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Article in press - uncorrected proof Clin Chem Lab Med 2006;44(2):144–149 2006 by Walter de Gruyter • Berlin • New York. DOI 10.1515/CCLM.2006.027 2006/39

Review

Autoimmune bullous disorders1)

Ru¨ diger Eming* and Michael Hertl for the Bullous autoimmune dermatoses have a common members of the Autoimmune Diagnostics pathogenic mechanism involving binding of autoan- Working Group tibodies to specific adhesion molecules in epidermal desmosomes, and in some cases in the area of the Klinik fu¨ r Dermatologie und Allergologie, Philipps- dermo-epidermal basement membrane zone. The Universita¨ t Marburg, Marburg, Germany binding of circulating autoantibodies and the induc- tion of an inflammatory reaction in the area of target Abstract structures lead to loss of adhesion with subsequent intra- or subepidermal blister formation (1). The clin- Bullous skin diseases represent a group of organ-spe- ical appearance is heterogeneous and secondary cific autoimmune disorders characterised by binding eruptions such as erosions, encrustation, impetigini- of circulating autoantibodies to adhesion molecules sation, and scarred secondary erosions can dominate of the epidermis and the dermo-epidermal basement the clinical picture. Diagnosis of this organ-specific membrane zone. Binding of these autoantibodies to chronic autoimmune disease is frequently a problem. their antigenic targets results in loss of adhesion Therefore, a diagnostic concept to allow standardi- between epidermal and at the level of sation of the available examination methods (Figure the basement membrane zone. Chronic blisters and 1) was developed by the autoimmune diagnostic secondary painful erosions are the clinical hallmark working group of the United German Society for Clin- of autoimmune bullous disorders. Histopathology ical Chemistry and Laboratory Medicine (DGKL). reveals the location of blister formation and helps to classify the subtype of the bullous skin disorder. Immunofluorescence is crucial for diagnosing auto- immune bullous skin disorders. Tissue-bound History and clinical findings autoantibodies are detected by direct immuno- For the most part, bullous autoimmune dermatoses fluorescence of perilesional skin. Circulating auto- exhibit a chronic progression, in which the principal antibodies can be visualised by indirect immuno- clinical symptoms are blisters and painful secondary fluorescence using tissue substrates such as monkey erosions on the skin and mucous membranes that oesophagus and sodium chloride-split human skin. lack a tendency to heal. The most frequent adult bul- Most of the autoantigens are available as recombi- lous skin disease, the bullous (BP), dem- nant proteins, which allows for autoantibody screen- onstrates taut blisters on the torso and extremities. A ing by ELISA or immunoblot analysis to confirm the prodromal phase with pruritus and papulovesicular or primary diagnosis and, importantly, for immuno- urticarial plaques can precede the occurrence of blis- serological follow-up of patients. ters. In diseases of the group, loose fragile blisters are often no longer detectable and erosions Keywords: adhesion molecules; autoantibodies; base- with a crusty surface are frequently prominent. Table ment membrane zone; bullous skin diseases; des- 1 shows the clinical characteristics of different bullous mosomes; ELISA; immunofluorescence; sodium autoimmune dermatoses. chloride-split skin. Clinical differential diagnosis

Introduction The most important differential diagnoses of bullous autoimmune dermatoses include: a) infectious dis- Bullous autoimmune skin disorders, including some eases in connection with bacterial and viral infections; life-threatening diseases, are manifest in the skin and b) immunological causes, such as bullous drug- mucous membranes and are clinically characterised induced skin rashes or erythema exsudativum by the appearance of blisters and secondary erosions. multiforme (EEM); and c) the group of hereditary blis- ter-forming dermatoses. Table 2 summarises these 1) The German version of this article has been published in differential diagnoses. LaboratoriumsMedizin 2005;29(4):257–62. The English ver- sion of the article contains additional figures and is pub- lished in Clin Chem Lab Med with kind permission from the Classification of bullous autoimmune dermatoses authors. *Corresponding author: Dr. med. Ru¨ diger Eming, Klinik fu¨r Classification of the blister-forming autoimmune skin Dermatologie und Allergologie, Philipps-Universita¨t diseases is based on the localisation of the blister for- Marburg, Deutschhausstraße 9, 35033 Marburg, Germany Phone: q49-6421-2866280, Fax: q49-6421-2862902, mation (2). The diseases are categorised into three E-mail: [email protected] groups: those that exhibit an intra-epidermal loss of Article in press - uncorrected proof

Eming and Hertl: Autoimmune bullous disorders 145

Figure 1 Diagnosis of bullous autoimmune skin diseases.

