Clinical, histological and immunpathological findings in 32 patients with dermatitis herpetiformis Duhring

© The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2010/0804 JDDG | 4˙2010 (Band 8)

JDDG; 2010 • 8:265–270 Submitted: 18.8.2009 | Accepted: 30.8.2009

Keywords• celiac disease• tissue transglutaminase• epidermal transglutaminase

SummaryBackground: Dermatitis herpetiformis is a chronic severely pruritic dermatosis.It is a cutaneous manifestation of celiac disease. The aim of our study was tocollect clinical, histological and immunopathological data on patients whowere treated in the University Departments of Dermatology in Würzburg andLübeck from 1996 to 2008.Patients and Methods: We retrospectively analyzed 32 patients. Only patientswith positive findings on direct immunofluorescence microscopy were includ-ed in this study.Results: All patients demonstrated skin lesions in the predilection areas ofknees, elbows, gluteal region and scalp. The male to female ratio was 1.5 : 1 andthe average age was 43 years. The interval between the first symptoms anddiagnosis ranged from 6 weeks to 20 years. Direct immunofluorescencemicroscopy showed that granular IgA deposits were more often found contin-uously along the dermal-epidermal junction rather than focally in the tips ofthe dermal papillae. Results of small intestinal biopsies were available from 29patients and confirmed the presence of celiac disease in all cases. None of thepatients reported gastrointestinal symptoms. IgA antibodies against tissuetransglutaminase and epidermal transglutaminase were found in 88 % and94 % of patient sera, respectively. Conclusions: The detection of IgA autoantibodies against epidermal transglut-aminase is the most sensitive serological test in the diagnosis of dermatitis her-petiformis. Our observations confirm that patients with dermatitis herpeti-formis usually do not demonstrate apparent gastrointestinal symptoms.

Clinical, histological and immunpathological findingsin 32 patients with dermatitis herpetiformis DuhringChristian Rose1, 2, Eva-Bettina Bröcker2, Detlef Zillikens1

(1) Department of Dermatology, Allergology and Venereology, University of Lübeck, Germany(2) Department of Dermatology, Venereology and Allergology, University of Würzburg, Germany

IntroductionDermatitis herpetiformis (DH) is a rareblistering dermatosis in Germany. Clini-cally, highly pruritic vesicles that are usu-ally quickly excoriated appear in sym-metrical distribution with a predilectionfor extensor surfaces. Louis AdolphusDuhring first described and named thedisease solely on the basis of clinical find-ings 125 years ago [1]. The gold standardfor diagnosis is the immunofluorescencemicroscopic detection of granular IgAdeposits in the skin. In classical cases,histology reveals a subepidermal blisterwith a predominance of neutrophilicgranulocytes.

DH is viewed as a cutaneous manifesta-tion of celiac disease. All patients withDH have this intestinal disease, whichusually has only mild manifestations;only 10 % of patients have gastrointesti-nal signs and symptoms [2, 3]. Patientswith celiac disease and DH demonstratethe same HLA class II characteristics. Al-most all patients express HLA-DQ2 orHLA-DQ8 [2]. Serologically, the detection of IgA au-toantibodies to tissue transglutaminaseusing ELISA is a sensitive and specifictest for the diagnosis of celiac disease.The antibodies towards endomysium de-tected in indirect immunofluorescence

microscopy recognize tissue transgluta-minase as antigen [4]. The autoantigen in DH is epidermaltransglutaminase. Serologically, IgA au-toantibodies directed against this canbe found in most DH patients [5]. Inthe skin of patients epidermal transglu-taminase is found at the same site asgranular IgA deposits. Patients withDH do not possess circulating antibod-ies towards cell-cell or cell-matrix pro-teins of the skin and thus differ funda-mentally from patients with otherautoimmune bullous diseases. Today it is presumed that DH results from the deposition of immune complexes

DOI: 10.1111/j.1610-0387.2009.07292.x Original Article 265

consisting of epidermal transglutami-nase and IgA. The goal of our study was to characterizeclinical, histological and immunopatho-logical features of patients presenting atthe University Departments of Derma-tology in Würzburg and Lübeck in thetime period from 1996 to 2008.

