus, andperineum (Fig 1, A, B and C). In one patient, anintact blister was seen. Structural architecture losswas observed in 5 adult patients, including fusion ofthe labia majora and minora and stenosis of thevaginal introitus, whereas only 2 patients in thejuvenile group developed fusion of the labia (Fig 1,B and C ). Examination of the vaginal mucosa wasnot performed. Extragenital mucosal involvementwas seen in 6/14 patients, of which 1 patient in thejuvenile group presented with erythematous swollengingiva and 5 adult patients with erythema, erosions,and blisters involving the gingiva, palatal surface,and buccal mucosa. One patient presented withFig 1. Lesions in juvenile and adult vulvar pemphigoid demonstrating erosions (A and C), scarformation (B and C), and complete fusion of the labia (B and C).JAAD CASE REPORTSJULY 202178 Rashid et alnasal crustae in addition to involvement of the oralmucosa. Furthermore, 1 adult patient had skininvolvement confined to the submammary region.Diagnostic findingsIn all patients (14/14), a biopsy for DIF wasperformed from perilesional mucosa and/or healthyskin, revealing linear deposition of IgG, IgA, and/orC3c complement component 3 along the EBMZ (Fig2,A). An n-serrated immunodeposition pattern alongthe EBMZwas identified in 4/14 biopsies for DIF, andin the remaining biopsies the serration pattern couldnot be identified. IIF on SSS revealed circulating IgGand/or IgA autoantibodies in 6/14 patients at theepidermal side of the split (Fig 2, B). Immunoblot forBP180 was positive for IgG and/or IgA in 8/14patients, and 7/14 patients showed positivity forIgG against the NC16A domain of BP180, as detectedby ELISA. A biopsy for histopathology was per-formed in 13/14 patients, revealing subepidermalblistering in 10 patients accompanied with a dermalinfiltrate consisting of lymphocytes, plasma cells,and eosinophils. One patient showed a band-likeinfiltrate of lymphocytes at the epidermal-dermaljunction; furthermore, in 1 patient, basal vacuolardegeneration and homogenization of the dermalcollagen was observed. Bacterial, fungal, and viralcultures were negative for all patients.TherapyAfter confirmation of the diagnosis, 8/14patients required systemic immunosuppressive orimmunomodulatory therapy in addition to localtherapy. In the juvenile group, 2/6 patients receiveddapsone in addition to local therapy, while 4/6patients received only topical corticosteroids. In 1patient, dapsone was discontinued after 1 year dueto hemolysis and replaced by prednisone followedby topical clobetasol propionate. Flare-ups werefrequently observed during treatment in this patient.The clinical outcome of the second patient is un-known, as follow-up took place in another hospitalafter the diagnosis was made. The remaining 4patients in the juvenile group responded well totopical triamcinolone acetonide and clobetasol onlyand did not experience flare-ups during treatment.The median duration until clinical response was2 months (range 0-28) in the juvenile group.Six out of 8 patients in the adult group requiredsystemic immunosuppressive therapy due to wors-ening of vulvar symptoms and poor response tolocal therapy. Systemic treatment included doxycy-cline, prednisone, dapsone, methotrexate, azathio-prine, cyclophosphamide, mycophenolic acid, andrituximab. The median duration until clinicalresponse was 1.5 months (range, 0-18). Flare-upswere seen in 5 out of 8 patients during treatment.These patients received several systemicFig 2. A, Direct immunofluorescence microscopyshowing linear C3c deposition along the epidermalbasement membrane zone in an n-serrated pattern. B,Indirect immunofluorescence on a substrate of salt splitskin, showing IgG bound to the epidermal basementmembrane zone (arrow) of the artificial split. Theepidermal side is depicted with * and the dermal side isdepicted with .̂JAAD CASE REPORTSVOLUME 13Rashid et al 79immunosuppressive agents during follow-up. Theremaining 2 patients who were treated with topicaltreatment only did not experience flare-ups duringtreatment.DISCUSSIONThis case series of 14 patients with juvenile andadult VP demonstrates the broad clinical spectrum ofthis disease. In the presence of vulvar erosions,ulcerations, blisters, and scarring, VP should beconsidered in the differential diagnosis. In addition,examining extragenital mucosal surfaces and per-forming immunofluorescence microscopy and im-munoserology is mandatory to differentiate betweenconditions with similar clinical findings.VP is often misdiagnosed for LS or ELPV, resultingin therapeutic delay.8,10 In children, VP may also bemistaken for sexual abuse.11 Differentiating betweenLS, ELPV, and VP is often challenging due to over-lapping clinical presentation and the presence ofchronic inflammation. The presence of Wickhamstriae, patchy hair loss, or nail abnormalities candistinguish lichen planus from pemphigoid. Vaginalinvolvement is common in ELVP but has not beenpreviously