Prospective analysis of the incidence of autoimmune bullous disorders in Lower Franconia, Germany

434 Original Article DOI: 10.1111/j.1610-0387.2008.06976.x

JDDG | 5˙2009 (Band 7) © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2009/0705

JDDG; 2009 • 7:434–439 Submitted: 26.8.2008 | Accepted: 21.10.2008

Keywords• autoantibody• epidemiology• bullous pemphigoid• pemphigoid gestationis• dermatitis herpetiformis• linear IgA disease• pemphigus

SummaryBackground: Only limited epidemiologic data are available on autoimmunebullous diseases. Improved diagnostic tools should have led to an increased inci-dence. To test this hypothesis, all patients with autoimmune bullous disorders whowere treated in the Department of Dermatology at the University of Würzburg,Germany, between January 2001 and June 2002 were analysed prospectively.Patients and Methods: Epidemiologic data of patients diagnosed with an autoimmune bullous disease during this time period were registered and stati-stically evaluated. Diagnosis was based on the clinical picture and specific immunopathological findings. Only patients from Lower Franconia, a well-defi-ned administrative region of Southern Germany, were included into this study.Results: During the study period, 41 patients with an autoimmune bullous di-sease were diagnosed, including 27 with bullous pemphigoid, 4 with pemphi-goid gestationis and mucous membrane pemphigoid, 2 with dermatitis herpe-tiformis and linear IgA disease, and 1 with epidermolysis bullosa acquisita andpemphigus vulgaris, respectively. The highest incidence was calculated forbullous pemphigoid (13.4 per 1 million inhabitants per year) followed by pem-phigoid gestationis (2.0) and mucous membrane pemphigoid (2.0). Patientswith mucous membrane pemphigoid were found to have the highest meanage at disease onset (76 years) followed by patients with bullous pemphigoid(74 years). Conclusions: This is the first prospective study on the incidence of autoimmunebullous disorders. Subepidermal blistering autoimmune diseases were shown tobe more frequent than previously reported for Central Europe. This is most likelydue to improved diagnostic tools for and increased awareness of these diseases.

Prospective analysis of the incidence of autoimmunebullous disorders in Lower Franconia, GermanyFranziska Bertram1, Eva-B. Bröcker1, Detlef Zillikens1,2, Enno Schmidt1,2

Departments of Dermatology, Allergy and Venereology (1) University of Würzburg(2) University ofLübeck

IntroductionAutoimmune bullous disorders are char-acterized by autoantibodies againstdesmosomal and hemidesmosomalstructural proteins of the skin. In thepemphigus group, autoantibodies are directed against desmosomal proteins resulting in an intraepidermal loss of cellcontact. This group includes pemphigus

vulgaris, pemphigus foliaceus, IgA pem-phigus, and paraneoplastic pemphigus.Subepidermal autoimmune bullous dis-orders are characterized by antibodiesagainst structural proteins of the dermo-epidermal junctional. This group in-cludes bullous pemphigoid (BP), mucousmembrane pemphigoid, pemphigoid ges-tationis, linear IgA disease, epidermolysis

bullosa acquisita, lichen planus pem-phigoides, and anti-p200 pemphigoid.Furthermore dermatitis herpetiformiswith antibodies against epidermal/tissuetransglutaminase and bullous systemiclupus erythematosus feature subepider-mal blistering [1]. In Germany and France, in 1995, BP was identified as the most common

Incidence of autoimmune bullous disorders Original Article 435

© The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2009/0705 JDDG | 5˙2009 (Band 7)