Table 1 Clinical characteristics of bullous autoimmune skin diseases.

Disease Clinical characteristics

Pemphigus vulgaris (PV)/foliaceus (PF) Loose blisters/erosions on mucous membranes (PV) and skin (PF, PV); PF predominantly in seborrheic skin areas (PNP) Haemorrhagic stomatitis, polymorph exanthema; lichenoid efflorescences palmoplantar; frequent associations: haematologic malignoma, thymoma, Castleman tumour IgA-pemphigus Fragile, annular, rim-accentuated blisters or pustules, or crusty erosions on the skin; rarely affection of mucous membranes (BP) Urticarial, pruriginous plaques with taut blisters or erosions; intertriginous areas on the flexor side of the extremities; 10–30% involvement of the mucous membranes Pemphigoid gestationis (PG) Erythematous papules and plaques, eczema, pruritus; often 2nd or 3rd trimester Mucous membrane pemphigoid (MMP, formerly Erosions and ulcerations with atrophy of the mucous cicatricial pemphigoid, CP) membranes (beware conjunctivitis, symblephara), involvement of skin in ;25% of cases, capillitium, head, upper trunk Linear IgA bullous dermatosis (LABD/CBDC) Most frequent form in childhood; polymorph, often centrifugally grouped, pearl string-like arranged taut blisters, often mucous membrane involvement; associations: colitis ulcerosa; primary sclerosing cholangitis Epidermolysis bullosa acquisita (EBA) Mechanobullous, inflammatory and atrophic variant, frequent involvement of mucous membranes; scarring and formation of milia (DH) Accentuated excoriated papule vesicles at extensor side or small blisters; pruriginous papulae, erythematous plaques, intense pruritus; coeliac disease does not have to be clinically manifest Article in press - uncorrected proof

146 Eming and Hertl: Autoimmune bullous disorders

Table 2 Differential diagnoses of bullous skin diseases.

Disease groups Disease Clinical/diagnostic characteristics

Hereditary bullous Epidermolysis bullosa simplex Occurrence at birth or early childhood; diseases group, basal membrane bullous clinical findings according to genetic defect; epidermolysis group, dystrophic DIF and IIF negative bullous epidermolysis group Infectious diseases contagiosa Microbiology, other signs of inflammation; IF and serology negative Staphylococcal scalded-skin Most widely described epidermolysis, syndrome histology; IF and serology negative Bullous erysipelas Clinical and serological inflammation parameters; IF and serology negative HSV evidence in blister fluid; IF and serology negative Varicella zoster virus Clinical picture, general symptoms; IF and serology negative Immunological Bullous systemic IF and serology positive (anti-collagen VII-Ak), diseases erythematosus (SLE) ANA positive; other SLE criteria positive Erosive lichen ruber planus IF: subepidermal cytoid bodies, IIF negative; cutaneous involvement, hepatopathy Erythema exsudativum multiforme History; IF and serology with majus form (EEM) sometimes positive, ICS pattern (anti-desmoplakin-Ak) Bullous drug-induced exanthema EEM-like picture or laminar epidermolysis, (SJS, TEN) histology; IF and serology negative Subcorneal pustulosis (Sneddon- Leukocytosis, serologic signs of inflammation, Wilkinson) DIF and serology negative Other diseases Porphyrins in serum and urine, IF and serology negative, light-exposed areas Bullosis diabeticorum Glucose in serum/urine, IF and serology negative Traumatic/toxic blister formation History; DIF and serology negative IF, immunofluorescence; DIF, direct immunofluorescence; IIF, indirect immunofluorescence. adhesion (); those with skin-splitting in overview of this classification is given in Table 3. In the area of the basement membrane zone; and der- diagnosing bullous autoimmune skin diseases, his- matoses with damaged sublaminal adherence. An tological examination of diseased skin allows differ- entiation between intra- and subepidermal blister Table 3 Classification of bullous autoimmune skin diseases. formation. Thus, histology plays a major role in dif- ferentiating intra-epidermal (desmosomal) from sub- I. Intraepidermal loss of adhesion (desmosome) epidermal loss of adhesion. However, definitive 1. classification is not possible from histological findings 1.1. (Neumann type, Hallopeau alone. type) 1.2. Pemphigus herpetiformis 2. Direct and indirect immunofluorescence 2.1. Fogo selvagem (endemic type) 2.2. (Senear-Usher) Direct immunofluorescence The diagnosis of bul- 2.3. Pemphigus sebhorrhoicus lous autoimmune skin diseases involves immuno- 3. Paraneoplastic pemphigus histological and immunoserological tests (3). Using 4. Drug-induced pemphigus direct immunofluorescence (DIF) of perilesional skin 5. IgA pemphigus tissue-bound autoantibodies, mostly classified as IgG, 5.1. Subcorneal pustulous dermatosis 5.2. Intraepidermal neutrophile dermatosis but also including IgA (linear IgA dermatosis, IgA pemphigus, IgA-type Epidermolysis bullosa acqusita), II. Subepidermal loss of adhesion (lamina lucida/ as well as the complement factor C3, can be verified. densa) The localisation of tissue-bound autoantibodies leads 1.1. Bullous pemphigoid 1.2. Pemphigoid gestationis to characteristic fluorescent patterns, which allow 1.3. Mucous membrane pemphigoid allocation to specific entities (Figure 2). Intercellular 1.4. Other pemphigoid types reticulate (desmosomal) deposits of IgG (or IgA in IgA 2. Linear IgA- bullous dermatosis pemphigus) and complement factors (frequently C3) 2.1. Chronic bullous dermatosis of childhood are obvious in all pemphigus diseases. Linear depos- 2.2. Adult forms its of IgG and C3 in the area of the dermo-epidermal 3. Epidermolysis bullosa acquisita basement membrane zone can be found in the pem- III. Subepidermal loss of adhesion (dermal) phigoid group and Epidermolysis bullosa acqusita. 1. Dermatitis herpetiformis Duhring Linear deposits of IgA at the basal membrane are Article in press - uncorrected proof

