![DOI: 10.1111/j.1610-0387.2011.07809.x Academy 927
© The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2011/0911 JDDG | 11˙2011 (Band 9)
Section Editor
Prof. Dr. Jan C.Simon,
Leipzig
Keywords
• autoantibodies
• immune serology
• immunosuppressive agents
• immunfluorescence microscopy
• immunoadsorption
• rituximab
• high-dose immunglobulins
JDDG; 2011 • 9:927–947 Submitted:22.6.2011 | Accepted:22.8.2011
CME
Autoimmune bullous skin diseases.
Part 2: diagnosis and therapy
Andrea Kneisel,Michael Hertl
Department of Dermatology and Allergy,University Clinic Marburg,Germany
Summary
Autoimmune bullous skin diseases represent a heterogenous group of disor-
ders of skin and mucosa which are commonly associated with IgG or IgA
autoantibodies against distinct adhesion molecules of the skin.The antibody-
induced loss of adhesion between epidermis and dermis results in blister for-
mation and extensive erosions. There is a great need for rapidly establishing
the diagnosis of these disorders since they may run a severe and potentially
life-threatening course. In addition, because of their rarity and heterogeneous
symptoms, autoimmune bullous skin diseases often pose a major diagnostic
challenge.While histopathological examinations provide evidence for the level
of blister formation, immunofluorescence microscopy has been established to
identify tissue-bound and circulating autoantibodies. Direct immunofluores-
cence microscopy represents the gold standard for detecting tissue-bound
autoantibodies. Indirect immunofluorescence microscopy with defined tissue
substrates is considered the first step in detecting circulating autoantibodies.
Confirmatory tests such as ELISA, immunoblot or immunoprecipitation analy-
ses are performed utilizing recombinant proteins or keratinocyte extracts.The
later assays can be used for primary diagnosis as well as for immunoserological
follow-up. Systemic immunosuppressive drugs usually represent the main
therapeutic regimen. Initially, systemic corticosteroids are commonly adminis-
tered in combination with steroid-sparing, immunosuppressive agents. Novel
targeted treatments such as immunoadsorption, rituximab or high-dose intra-
venous immunoglobulins have proven to be highly effective in severe and
refractory pemphigus. This review presents a state-of-the-art algorithm for
making the diagnosis of autoimmune bullous disorders and provides an
overview on currently available therapeutic options.
1 Diagnosis
Due to the frequently heterogeneous clinical features it is often not possible to make
an exact diagnosis of autoimmune bullous dermatoses solely on the basis of clinical
findings. On the contrary, various diagnostic techniques including direct and indi-
rect immunofluorescence microscopy as well as immune serology are employed.
Depending on the location of the autoantigens intraepidemal or subepidermal loss of
adhesion results which often but not always explains the clinical findings (Figure 1).
Only the overall view of these tests can lead to the final diagnosis in the end (Table 1
and Figure 2) [1]. For a targeted securing of the diagnosis a generally valid step-by-
step diagnostic approach is recommendable (Figure 3). All diagnostics include first a](https://image.slidesharecdn.com/autoimmunebullousskindiseases-240408025347-31f7a04f/85/Autoimmune-bullous-skin-diseases-diagnosis-and-therapy-pdf-1-320.jpg)
![928 Academy
JDDG | 11˙2011 (Band 9) © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2011/0911
Figure 1: Schematic representation of autoantigens of autoimmune bullous disorders (modified from
Rose et al. 2007). With the pemphigus group of diseases, the production of autoantibodies against
structural antigens of the desmosome (desmoglein 1 and 3, desmocollins) results in intraepidermal
loss of adhesion. Conditions showing subepidermal loss of adhesion are characterized by the produc-
tion of autoantibodies against hemidesmosomal proteins (BP180, BP230, ␣64-integrin, laminin
332, laminin ␥1), anchoring filament proteins (collagen VII), protease inhibitors (A2ML1) or
enzymes (epidermal transglutaminase).
comprehensive history and recording of clinical findings with inspection of the skin
and neighboring mucous membranes. Using the example of two clinical manifesta-
tions of bullous skin diseases (with and without mucous membrane involvement) the
diagnostic procedure leading to the final diagnosis is depicted in the form of algo-
rithms (Figure 4 and 5). After taking history and recording clinical findings skin
biopsies are performed for histology and direct immunofluorescence microscopy.
1.1 Histology
Histological examination serves only as orientation as to the level of loss of adhesion
(intraepidermal or subepidermal) as well as for characterization of the cutaneous
inflammatory infiltrate. The tissue biopsy should include in addition to a fresh blister
healthy skin also in order to prevent separation of the skin during processing (Figure 6).