Materials and methodsAll DH patients that were treated from1996 to 2003 at the Department of Der-matology of the University of Würzburgand from 2002 to 2008 at the Depart-ment of Dermatology of the Universityof Lübeck were included in our study.The first diagnosis of the disease wasmade as far back as 1973. Clinical find-ings were documented, skin biopsies per-formed and serum was collected duringthe active stage of the disease usually be-fore the start of therapy. At the sametime small bowel biopsies from the duo-denum or upper jejunum were per-formed on most patients. The histologi-cal severity of celiac disease wasdetermined using the modified Marshclassification [6]. For histopathology le-sions were biopsied. For direct immuno-fluorescence (IF) perilesional skin wasbiopsied and processed on a frozen basis.The criterion for inclusion in the studywas a positive direct immunofluores-cence with the detection of granular IgAdeposits in the skin. Monkey esophaguswas used as substrate for indirect im-munofluorescence. Titers of IgA autoan-tibodies towards tissue transglutaminaseand epidermal transglutaminase were de-termined with commercially availableELISA systems (Immundiagnostik AG,Bensheim, Germany).

Results EpidemiologyIn the observation period 24 patients atthe University of Würzburg and 8 patients in Lübeck were seen. In 6 casesthe diagnosis had already been madeduring previous inpatient stays, but thepatients were still in need of treatment. Of the patients 19 were male (60 %) and13 female (40 %) (Figure 1). The meanage (± standard deviation [SD]) at thetime of diagnosis was 43 (± 19) years, themedian 42 years. The youngest patientwas 10 years, the oldest 84 years. Themean age (± SD) of the women with45 ± 21 was slightly higher than that ofthe men with 41 ± 9 years.

Clinical findings and therapyAt the time of diagnosis all patients hadhighly pruritic, often burning cutaneouslesions. In addition to small vesiclesmostly excoriated erythematous papulesand plaques were observed. These weredistributed symmetrically and involvedprimarily the extensor surfaces of the limbs, especially elbows and knees and the buttocks as well as the scalp (Figure 2). The back was also frequentlyaffected. In three patients up to 2 mm large mac-ular hemorrhages were seen on the flexorsurfaces of various fingers (Figure 2f ).Mucous membranes were not involved inany patient. One woman also had vitiligothat had manifested 20 years before der-matitis herpetiformis (Figure 2b). Twowomen had type I diabetes mellitus.Three patients had thyroid autoantibod-ies in the serum, but all were euthyroid. The time interval between the first reported signs and symptoms and the diagnosis was quite variable and rangedfrom weeks to up to 20 years. The aver-age interval until diagnosis was 3.2 years;in 53 % of patients two or more years.Therapeutically, a strict gluten-free dietwas recommended to all patients withthe corresponding dietary counseling.Further, dapsone was administered in adose of 50 to 150 mg daily. One patient

refused dapsone therapy. Dapsone waseffective in all patients and toleratedwithout side effects.

Direct immunofluorescence In all 32 patients direct IF was per-formed on perilesional skin and granularIgA deposits at the junctional zone wereobserved in all cases. In 13 patients(41 %) these were limited to the papil-lary dermis. In 19 cases (59 %) continu-ous IgA deposits were found along thejunctional zone (Figure 3). In 15 cases(47 %) complement component C3 wasalso found. In 3 cases (9 %) we observedIgM deposits with complement C3 alsobeing observed in these patients.

Histology of skin and small bowelThe skin biopsies of 31 patients were examined histologically. In 30 patientssubepidermal clefting was observed with amarked inflammatory infiltrate. In 60 %(18 patients) neutrophilic granulocytesdominated the infiltrate (Figure 4). In10 patients (33 %) a mixed cellular infil-trate consisting of neutrophilic andeosinophilic granulocytes was seen and intwo cases (7 %) eosinophilic granulocytespredominated. In two biopsies of thesame patient only a superficial lympho-cytic inflammatory infiltrate was pres-ent. Here clefting was also not observed.