at the Department of Dermatology, Uni-versity of Würzburg. Further BP patientsin prodromal stages and those lackingthe classical phenotype were diagnosed.As the incidence of BP clearly rises with increasing age being 189 newcases/million/year in those over 80 yearsof age, the observed increase in incidencein comparison to the study from 1989 to1994 can, to a small part, be explained bythe increased proportion of the elderly inthe population. From 1992 to 2002 thenumber of over 70-year-olds, who con-stituted three-fourth of our BP patients,rose by 15 % in Lower Franconia. Thehigher incidence in the 51 to 60-year-oldBP patients in comparison to those onedecade older (Table 3) is very probablydue to the small case number and is notfound in larger collectives [4, 10]. The incidence of all subepidermal blis-tering disorders which was 19.9 in ourstudy, of which BP constituted abouttwo-thirds of the cases, was recently ana-lyzed in Scotland and Great Britain.While the incidence of subepidermalblistering disorders was found to be 14 inthe Grampian region in northeast Scot-land for the years 1991 to 2002, in GreatBritain for 2001 to 2005, it was calculatedat 43/million/year [10, 11]. While datacollection including establishment of thediagnosis was performed by dermatolo-gists in Lower Franconia, France andSingapore, the data in Great Britain wastaken as random samples from a report-ing system for general practitioners [10];in Scotland they originate from the database of the Institute for Pathology of theAberdeen Royal Infirmary [10]. A possi-bly too high estimate of incidence mayhave been caused by imprecise diagnosticcriteria and double reports. Besides thelack of validated diagnoses by dermatolo-gists doubts of the distinct increase in in-cidence of BP in Great Britain reported byLangan et al. arise, as the number of positive direct immunofluorescence mi-croscopy findings of the St. John’s Insti-tute of Dermatology at St. Thomas Hospi-tal, London, did not rise correspondinglyduring the same time period [10, 12]. Alarge advantage of this survey, however, isthe inclusion of patients from the wholecountry which prevents a falsely too lowestimation of incidence caused by treat-ment of patients in neighboring regionsand thus non-inclusion. In the presentstudy, women were affected by BP about1.2 times more often than men, which

The population structure of Lower Fran-conia for the years 2001/2002 was pro-vided by the Bavarian State Office forStatistics and Data Processing(www.statistik.bayern.de). The Depart-ment of Dermatology, University ofWürzburg, is the only dermatologicclinic in Lower Franconia.

ResultsForty patients with subepidermal autoim-mune bullous disorders as well as one patient with pemphigus vulgaris were di-agnosed. The incidence of the individualdiseases and the age distribution of the pa-tients are depicted in Table 2. By far themost common disease was BP with a totalof 27 patients and an incidence of 13.4newly diagnosed cases per million popula-tion and year. Table 3 depicts the age- andgender-specific incidence of BP.

DiscussionIncidences of autoimmune bullous dis-orders published to date have been as-sessed retrospectively. The present studywas performed prospectively. This typeof analysis usually provides a more exactassessment of epidemiologic data thanretrospective studies. Since no registryexists in German to which all patientswith autoimmune bullous disorders arereported, it is probable that the inci-dences determined in the present studyare too low; it can be assumed that sev-eral patients from Lower Franconia werealso treated in hospitals outside of thisregion. The relatively short observationperiod (18 months) is also a possiblesource of error, in that with exception ofBP, a single patient already causes dra-matic changes in incidence.

Bullous pemphigoidBP is the most common autoimmunebullous disorder in Central Europe andSingapore. In France for the years 1984to 1992, a regional incidence of 7.4 newcases/million/year was calculated [3], inSingapore 7.6 [9]. In the present study,we found a total incidence of 13.4 newcases per million population per year.This number is distinctly higher than inFrance and Singapore (for the years 1988and 1999) as well as in comparison to aretrospective analysis of patients inLower Franconia between 1989 and1994, where the incidence was 6.6 [2].This increase can most likely be explained by improved diagnostic tools

autoimmune bullous disorder with re-gional incidences of 6.6 and 7.4 newlydiagnosed cases/million/year, respec-tively [2, 3]. The incidence of BP in-creases with increasing age of patientsand to about 150 in those over 90 years[4]. In the present study, we examined ifusing improved diagnostic tools (ELISAand immunoblotting with cellular andrecombinant fragments of the targetantigens) leads to a higher incidence ofautoimmune bullous disorders. To thisend, patients with autoimmune bullousdisorders in Lower Franconia who werenewly diagnosed at the Department ofDermatology, University of Würzburg,in the time period from January 2001 toJune 2002 were analyzed prospectively.In comparison to a retrospective analysisperformed 10 years previously in thesame region the incidence was double forBP, mucous membrane pemphigoid andepidermolysis bullosa acquisita as well asfour-fold for pemphigoid gestationis andlinear IgA disease [2].