1.1.1 Histology of the pemphigus diseases
The group of pemphigus diseases is characterized histologically by an intraepidermal
loss of adhesion. In pemphigus vulgaris in addition to the intraepidermal, suprabasal
acantholysis, i. e. loss of keratinocyte adhesion, sometimes what is termed a “tomb-
stone effect” of residual basal keratinocytes on the dermo-epidermal junction zone
(floor of blister) is seen (Figure 2) [2]. In older blisters neutrophilic and eosinophilic
granulocytes are detected, further a scant perivascular round cell infiltrate is found in
the upper dermal vascular plexus.
Histologically pemphigus foliaceus reveals a superficial, not always visible subcorneal
acantholysis in the upper stratum spinosum or granulosum. Further, a slight inflam-
matory infiltration of the upper dermis is present.
An interface dermatitis with vacuolar degeneration of basal keratinocytes and
keratinocyte necroses with slight acantholysis are seen histologically in paraneoplastic
pemphigus. In addition, a lichenoid infiltration is found in the vicinity of the dermo-
epidermal junction zone.
IgA pemphigus is characterized histologically by an intraepidermal or subcorneal infil-
tration of neutrophils; classical signs of acantholysis are usually missing.
1.1.2 Histology of disease with subepidermal loss of adhesion
In the pemphigoid diseases subepidermal loss of adhesion is detected histologically.
The cell-rich variety of bullous pemphigoid reveals subepidermal blistering with a
Histological examination serves as ori-
entation as to the level of loss of adhe-
sion as well as the inflammatory infil-
trate.
Pemphigus diseases are characterized
histologically by an intraepidermal
loss of adhesion.
Pemphigus vulgaris histologically dis-
plays suprabasal acantholysis with
a “tombstone effect” of basal ker-
atinocytes.
IgA pemphigus reveals an intraepider-
mal or subcorneal infiltration of neu-
trophils histologically.
In the pemphigoid diseases subepi-
dermal loss of adhesion is detected
histologically.](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)
Recommended
More Related Content
Similar to Autoimmune bullous skin diseases. diagnosis and therapy.pdf
Similar to Autoimmune bullous skin diseases. diagnosis and therapy.pdf (20)
Recently uploaded
Recently uploaded (20)
Autoimmune bullous skin diseases. diagnosis and therapy.pdf
- 1. DOI: 10.1111/j.1610-0387.2011.07809.x Academy 927 © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2011/0911 JDDG | 11˙2011 (Band 9) Section Editor Prof. Dr. Jan C.Simon, Leipzig Keywords • autoantibodies • immune serology • immunosuppressive agents • immunfluorescence microscopy • immunoadsorption • rituximab • high-dose immunglobulins JDDG; 2011 • 9:927–947 Submitted:22.6.2011 | Accepted:22.8.2011 CME Autoimmune bullous skin diseases. Part 2: diagnosis and therapy Andrea Kneisel,Michael Hertl Department of Dermatology and Allergy,University Clinic Marburg,Germany Summary Autoimmune bullous skin diseases represent a heterogenous group of disor- ders of skin and mucosa which are commonly associated with IgG or IgA autoantibodies against distinct adhesion molecules of the skin.The antibody- induced loss of adhesion between epidermis and dermis results in blister for- mation and extensive erosions. There is a great need for rapidly establishing the diagnosis of these disorders since they may run a severe and potentially life-threatening course. In addition, because of their rarity and heterogeneous symptoms, autoimmune bullous skin diseases often pose a major diagnostic challenge.While histopathological examinations provide evidence for the level of blister formation, immunofluorescence microscopy has been established to identify tissue-bound and circulating autoantibodies. Direct immunofluores- cence microscopy represents the gold standard for detecting tissue-bound autoantibodies. Indirect immunofluorescence microscopy with defined tissue substrates is considered the first step in detecting circulating autoantibodies. Confirmatory tests such as ELISA, immunoblot or immunoprecipitation analy- ses are performed utilizing recombinant proteins or keratinocyte extracts.The later assays can be used for primary diagnosis as well as for immunoserological follow-up. Systemic immunosuppressive drugs usually represent the main therapeutic regimen. Initially, systemic corticosteroids are commonly adminis- tered in combination with steroid-sparing, immunosuppressive agents. Novel targeted treatments such as immunoadsorption, rituximab or high-dose intra- venous immunoglobulins have proven to be highly effective in severe and refractory pemphigus. This review presents a state-of-the-art algorithm for making the diagnosis of autoimmune bullous disorders and provides an overview on currently available therapeutic options. 