Eming and Hertl: Autoimmune bullous disorders 147

Figure 2 Characteristic immunofluorescent pattern of tissue-bound autoantibodies with direct immunofluorescence. (A) Inter- cellular (desmosomal) deposits of IgG in diseases of the pemphigus type. (B) Linear deposits of IgG (and IgA) in the area of the basement membrane zone in pemphigoid, epidermolysis bullosa acquisita, and linear IgA dermatosis. (C) Dermatitis herpetiformis Duhring shows granular IgA deposits in the dermal papillae. characteristic of linear IgA dermatosis and are also Indirect immunofluorescence Indirect immunofluo- found in IgA-type Epidermolysis bullosa acqusita. The rescence (IIF) detects circulating serum autoantibod- DIF of Dermatitis herpetiformis Duhring shows gran- ies in patients (Figure 3A, B). In this test, monkey ular IgA deposits in the dermal papillae and occasion- oesophagus is used as a substrate for pemphigus dis- ally in the basement membrane area. eases. In certain cases, plakin-rich tissue, such as

Figure 3 (A, B) Proof of circulating autoantibodies with indirect immunofluorescence. (A) Intercellular, intraepidermal IgG (and rarely IgA) binding in pemphigus on monkey oesophagus. (B) IgA reactivity in the endomysium of smooth muscle in dermatitis herpetiformis Duhring. (C–E) Three characteristic fluorescence patterns in the so-called NaCl-split skin test. Human skin shows an artificial splitting in the area of the lamina lucida of the basement membrane zone after incubation with 1 M NaCl. (C) Pemphigoid-type IgG reactivity to autoantigens in the epidermal part (blister roof) can be seen. (D) Binding of circulating IgG autoantibodies with reactivity to the dermal area in epidermolysis bullosa acquisita. (E) Staining in the epi- dermal and dermal areas of the NaCl-split skin in scarred mucous membrane pemphigoid (anti-laminin-5-antibody). In linear IgA dermatosis, IgA reactivity occurs in the epidermal area (blister roof). Article in press - uncorrected proof

148 Eming and Hertl: Autoimmune bullous disorders

Table 4 Immunofluorescence in bullous autoimmune skin diseases.