reported in VP.4,5,12 In this study, exam-ination of the vaginal mucosa was not performed.However, patients diagnosed with VP should beexamined by a gynecologist with expertise in ELVPfor evaluation of vaginal involvement. In contrast toLS, MMP and ELPV may affect other mucosal sites,such as the ocular, nasal, pharyngeal, and laryngealmucosa. In this study, the presence of extragenitalinvolvement might have led to a quicker diagnosis.Extragenital involvement, including the oral andnasal mucosa, was observed more often in the adultgroup. In addition, more patients in the adult grouppresented with scar formation.Histopathology can often be used to differentiateVP from ELVP and LS. However, in some cases,histologic differences are not that clear and mayoverlap. A lesional biopsy for histopathology inpemphigoid can show subepidermal splitting com-bined with a moderate to dense infiltrate composedof lymphocytes, neutrophils, and eosinophils. Thiscan also be seen in bullous LS, which is caused byeither increased vacuolar degeneration of the basalmembrane zone or edema in the papillarydermis.13,14 In this study, a subepidermal split wasseen in 10 patients. Moreover, histopathologic fea-tures mimicking lichen planus and LS wereobserved.Overall, VP of the juvenile form respondspromptly to potent topical therapy and generallydoes not require systemic therapy. In the juvenilegroup, 4 out of 6 patients had relatively milddisease and responded well to potent topicalsteroids, with the exception of 2 patients, whowere treated with systemic corticosteroids anddapsone. In contrast, the majority of the adultpatients required systemic therapy and oftenshowed flare-ups.In conclusion, VP presents a broad spectrum ofsymptoms and can be challenging to diagnose.Performing careful examination of other mucosaeand skin with additional immunofluorescence andimmunoserology is essential for an adequatediagnosis.Conflicts of interestDr Horvath reports fees from Janssen-Cilag (AdvisoryBoards, Educational grants, Consultations, InvestigatorJAAD CASE REPORTSJULY 202180 Rashid et alInitiative Studies), AbbVie (Advisory Boards, Educationalgrants, Consultations, Investigator Initiative Studies),Novartis Pharma (Advisory Boards, Consultations,Investigator Initiative Studies), UCB Pharma (AdvisoryBoards, Consultations), Leo Pharma (Consultations),Solenne B.V. (Investigator Initiative Studies), Celgene(Consultations, Investigator Initiative Studies), Akari ther-apeutics (Consultations, Investigator Initiative Studies),Philips (Consultation), Roche (Consultation), Regeneron(Consultation) and Sanofi (Consultation), which fees werepaid to the institution. The remaining authors declare noconflict of interest.REFERENCES1. Chan LS, Ahmed AR, Anhalt GJ, et al. The first internationalconsensus on mucous membrane pemphigoid: definition,diagnostic criteria, pathogenic factors, medical treatment,and prognostic indicators. Arch Dermatol. 2002;138(3):370-379.2. Goldstein AT, Anhalt GJ, Klingman D, Burrows LJ. Mucousmembrane pemphigoid of the vulva. Obstet Gynecol. 2005;105(5 Pt 2):1188-1190.3. Farrell AM, Kirtschig G, Dalziel KL, et al. Childhood vulvalpemphigoid: a clinical and immunopathological study of fivepatients. Br J Dermatol. 1999;140(2):308-312.4. Jolliffe DS, Sim-Davis D. Cicatricial pemphigoid in a young girl:report of a case. Clin Exp Dermatol. 1977;2(3):281-284.5. Stage AH, Humeniuk JM, Easley WK. Bullous pemphigoid of thevulva: a case report. Am J Obstet Gynecol. 1984;150(2):169-170.6. Belzile E, Funaro D, Powell J. Localized vulvar bullouspemphigoid of childhood: a rare cause of persistent vulvarerosions in children. Pediatr Dermatol. 2019;36(3):349-351.7. Venning VA, Frith PA, Bron AJ, Millard PR, Wojnarowska F.Mucosal involvement in bullous and cicatricial pemphigoid. Aclinical and immunopathological study. Br J Dermatol. 1988;118(1):7-15.8. Marren P, Walkden V, Mallon E, Wojnarowska F. Vulvalcicatricial pemphigoid may mimic lichen sclerosus. Br JDermatol. 1996;134(3):522-524.9. Loyal J, Rashtak S. Vulvar lichen planus pemphigoides. Int JWomens Dermatol. 2017;3(4):225-227.10. de Waard MM, Jonkman MF. Vulvair gelokaliseerd pemfigo€ıd.NTvDV. 2008;18(4):204-207.11. Levine V, Sanchez M, Nestor M. Localized vulvar pemphigoidin a child misdiagnosed as sexual abuse. Arch Dermatol. 1992;128(6):804-806.12. Rogers M, Painter D. Cicatricial pemphigoid in a four-year-oldchild: a case report. Australas J Dermatol. 1981;22(1):21-23.13. Kavak A, Erdogan B, Topkarc Z, S€onmezler H, Sakız D. Bullouslichen sclerosus: isolated vulvar involvement. Dermatol OnlineJ. 2018;24(2):13030/qt3mk9801x.14. Hallel-Halevy D, Grunwald MH, Yerushalmi J, Halevy S. Bullouslichen sclerosus et atrophicus. J Am Acad Dermatol. 1998;39(3):500-501.

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Juvenile and adult vulvar pemphigoid, an under recognized entity:Case series of fourteen patients

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