1 Diagnosis Due to the frequently heterogeneous clinical features it is often not possible to make an exact diagnosis of autoimmune bullous dermatoses solely on the basis of clinical findings. On the contrary, various diagnostic techniques including direct and indi- rect immunofluorescence microscopy as well as immune serology are employed. Depending on the location of the autoantigens intraepidemal or subepidermal loss of adhesion results which often but not always explains the clinical findings (Figure 1). Only the overall view of these tests can lead to the final diagnosis in the end (Table 1 and Figure 2) [1]. For a targeted securing of the diagnosis a generally valid step-by- step diagnostic approach is recommendable (Figure 3). All diagnostics include first a
- 2. 928 Academy JDDG | 11˙2011 (Band 9) © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2011/0911 Figure 1: Schematic representation of autoantigens of autoimmune bullous disorders (modified from Rose et al. 2007). With the pemphigus group of diseases, the production of autoantibodies against structural antigens of the desmosome (desmoglein 1 and 3, desmocollins) results in intraepidermal loss of adhesion. Conditions showing subepidermal loss of adhesion are characterized by the produc- tion of autoantibodies against hemidesmosomal proteins (BP180, BP230, ␣64-integrin, laminin 332, laminin ␥1), anchoring filament proteins (collagen VII), protease inhibitors (A2ML1) or enzymes (epidermal transglutaminase). comprehensive history and recording of clinical findings with inspection of the skin and neighboring mucous membranes. Using the example of two clinical manifesta- tions of bullous skin diseases (with and without mucous membrane involvement) the diagnostic procedure leading to the final diagnosis is depicted in the form of algo- rithms (Figure 4 and 5). After taking history and recording clinical findings skin biopsies are performed for histology and direct immunofluorescence microscopy. 1.1 Histology Histological examination serves only as orientation as to the level of loss of adhesion (intraepidermal or subepidermal) as well as for characterization of the cutaneous inflammatory infiltrate. The tissue biopsy should include in addition to a fresh blister healthy skin also in order to prevent separation of the skin during processing (Figure 6). 1.1.1 Histology of the pemphigus diseases The group of pemphigus diseases is characterized histologically by an intraepidermal loss of adhesion. In pemphigus vulgaris in addition to the intraepidermal, suprabasal acantholysis, i. e. loss of keratinocyte adhesion, sometimes what is termed a “tomb- stone effect” of residual basal keratinocytes on the dermo-epidermal junction zone (floor of blister) is seen (Figure 2) [2]. In older blisters neutrophilic and eosinophilic granulocytes are detected, further a scant perivascular round cell infiltrate is found in the upper dermal vascular plexus. Histologically pemphigus foliaceus reveals a superficial, not always visible subcorneal acantholysis in the upper stratum spinosum or granulosum. Further, a slight inflam- matory infiltration of the upper dermis is present. An interface dermatitis with vacuolar degeneration of basal keratinocytes and keratinocyte necroses with slight acantholysis are seen histologically in paraneoplastic pemphigus. In addition, a lichenoid infiltration is found in the vicinity of the dermo- epidermal junction zone. IgA pemphigus is characterized histologically by an intraepidermal or subcorneal infil- tration of neutrophils; classical signs of acantholysis are usually missing. 1.1.2 Histology of disease with subepidermal loss of adhesion In the pemphigoid diseases subepidermal loss of adhesion is detected histologically. The cell-rich variety of bullous pemphigoid reveals subepidermal blistering with a Histological examination serves as ori- entation as to the level of loss of adhe- sion as well as the inflammatory infil- trate. Pemphigus diseases are characterized histologically by an intraepidermal loss of adhesion. Pemphigus vulgaris histologically dis- plays suprabasal acantholysis with a “tombstone effect” of basal ker- atinocytes. IgA pemphigus reveals an intraepider- mal or subcorneal infiltration of neu- trophils histologically. In the pemphigoid diseases subepi- dermal loss of adhesion is detected histologically.