Disease Direct Indirect Target antigens immunofluorescence immunofluorescence

Pemphigus vulgaris (PV), Intercellular IgG and C3 Intercellular IgG Dsg3 (PV), Dsg1 (PF, PV), pemphigus foliaceus (monkey oesophagus) Dsg4 (assoc. with anti- (PF) Dsg1) (seldom plakins) Paraneoplastic Intercellular IgG and C3; linear Intercellular IgG (rat bladder) Dsg1/Dsg3, plakins pemphigus IgG and C3 at the BMZ (desmoplakin, envoplakin, periplakin), BP230, 170 kDa-antigen IgA-pemphigus Intercellular IgA and C3 Intercellular IgA (monkey Desmocollin 1, Dsg1/Dsg3 oesophagus) in 50% Bullous pemphigoid Linear IgG (IgA) and C3 at the IgG epidermal (SSS) BP180, BP230 BMZ Pemphigoid gestationis Linear IgG -C3 at the BMZ IgG epidermal (SSS) BP180 (BP230) Mucous membrane Linear IgG and/or IgA and/or IgG or IgA epidermal BP180 (BP230), pemphigoid C3 at the BMZ "dermal (SSS) laminin-5, 6b4-integrin Linear IgA-bullous Linear IgA (and C3) at the IgA epidermal, where applicable LAD-1, BP180, BP230 dermatosis BMZ dermal (SSS) Epidermolysis bullosa Linear IgG and C3 at the BMZ; IgG (or IgA) and C3 dermal Collagen VII acquisita (EBA) linear IgA and C3 at the BMZ (SSS) (IgA-type EBA) Dermatitis herpetiformis Granular IgA deposits at IgA against endomysium of Epidermal dermal papillae smooth muscle cells transglutaminase (monkey oesophagus) BMZ, basement membrane zone; SSS, sodium chloride-split skin. guinea pig oesophagus or rat bladder epithelia, is to the diagnosis of bullous autoimmune dermatoses. used. The different DIF and IIF tests with their respec- The identification of autoantigens of most autoim- tive target antigens are summarised in Table 4. mune blistering skin diseases has allowed their use An additional substrate for IIF is sodium chloride- in immunoserological procedures in the last few split skin. This test is used to further differentiate years (4–8). These antigens are either prepared by pemphigoid, linear IgA dermatosis, and EBA (Figure recombination or from epidermal extracts or cultured 3C–E). Pemphigoid disease and EBA demonstrate keratinocytes. Commercial test systems are currently immunohistologically linear deposits of IgG and C3 only available for the autoantigens Dsg1/Dsg3 (pem- in the area of the dermo-epidermal basement phigus group) for the NC16A region of BP (bullous membrane zone. In addition, linear IgA deposits in the pemphigoid) and for tissue transglutaminase (der- area of the basement membrane zone are character- matitis herpetiformis). A type VII-collagen has been istic of linear IgA dermatosis, but can also be found described for EBA, but is not commercially available in the IgA variant of EBA. For the sodium chloride (9). Therefore, dermal protein extracts for immuno- split-skin test, human skin is incubated in 1 M NaCl blot analysis are used for proof of autoantibodies in solution, so that an artificial split is induced in the EBA. Furthermore, specialised laboratories, including area of the lamina lucida of the basement membrane the Departments of Dermatology in Marburg, Frei- zone. This splitting separates pemphigoid autoanti- burg, and Lu¨ beck, carry out additional serological gens from those of EBA. Sera of pemphigoid patients tests in the form of ELISAs, immunoblots, and immu- typically show IgG binding to target antigens in the noprecipitation with recombinant and native varieties area of the blister roof (epidermal part), whereas sera of the autoantigens Dsg1/Dsg3, BP180/BP230 and of patients with EBA show IgG reactivity at the base laminin-5 (10–12). of the blister (dermal part). IgA autoantibodies can be verified in 60–70% of patients with linear IgA der- Diagnostic course matosis, with a reactivity to autoantigens in the epi- dermal area of the NaCl-split skin. A specific The current immunoserologic course of tests com- characteristic of sera from patients with mucous monly used is based on recent developments in the membrane pemphigoid is that laminin-5 (epiligrin)- diagnostic field of bullous autoimmune skin diseases. reactive sera show reactivity to the epidermal and ELISA tests are at present the most important method dermal parts of the NaCl-split skin, where the IgG for diagnosis. A correlation between disease activity reactivity shows a typical pattern at the blister base. and antibody titres was verified, especially for pem- phigus and pemphigoid diseases (13). The frequency Immunoserological tests with recombinant of serological controls during the disease course autoantigens or autoantigen extracts mainly depends on the clinical picture. In phases of active disease, monitoring of autoantibodies is rec- ELISA and immunoblot tests with recombinant and ommended every 4 weeks. With stable skin condi- purified native autoantigens are an important addition tions, quarterly check-ups seem reasonable. Article in press - uncorrected proof