266 Original Article Dermatitis herpetiformis

JDDG | 4˙2010 (Band 8) © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2010/0804

Figure 1: Age and sex distribution of 32 patients with dermatitis herpetiformis.

Dermatitis herpetiformis Original Article 267


type IIIb) and eight total villous atrophy(Marsh type IIIc). In two cases celiac disease was known before the appearanceof DH. At the time of diagnosis of

Results of histological examination ofsmall bowel biopsies were available for21 patients and in all cases secured thediagnosis of celiac disease. Two patients

were in the Marsh type I (infiltrativetype) stage and 27 in Marsh type III (destructive type) stage. Of these 14 had only mild villous atrophy (Marsh

Figure 2: Clinical spectrum of dermatitis herpetiformis. Symmetrically distributed excoriated papules and plaques in the gluteal area (“gluteal butterfly”)(a). Excoriated papules on the elbows and abdomen; in addition, vitiligo is present on the chest (b). Excoriated papules and plaques behind the ears andon the scalp of the same patient (c). Excoriated papules and plaques on the extensor surfaces of the knees (d). Grouped papules, excoriations and vesicles(e). Petechial hemorrhage on the lateral aspect of the index finger and on the tip of the thumb (f ).

Figure 3: Direct immunofluorescence of perile-sional skin. Granular deposits of IgA in the tipsof the dermal papillae (a). Continuous granulardeposits of IgA at the dermal-epidermal junc-tion (b).

Figure 4: Histologic examination of a lesional skin biopsy. Dense granulocytic inflammatory infiltratewith abscess formation in the tip of a dermal papilla (hematoxylin & eosin stain).

DH no patient reported gastrointestinalsymptoms.

Indirect immunofluorescence and ELISAIn 31 patients indirect IF was performedand in 27 patients (87 %) IgA antibodiestowards endomysium were found(Table 1). Using ELISA IgA antibodiestowards tissue transglutaminase weremeasured in 25 patients and towards epi-dermal transglutaminase in 17 patients.In 22 patients (88 %) IgA antibodies to-wards tissue transglutaminase and in 16(94 %) towards epidermal transglutami-nase were indeed detected. All patientswith histologically proven severe or totalvillous atrophy (Marsh type IIIb andIIIc) possessed autoantibodies towardsendomysium, tissue transglutaminaseand epidermal transglutaminase. In twopatients only antibodies towards epider-mal transglutaminase but not towardsendomysium or tissue transglutaminasewere found. A single patient was negativefor all three serological parameters.

DiscussionDH is a rare skin disease in Germany. Inthe study period of 13 years only 32 pa-tients were treated at the two UniversityDepartments of Dermatology. The inci-dence of the diseases varies with geogra-phy and depends on the immunogeneticbackground of the population [2]. In arecent prospective study on the inci-dence of autoimmune bullous disordersin Lower Franconia, Germany, an inci-dence of DH of 1 : 1,000,000 new casesper year was observed [7]. In Scandi-navia, Ireland, England, Hungary andNorth America DH is more frequentthan in Germany [2]. In Sweden andUtah (USA) an incidence of 11 and 9.8new disease cases/million/year, respec-tively, was reported [8, 9]. The rarity ofthis disease may explain the long time in-terval until the diagnosis is made, whichon average was 3.2 years in our patients.DH is somewhat more common in menthan in women with the ratio of 1.5 : 1that is observed corresponding to the lit-erature. The average age of somewhatover 40 years observed here also corre-sponds to the results of various largestudies in other European nations andthe USA [10–12]. In all patients in this study the sites ofpredilection, i. e. the extensor surfaces ofthe limbs, especially knees and elbows,the scalp and the buttocks, were affected



Table 1: Comparison of the histological results of small bowel biopsy(Marsh classification), direct and indirect immunofluorescence and ELISAof 32 patients with dermatitis herpetiformis.