Patients and methodsDiagnosis was made on the basis of clin-ical findings as well as various im-munopathological examinations and isdepicted in detail in Table 1. The follow-ing detection methods for tissue-boundand circulating autoantibodies were em-ployed: direct immunofluorescence (IF)microscopy of a perilesional mucousmembrane or skin biopsy, indirect IF mi-croscopy on monkey esophagus as well asindirect IF microscopy and comple-ment-binding test on 1M NaCl split hu-man skin [5]. ELISA with the recombi-nant 16th non-collagenous domain ofcollagen type XVII (BP180 NC16A) [6],ELISA with recombinant desmoglein 1 and desmoglein 3 (MBL, Nagoya,Japan), ELISA with tissue transglutami-nase (Phadia, Freiburg, Germany), im-munoblot with a concentrated mediumof cultured human keratinocytes to de-tect the soluble ectodomain of collagentype XVII (LAD-1) [7], immunoblotwith the recombinant C-terminal por-tion of collagen type XVII (BP180 4575;amino acids 1365-1413) as well as im-munoblot with an extract of human der-mis [8]. The epidemiologic data of patients livingin the government district of LowerFranconia were assessed using a stan-dardized questionnaire in the time pe-riod from January 2001 to June 2002.

436 Original Article Incidence of autoimmune bullous disorders


Diagnosis Diagnostic criteria

Clinical features Direct IF1 Indirect IF2 ELISA/immunoblot

Bullous pemphigoidn = 27

Blisters/erosions notpredominantly onmucous membranes25/273

IgG > IgA and/or C3along the BMZ24/244

Split skin: IgG > IgAon the blister roof27/27

IgG reactivity toBP180 9/14

Pemphigoid gestatio-nis n = 4

As in bullous pemphigoid but association with pregnancy

4/4 3/3 4/4 4/4

Mucous membranepemphigoid5

n = 4

Blisters/erosions pre-dominantly onmucous membranes 4/4

IgG and/or IgAand/or C3 along theBMZ 2/4

Split skin:: IgGand/or IgA on theblister roof and/orblister floor 1/4

IgG- and/or IgA reac-tivity to BP180 orlaminin 332 4/4

Linear IgA disease n = 2


IgA > IgG along theBMZ 1/26

Split skin: IgA > IgGon the blister roof 2/2

IgA reactivity toBP180 fragments 1/2

Dermatitisherpetiformis n = 2

Urticarial plaques orvesicles 2/2

Granular IgA in thedermal papillae 2/2

Monkey esophagus:IgA to endomysium2/2

IgA reactivity to tissuetransglutaminase 2/2

Epidermolysis bullosaacquisita n = 1


IgG and/or C3 alongthe BMZ 1/1

Split skin: IgG on theblister floor 1/1

IgG reactivity to collagen type VII 1/1

Anti-p200-pemphigoid

Blisters/erosions notpredominantly onmucous membranes

IgG and/or C3 alongthe BMZ

Split skin: IgG on theblister floor

IgG reactivity to a200 kDa heavy pro-tein in dermal extract

Lichen planuspemphigoides

Blisters/erosions andlichenoid papules

IgG and/or C3 alongthe BMZ

Split skin: IgG on theblister roof

IgG reactivity to 16th

non-collagenous domain of BP180

Bullous lupus erythe-matosus

Blisters/erosions; ful-fillment of ACR diag-nostic criteria for SLE

Band-like depositionof IgG/IgM/IgA/C3in the BMZ

Split skin: IgG on theblister floor

IgG reactivity to collagen type VII

Pemphigus vulgarisn = 1

Blisters/erosions onmucous membranesand/or skin 1/1

IgG and/or C3 inter-cellularly in epidermis/mucous membraneepithelium 1/1

Monkey esophagus:IgG intercellularly inepithelium 1/1

IgG reactivity todesmoglein 3 1/1

Pemphigus foliaceusBlisters/erosions onskin

as for pemphigus vulgarisIgG reactivity todesmoglein 1

IgA pemphigusBlisters/erosions onmucous membranesand/or skin

IgA intercellularly inepidermis/mucousmembrane epithelium

Monkey esophagus:IgA intercellularly inepithelium

–

Paraneoplastic pem-phigus7

Blisters/erosions onmucous membranes;neoplasia

IgG and/or C3 intercellularly in epidermis/mucousmembrane epithelium

Monkey esophagus:IgG intercellularly inepitheliumMonkey bladder: IgGin urothelium

IgG reactivity todesmoglein 1 and/or3

Table 1: Diagnostic criteria of autoimmune bullous disorders.



corresponds to the results from Franceand Uganda [3, 13]. In Singapore,women predominated 2 : 1, in Kuwait ina study of patient data from 1991 to 2002even by 6 : 1 [9, 14]. In these studies – itmust be noted – only absolute patientnumbers were compared and not thegender-specific incidence. The presentanalysis, in agreement with Jung et al.[4], found that in the over 80-year-oldsabsolutely about double as many womenthan men were diagnosed with BP, theage-specific incidence of BP due to thesmall number of older men in the popu-lation was, however, significantly higherin men than in women.