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Fundamentally there are three goals. In the first (IgG1, IgG4, IgA, IgE) against desmoglein 3 in patients instance, ELISA tests, as well as semi-quantitative with acute onset and chronic pemphigus vulgaris. Br J immunoblots and immunoprecipitation, allow a cor- Dermatol 2001;144:1183–8. 8. relation between the clinical picture and the extent of Thoma-Uszynski S, Uter W, Schwietzke S, Hofmann SC, Hunziker T, Bernard P, et al. BP230 and BP180 auto- the antibody titre. Secondly, these examination meth- antibodies in bullous pemphigoid. J Invest Dermatol ods allow characterisation of the autoantibody sub- 2004;122:1413–22. classes. In the acute stages of pemphigus disease 9. Chen M, Chan LS, Cai X, O’Toole EA, Sample JC, Wood- there is already evidence that besides IgG4, desmo- ley DT. Development of an ELISA for rapid detection of glein-reactive autoantibodies of the class IgG1 can be anti-type VII collagen autoantibodies in epidermolysis detected, as well as sporadic detection of IgE (7). bullosa acquisita. J Invest Dermatol 1997;108:68–72. Thirdly, characterisation of the epitope specificity of 10. Haase C, Bu¨ dinger L, Borradori L, Yee C, Merk HF, Yan- autoantibodies is possible (14, 15). Therefore, immu- cey K, et al. Detection of IgG autoantibodies in the sera noserology not only confirms diagnosis, but also of patients with bullous and : ELISA studies utilizing a baculovirus-encoded form of provides a better understanding of the immuno- bullous pemphigoid antigen 2. J Invest Dermatol 1998; pathogenesis of these diseases. 110:282–6. 11. Hofmann SC, Thoma-Uszynski S, Hunziker T, Bernard P, Koebnick C, Stauber A, et al. Severity and phenotype of References bullous pemphigoid relate to autoantibody profile against the NH2- und COOH-terminal regions of BP180 ectodomain. J Invest Dermatol 2002;119:1065–73. 1. Sitaru C, Zillikens D. Mechanisms of blister induction by 12. Bekou V, Thoma-Uszynski S, Wendler O, Uter W, autoantibodies. Exp Dermatol 2005;14:861–75. Schwietzke S, Hunziker T, et al. Detection of laminin 5- 2. Hertl M. Humoral and cellular autoimmunity in autoim- specific auto-antibodies in mucous membrane and bul- mune bullous skin disorders. Int Arch Allergy Immumol lous pemphigoid sera by ELISA. J Invest Dermatol 2000;122:91–100. 2005;124:732–40. 3. Hertl M, Schuler G. Bullous autoimmune dermatoses. 3: 13. Amagai M, Komai A, Hashimoto T, Shirakata Y, Hashi- Diagnosis and therapy Hautarzt 2002;53:352–66. mito K, Yamada T, et al. Usefulness of enzyme-linked 4. Chorzelski TP, Sulej J, Tchorzewska H, Jablonska S, Beut- immunosorbent assay using recombinant desmogleins ner EH, Kumar V. IgA class endomysium antibodies in 1 and 3 for serodiagnosis of pemphigus. Br J Dermatol dermatitis herpetiformis and coeliac disease. Ann NY Acad Sci 1983;4:325–34. 1999;140:351–7. 5. Zillikens D, Rose PA, Balding SD, Liu Z, Olague-Marchan 14. Sekiguchi M, Futei Y, Fujii Y, Iwasaki T, Nishikawa T, M, Diaz L, et al. Tight clustering of extracellular BP180 Amagai M. Dominant autoimmune epitopes recognized epitopes recognized by bullous pemphigoid autoantibod- by pemphigus antibodies map to the N-terminal ies. J Invest Dermatol 1997;109:573–9. adhesive region of desmogleins. J Immunol 2001;167: 6. Dieterich W, Laag E, Bruckner-Tuderman L, Reunala T, 5439–48. Karpati S, Zagoni T, et al. Antibodies to tissue transglu- 15. Hacker-Foegen MK, Janson M, Amagai M, Fairley JA, taminase as serologic markers in patients with dermatitis Lin MS. Pathogenicity and epitope characteristics of anti- herpetiformis. J Invest Dermatol 1999;113:133–6. desmoglein-1 from pemphigus foliaceus patients 7. Spa¨ th S, Riechers R, Borradori L, Zillikens D, Bu¨ dinger L, expressing only IgG1 autoantibodies. J Invest Dermatol Hertl M. Detection of autoantibodies of various subclasses 2003;121:1373–8.