PatientMarshtype

IgA-DIFpattern

Endomysium (IIF)

tTG(ELISA)

eTG(ELISA)

1 I Continuous – – +

2 I Continuous + + n.d.

3 IIIa Papillary + + n.d.

4 IIIa Continuous + + n.d.

5 IIIa Continuous + + +

6 IIIa Papillary – n.d. n.d.


8 IIIa Papillary + + +


10 IIIa Continuous + n.d n.d.



13 IIIa Continuous + n.d. n.d.

14 IIIa Papillary – – +

15 IIIa Continuous – – –


17 IIIb Continuous + n.d. n.d.

18 IIIb Papillary + + +

19 IIIb Papillary + + +

20 IIIb Papillary + + n.d.

21 IIIb Papillary + n.d. n.d.

22 IIIc Continuous + + n.d.

23 IIIc Continuous + + n.d.

24 IIIc Papillary + + n.d.

25 IIIc Continuous + + +


27 IIIc Continuous n.d. n.d. n.d.

28 IIIc Papillary + + +


30 n.d. Continuous + n.d. n.d.

31 n.d. Papillary + + n.d.

32 n.d. Continuous + + +

Positive27/31 (87 %)

22/25 (88 %)

16/17(94 %)

DIF, direct immunofluorescence; IIF, indirect immunofluorescence, fTG, tissuetransglutaminase; eTG, epidermal transglutaminase; n.d., not done.


symmetrically. Sparing of these sitesmakes the diagnosis of DH improbable.Symmetrical involvement of the but-tocks led Klaus Wolff, Chairman of theDepartment of Dermatology of the Uni-versity of Vienna, Austria (1981–2004)to coin the descriptive phrase “glutealbutterfly” (Figure 2a). In three patientssmall palmar petechial hemorrhages wereseen (Figure 2f ). These are observedmore frequently in children, but can alsooccur in adults, as in our patients. Inter-estingly, such acral hemorrhages have todate not been reported for any other au-toimmune bullous disorder [13]. The gold standard in the diagnosis ofDH is the detection of granular IgA de-posits in the upper dermis in direct im-munofluorescence. Two patterns can befound here. In addition to focal depositsin the tips of the dermal papillae IgA canbe deposited continuously along the der-mal-epidermal junction (Figure 3) [2].We observed the pattern of continuousdeposits somewhat more frequently thanfocal deposits in the tips of the dermalpapillae. Data on how frequently bothpatterns are found were not available un-til now. The type of pattern does not cor-relate with the severity of the skin diseaseor celiac disease [14]. The differentiationof the continuous pattern from linear de-posits as diagnostic for linear IgA diseaseis crucial. Linear IgA disease was first dif-ferentiated from DH on the basis of thedifferent pattern in direct immunofluo-rescence by Chorzelski and coworkers in1979 [15]. This disorder is not associ-ated with celiac disease. For histopathological studies in autoim-mune bullous disorders it is important tobiopsy a fresh, intact blister. This waspossible in most patients revealing asubepidermal blister with a significantinflammatory reaction. Even though themajority of patients displayed a neu-trophil-rich infiltration as is typically de-scribed in DH, histopathological find-ings alone do not allow for a definitivedifferentiation from various other au-toimmune bullous disorders. These in-clude linear IgA disease, bullous pem-phigoid, anti-laminin �-1 pemphigoidor the inflammatory variety of epider-molysis bullosa acquisita [16]. If a freshblister is not biopsied, as in one of ourpatients, no specific findings will beseen. In a recent study by a dermatohis-tological laboratory in almost 40 % ofDH cases unspecific findings with lym-