Other subepidermal autoimmune bullousdisordersAs the second most common autoim-mune bullous disorder following BP we identified mucous membrane pemphigoid and pemphigoid gestationiswith an incidence of 2.0 newcases/million/year each. As with BP, theincidence of pemphigoid gestationis in thepresent study is distinctly higher than inFrance (0.84) and than reported 10 yearsago in Lower Franconia (1.0) [2, 3]. InKuwait, a similar incidence (1.83) was re-ported [14]. The incidence that we calcu-lated with 1 case to 256 live births wasalso significantly higher than the observa-tion in the 1970s in England and in the1980s in Switzerland with 1 case in 3,000to 4,000 or 7,000 pregnancies, respec-tively [15, 16]. In agreement with paststudies, the women developed the diseaseusually in the second or third trimester ofpregnancy [5]. The distinctly higher inci-dence in our study might be explained bythe fact that we consistently includedpemphigoid gestationis in the differentialdiagnosis in all pregnant patients withlong-standing pruritic skin lesions.

Bernard et al. calculated an incidence ofmucous membrane pemphigoid in France of 1.25 new cases/million/year[3], Zillikens et al. an incidence for lowerFranconia of 0.67 [2]. For ocular pem-phigoid, a mucous membrane pem-phigoid with conjunctival involvementexclusively, an incidence of 1 newcase/million/year was reported in Eng-land [17]. While in studies on large col-lectives with in part over 400 patientswith mucous membrane pemphigoid, amean age of manifestation was reportedbetween 62 and 66 years [17, 18], themean age of manifestation of our 4 pa-tients with mucous membrane pem-phigoid was 76 years. The incidence of dermatitis herpeti-formis and linear IgA disease was 1 newcase/million/year each. The incidence ofdermatitis herpetiformis varies regionally

very considerably: in Scotland and Swe-den prevalences ranging from 115 to 200patients per million population are re-ported, in Sweden and Utah, USA, inci-dences of 11 and 9.8 newcases/million/year, respectively [19],while the disease appears only sporadi-cally in Japan and Africa [20]. These dif-ferences are related to the different im-munogenetic backgrounds of thepopulations. Thus, a clear association ofceliac disease with HLA-DQ2 and -DQ8 was found [21]. Dermatitis her-petiformis represents the cutaneousmanifestation of celiac disease and prac-tically all patients display at least histo-logical signs of this intestinal disease injejunal biopsy. The incidence of linear IgA disease was 1new case/million/year in our study andthus higher than in Singapore (0.26),

For making the diagnosis the criteria “clinical features”, “direct IF” and “indirect IF” must be fulfilled; in negative direct IFcirculating autoantibodies against distinct target antigens must be identified. IF, immunofluorescence1 Of a perilesional skin or mucous membrane biopsy2 Using human skin split by 1M NaCl solution3 One patient displayed highly pruritic erythemas and excoriations, the other presented clinically as prurigo simplex subacuta.Both patients had linear deposits of IgG and C3 in direct IF and epidermal binding of IgG in indirect IF on split human skin. 4 In 3 patients no direct IF, all 3 presented with tense blisters as well as IgG serum autoantibodies with epidermal binding inindirect IF on split human skin and reactivity in the BP180 NC16A ELISA.5 According to the international consensus conference on mucous membrane pemphigoid [30]6 The patient with negative direct IF displayed IgA reactivity to LAD-1 in Western blotting. 7 According to Anhalt [31].

Table 2: Incidence of autoimmune bullous disorders and mean age atmanifestation of patients in Lower Franconia from January 2001 to June2002.