phocytic infiltration, fibrosis and ectaticcapillary blood vessels are observed [17].This underscores the need to biopsy avesicle for histopathology. DH is viewed as the cutaneous manifes-tation of celiac disease, even if only fewpatients have gastrointestinal symptoms.None of our patients reported intestinalsymptoms specific for celiac disease. Inall 29 patients undergoing endoscopyhistological features of celiac disease werefound. The mild manifestation of celiacdisease in DH patients also explains thelower sensitivity of detection of circulat-ing antibodies in the serum of patients incomparison to the total group of patientswith celiac disease. For anti-endomy-sium and anti-tissue transglutaminaseantibodies the sensitivity was 87 and88 %, respectively, in our patients andconfirms reports in the literature [2, 12,18–20]. The autoantigen of DH is epidermaltransglutaminase [5]. We detected IgAantibodies towards this enzyme in 94 %of patients. In a recent study on a largernumber of patients, we demonstratedthat detection of IgA antibodies towardsepidermal transglutaminase was moresensitive than antibodies towards tissuetransglutaminase [21]. Further, in somepatients the antibody titer towards epi-dermal transglutaminase persists despitea gluten-free diet. In these patients pru-ritic cutaneous lesions also persisted. Theformation of these antibodies independ-ently of diet possibly explains the persist-ence of cutaneous complaints in thesepatients [21]. In order to finally judge thediagnostic significance of antibodies towards epidermal transglutaminase further studies on specificity includingpatients with other pruritic skin diseasesare needed. It is well-known that DH frequently oc-curs in association with other autoim-mune disorders [22]. Two of our patientshad type I diabetes mellitus; three otherspossessed thyroid autoantibodies. Onewoman also had vitiligo, an unusual co-incidence. Only 11 other case reports ofpatients with this association exist [23].Usually vitiligo was present long beforethe diagnosis of DH, as in our patient.Drug of choice to suppress pruritus andtreat cutaneous lesions of DH is dap-sone. All patients included here re-sponded promptly to this therapy inagreement with the relevant literature[11]. Even though dapsone can have a

variety of side effects and regular labora-tory monitoring, especially initially, isrecommended, this drug is well-toleratedby this patient group, as was the case inour patients. Therapy of celiac diseaseconsists of a lifelong strict gluten-freediet. Consistent observance of this diet istime-consuming and expensive in every-day life. Comprehensive help with thisdiet and information on other questionsregarding this disease is offered by theGerman Celiac Disease Society(Deutsche Zöliakie Gesellschaft e. V.;www.dzg-online.de), a self-help group ofaffected persons. In summary, our observations on 32 pa-tients with DH confirm the age andgender distribution of the disease re-ported in the literature. Even though nopatient reported gastrointestinal signsor symptoms, histologically we wereable to demonstrate celiac disease in allpatients undergone gastroscopy. Goldstandard in the diagnosis or exclusion of DH is direct immunofluorescence,where – in addition to granular IgA de-posits in the tips of the dermal papilla –often continuous deposits along thedermal-epidermal junction are found.The most sensitive serological test fordiagnosis is the detection of IgA au-toantibodies towards epidermal transg-lutaminase. <<<

Conflicts of interestNone.

Correspondence to

Dr. Christian RoseDepartment of Dermatology, Allergology and Venereology University of LübeckRatzeburger Allee 160 D-23538 Lübeck, GermanyTel.: +49-451-500-2512Fax: +49-451-500-5092E-mail: [email protected]



References1 Bogenrieder T, Stolz W. Aus der Neuen

Welt. Louis A. Duhring und die Der-matitis herpetiformis. Hautarzt 2003;54: 167–72.

2 Fry L. Dermatitis herpetiformis: pro-blems, progress and prospects. Eur JDermatol 2002; 12: 523–31.

3 Rose C, Zillikens D. Dermatitis herpetiformis Duhring. In Hertl M:Autoimmune diseases of the skin. Pathogenesis, diagnosis, management.2nd Edition, Wien: Springer, 2005:95–108.

4 Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Rieken EO, Schuppan D. Identification of tissuetransglutaminase as the autoantigen ofceliac disease. Nature Med 1997; 3:797–801.

5 Sárdy M, Kárpáti S, Merkl B, PaulssonM, Smyth N. Epidermal transglutami-nase (Tgase 3) is the autoantigen ofdermatitis herpetiformis. J Exp Med2002; 195: 747–57.

6 Oberhuber G, Caspary WF, KirchnerT, Borchard F, Stolte M. Empfehlungenzur Zöliakie-/Spruediagnostik. Patho-loge 2001; 22: 72–81.

7 Bertram F, Bröcker EB, Zillikens D,Schmidt E. Prospektive Untersuchungder Inzidenz blasenbildender Autoim-mundermatosen in Unterfranken. J Dtsch Dermatol Ges 2009; 7: 1–7.

8 Mobaken H, Kastrup W, Nilsson L. In-cidence and prevalence of dermatitisherpetiformis in Western Sweden. ActaDerm Venereol 1984; 64: 400–4.

9 Smith JB, Tulloch JE, Meyer LJ, ZoneJJ. The incidence and prevalence ofdermatitis herpetiformis in Utah. ArchDermatol 1992, 128: 1608–10.

10 Egan CA, O`Loughlin S, Gormally S,Powell FC. Dermatitis herpetiformis: areview of fifty-four patients. Ir J MedSci 1997; 166: 241–4.

11 Buckley DB, English J, Molloy W,Doyle CT, Whelton MJ. Dermatitisherpetiformis: a review of 119 cases.Clin Exp Dermaol 1983; 8: 477–87.

12 Alonso-Llamazares J, Gibson LE, Rogers III RS. Clinical, pathologic, andimmunopathologic features of dermati-tis herpetiformis: review of the Mayoclinic experience. Int J Dermatol 2007;46: 910–9.

13 Rose C, Zillikens D. Hämorrhagien anden Fingern einer 45-jährigen Frau:palmare Petechien bei Dermatitis herpetiformis. J Dtsch Dermatol Ges2003; 1: 743–5.

14 Beutner EH, Chorzelski TP, ReunalaTL, Kumar V. Immunopathology ofdermatitis herpetiformis. Clin Derma-tol 1992; 9: 295–311.

15 Chorzelski TP, Jablonska S, BeutnerEH, Bear SF, Furey NL. Linear IgAbullous dermatosis. In: Beutner EH,Chorzelski TP, Bear SF (eds): Immun-pathology of the skin. 2nd ed. NewYork: Wiley & Sons 1979: 315–23.

16 Rose C, Bröcker EB, Zillikens D. Stellenwert der histologischen Untersu-chung in der Diagnostik bullöser Au-toimmundermatosen. J Dtsch DermatolGes 2004; 2: 96–104.



17 Warren SJP, Cockerell CJ. Characte-rization of a subgroup of patients withdermatitis herpetiformis with nonclas-sical histologic features. Am J Derma-topathol 2002; 24: 305–8.

18 Dieterich W, Laag E, Bruckner-Tuderman L, Reunala T, Kárpáti S, Zágoni T, Riecken EO, Schuppan D.Antibodies to tissue transglutaminaseas serologic markers in patients withdermatitis herpetiformis. J Invest Der-matol 1999; 113: 133–6.

19 Rose C, Dieterich W, Bröcker EB,Schuppan D, Zillikens D. Circulatingautoantibodies to tissue transglutami-nase differentiates patients with derma-titis herpetiformis from those with li-near IgA disease. J Am Acad Dermatol1999; 41: 957–61.

20 Caproni M, Cardinali C, Renzi D,Calabrò, Fabbri P. Tissue transglutaminaseantibody assessment in dermatitis herpeti-formis. Br J Dermatol 2001; 144: 196–7.

21 Rose C, Armbruster FP, Ruppert J, IglBW, Zillikens D, Shimanovich I. Auto-antibodies against epidermal trans-glutaminase are a sensitive diagnosticmarker in patients with dermatitis her-petiformis on a normal or gluten-freediet. J Am Acad Dermatol 2009; 61:39–43.

22 Reunala T, Collin P. Diseases associatedwith dermatitis herpetiformis. Br JDermatol 1999; 136: 315–8.

23 Karabudak O, Dogan B, Yildirim S,Harmanyeri Y, Anadolu-Brasie R. Dermatitis herpetiformis and vitiligo. JChin Med Assoc 2007; 70: 504–6.

Documents

Clinical, histological and immunpathological findings in 32 patients with dermatitis herpetiformis Duhring