Diagnosis1 Numberof patients

Mean age atdisease mani-

festationIncidence2

Bullous pemphigoid 27 74.6 13.4

Mucous membrane pemphigoid 4 76.3 2

Pemphigoid gestationis 4 33 2

Linear IgA disease 2 31 1

Dermatitis herpetiformis 2 42.5 1

Epidermolysis bullosa acquisita 1 36 0.5

Pemphigus vulgaris 1 62 0.5

1 Only those diagnoses observed from January 2001 to June 2002 listed.2 New cases/million population/year; the average population in this time periodwas 1,340,912 (www.statistik.bayern.de).

438 Original Article Incidence of autoimmune bullous disorders


Kuwait (0.7) and France (0.48) as well asin Lower Franconia at the beginning ofthe 1990s (0.22) [2, 3, 9, 14]. Interest-ingly, linear IgA disease is much morefrequent in South Africa, Mali andUganda [13, 22, 23]. For Uganda for theyears 2000 and 2002, it was shown thatthe autoantibody class correlates withpatient age: Younger patients with an au-toimmune bullous disorder were morelikely to have IgA reactivity against thebasement membrane zone and older pa-tients more commonly IgG autoantibod-ies. The higher proportion of children inAfrican countries (in Uganda 50 % ofthe population is 14 years or younger incomparison to 16 % in Germany) thusexplains the relative high incidence oflinear IgA disease and the relative rarityof BP in Uganda [13]. Epidermolysis bullosa acquisita belongswith an incidence of 0.5 newcases/million/year in the present study inagreement with surveys in Singapore(0.26), Kuwait (0.23), France (0.19) andGermany (0.22) to the rare autoimmunebullous disorders [2, 3, 9, 14]. With inci-dences of under 0.3 in France, Singaporeand Kuwait bullous systemic lupus erythe-matosus, lichen planus pemphigoides andanti-p200 pemphigoid are even rarer [3,9, 14]. During the observation period wedid not diagnose these diseases in any pa-tient from Lower Franconia.

PemphigusIn Germany, Finland, France, Bulgaria,Macedonia, Serbia, Turkey, Iran, Con-

necticut (USA), Saudi Arabia, and Kuwaitdiseases of the pemphigus group are re-ported with an incidence of 1 to 6 newcases/million/year [14, 24–27]. Higherincidences possibly exist in Malaysia andChina [28, 29]. Recently, an incidence of7 new cases/million/year was reported inGreat Britain [10]. In this study, a registryof all diagnoses in offices of general prac-titioners was referred to, so that possiblypatients with other autoimmune bullousdisorders were also included. In the present study, one patient was di-agnosed with pemphigus vulgaris whichcorresponds to an incidence of 0.5 newcases/million/year. This relatively low in-cidence compared to Central Europecould be a result of the relative short ob-servation period of 18 months, in whichonly one patient with this disease wasregistered. IgA and paraneoplastic pem-phigus are so rare that no epidemiologicdata have been gathered to date. In thepresent study, no patients were diagnosedwith these two entities or with pemphi-gus foliaceus. In summary, this prospective studyshows a distinctly higher incidence of themost common autoimmune bullous dis-eases (BP, pemphigoid gestationis andmucous membrane pemphigoid) incomparison to a similar study in thesame region 10 years ago and data forCentral Europe up to now. This is prob-ably due to improved diagnostic toolsand the increased consciousness of thesediseases with the resulting more com-plete detection of these patients.

AcknowledgmentsWe thank Dr. Susanne Herzog,Würzburg, for the help in managementof the patients as well as Christa Knausand Silvana Noll, Würzburg, for thetechnical support.

Conflicts of interestNone.

Correspondence to

Enno Schmidt, MD, PhDDepartment of Dermatology, Allergyand VenereologyUniversity of LübeckRatzeburger Allee 160D-23538 Lübeck, GermanyTel.: +49-451-500-2538Fax: +49-451-500-2981E-mail: [email protected]

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Table 3: Age- and gender-specific incidence of bullous pemphigoid inLower Franconia from January 2001 to June 2002.

1New cases/million population/year

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Number ofcases/meanpopulation

from1/01–6/02

Incidence1

Number ofcases/meanpopulation

from1/01–6/02

Incidence1 Incidence1

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61–70 1/72757 9.2 1/77761 8.6 8.9

71–80 5/41186 80.9 3/62973 31.8 51.2

> 81 4/11960 223 8/30397 175.5 188.9

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Prospective analysis of the incidence of autoimmune bullous disorders in Lower Franconia, Germany