- 3. Academy 929 © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2011/0911 JDDG | 11˙2011 (Band 9) Table 1: Diagnostic characteristics of autoimmune bullous skin disorders (Abbreviations: DEJ: dermo-epidermal junction; Dsg: desmoglein; Dsc: desmocollin; SSS: salt- split human skin). 1 IgG autoantibodies if not otherwise mentioned. *Euroimmun AG (www.euroimmun.de) or MBL International (www.mblintl.com). **Available in specialized laboratories: Marburg: http://www.uni-marburg.de/fb20/dermallergo/autoimmunerkrankungen; Lübeck: http://www.derma.uni-luebeck.de/Infos+f%C3% BCr+%C3%84rzte/Autoimmunlabor.html; Freiburg: http://www.uniklinik-freiburg.de/; Würzburg: http://hautklinik.uk-wuerzburg.de/labor-fuer-autoimmundiagnostik. html. Intraepidermal loss of adhesion Diagnosis Clinical findings Histology DIF IIF Autoantigen 1 Pemphigus vulgaris (PV) Initial symptom: painful mucous membrane erosions, fragile blisters, erosions and crusts direct and indirect Nikolski signs positive Intraepidermal suprabasal acantholysis, occasionally “tombstone pattern” Intercellular IgG and C3 Monkey esophagus: intercellular IgG Dsg3* Dsg1* (Dsg4) Acetylcholine receptor Dsc1-3** Pemphigus foliaceus (PF) Fragile blisters and puff pastry-like scale in seborrheic areas Superficial subcorneal acantholysis Intercellular IgG and C3 See pemphigus vulgaris Dsg1* (Dsg4) Plakins Paraneoplastic pemphigus (PNP) Polymorphic features: hemorrhagic stomatitis, palmoplantar lichenoid exanthems, blisters favoring the trunk, partly multiforme-like Interface dermatitis, lichenoid infiltrate of the DEJ, keratinocyte necroses See pemphigus vulgaris, additionally IgG and C3 along the DEJ See pemphigus vulgaris IIF on plakin-rich substrates (monkey or rat urothelium) Dsg3* (IgG, IgA) Dsg1* Desmoplakin I and II Envoplakin* Periplakin (IgG, IgA) A2ML1 (170 kDa protein) Plektin, Dsc1-3** BP230* Drug-induced pemphigus See p. foliaceus rarely mucous membrane involvement See pemphigus vulgaris See pemphigus vul- garis See pemphigus vulgaris Dsg1* Dsg3* IgA pemphigus Intraepidermal neutrophilic dermatosis Fragile blisters and pustules, annular plaques with collarette-like scaling Intraepidermal infiltration by neutrophils Usually without classical acantholysis Intercellular IgA and C3 Intercellular IgA Dsg1* (IgA) Dsg3* (IgA) Subcorneal pustular dermatosis Subcorneal infiltration by neutrophils Dsc1** (IgA) Continued
- 4. 930 Academy JDDG | 11˙2011 (Band 9) © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2011/0911 Table 1: Continued. Subepidermal loss of adhesion Diagnosis Clinical findings Histology DIF IIF Autoantigen 1 Bullous pemphigoid (BP) Pruritus, tense blisters, erosions and crusts, urticarial, prurigo-like or eczematous plaques Subepidermal blistering cell-rich variety: marked inflammatory infiltrate (especially eosinophils) Linear C3 and IgG along the DEJ (IgM, IgA) Monkey esophagus: linear IgG SSS: epidermal linear IgG BP180* (=collagen XVII) BP230* Pemphigoid gesta- tionis Usually periumbilical start grouped, in part target lesion-like plaques, vesicles, pruritus, erythemas Subepidermal blistering tissue eosinophilia Linear C3 along the DEJ (IgG, IgA, IgM) Monkey esophagus: linear IgG SSS: epidermal linear IgG BP180* (BP230)* Mucous membrane pemphigoid Erosions and ulcerations of the mucous membranes, scarring, strictures, atrophy eye: symblepharon Subepidermal blistering fibrosis during the course Linear IgG and C3 along the DEJ (IgA, IgM) Monkey esophagus: linear IgG, IgA SSS: epidermal and dermal linear IgG (IgA) BP180* (IgG and IgA) Laminin 332** (=laminin 5) (BP230)* ␣6-integrin 4-integrin Lichen planus pemphigoides (LPP) Features of lichen planus and bullous pemphigoid blisters even on unaltered skin Lichenoid papule: histology of lichen planus blister: see bullous pemphigoid Linear IgG and C3 IgM: cytoid bodies SSS: epidermal linear IgG BP180* rarely BP230* Anti-laminin ␥1 pemphigoid Erythematous plaques and tense blisters on the trunk Subepidermal cleavage Linear IgG and C3 along the DEJ Monkey esophagus: linear IgG SSS: dermal linear IgG Laminin ␥1 chain** (200 kDa protein) Linear IgA dermatosis (LAD, LABD) Pearl necklace-like grouped blisters, annular lesions mucous membrane involvement Histology not diagnostic subepidermal blisters occasionally intrapapillary microabscesses Linear IgA and C3 along the DEJ Monkey esophagus: linear IgA SSS: epidermal or dermal linear IgA LAD-1** (97 or 170 kDa protein) (IgA) BP180* (IgA) BP230* (IgA) Epidermolysis bullosa acquisita (EBA) Mechanobullous variety with blis- ters at mechanically stressed sites inflammatory and atrophic variety mucous membrane involvement Subepidermal blistering with neutrophilic infiltrate in the dermal papillae Linear IgG, C3 (IgA) along the DEJ Monkey esophagus: linear IgG SSS: dermal linear IgG (IgA) Collagen type VII** (IgG, more rarely IgA) Dermatitis herpeti- formis (Duhring disease) (DHD) Burning pruritus, grouped excoriated papulovesicles with extensor surface and gluteal accentuation Subepidermal blistering papillary abscesses with neutrophils (pathognomic) Fine granular IgA and C3 focally in the tips of the papillae or granular- linear along the DEJ Monkey esophagus: IgA against endomysium Epidermal transglutami- nase* (cross reaction with tissue transglutaminase)
- 5. striking inflammatory infiltrate consisting predominantly of eosinophils, but also including lymphocytes and neutrophils. In the cell-poor variety the inflammatory infiltrate is correspondingly slight; a linear distribution of leukocytes and nuclear debris is found in the dermo-epidermal junction zone. Eosinophils are found within the blister as well as in the edematous papillary dermis (Figure 2). Pemphigus gestationis also displays subepidermal blistering with tissue eosinophilia. Mucous membrane pemphigoid is characterized histologically by in addition to subepi- dermal blistering and inflammatory infiltration of the upper dermis detection of tissue fibrosis during the course. Depending on the biopsy site, lichen planus pemphigoides displays either histological features of lichen planus with interface dermatitis, saw-tooth pattern acanthosis, hypergranulosis and a band-like lymphohistiocytic infiltrate below the epidermis, or findings resembling bullous pemphgoid (see above). Linear IgA dermatosis has less characteristic features histologically with subepidermal blistering as well as an infiltrate of lymphocytes and neutrophils; sometimes intra- papillary microabscesses are present. In anti-laminin ␥1 (anti-p200) pemphigoid subepidermal blistering with a diffuse neu- trophilic inflammatory infiltrate of the dermo-epidermal junction zone is also seen. Academy 931 © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2011/0911 JDDG | 11˙2011 (Band 9) Bullous pemphigoid histologically reveals subepidermal blistering with an inflammatory infiltrate rich in eosinophils. Figure 2: Diagnosis of autoimmune bullous skin diseases (abbreviations: DIF: direct immunofluorescencemicroscopy; IIF: indirect immunofluorescence microscopy; SSS: salt-split skin [sodium chloride-split skin]; DEJ: dermo-epidermal junction zone). 1 IgA autoantibodies. Pemphigus vulgaris: fragile blisters and erosions, intraepidermal suprabasal acantholysis with “tombstone appearance”, intercellular pattern of IgG (DIF and IIF). Pemphigus foliaceus: puff pastry-like scale formation, superficial subcorneal acantholysis, DIF and IIF as in pemphigus vulgaris. Bullous pemphigoid: tense blisters, subepidermal blister formation with eosinophilic infiltrate, linear deposition of IgG along the DEJ (DIF and IIF), epidermal staining (SSS). Linear IgA bullous dermatosis: annular, centrally excoriated lesions, subepidermal blister formation with intrapapillary microabscesses, linear IgA deposits along the DEJ (DIF and IIF), epidermal staining (SSS). Epidermolysis bullosa acquisita: nail dystrophy, mucosal involvement, subepidermal blister forma- tion with intrapapillary neutrophilic infiltrate, linear IgG deposits along the DEJ (DIF and IIF), dermal staining (SSS). Dermatitis herpetiformis: grouped excoriated papulovesicles, subepidermal blister formation with intrapapillary microabscesses, granular-linear deposition of IgA along the DEJ (DIF), IgA staining of the endomysium (IIF).
- 6. Epidermolysis bullosa acquisita also demonstrates subepidermal blisters with inflam- matory infiltration of the papillary dermis consisting primarily of neutrophilic gran- ulocytes and mononuclear cells. Dermatitis herpetiformis in the urticarial stage displays an unspecific neutrophilic infiltrate in the upper and mid dermis. The blistering stage is characterized by pathognomonic papillary abscesses consisting of neutrophils and eosinophils. Further, subepidermal blistering as well as migration of granulocytes into the blister as well as necroses of basal epidermal cells can be detected (Figure 2). 1.2 Direct immunofluorescence microscopy Direct immunofluorescence microscopy is still considered the gold standard in the diagnostics of autoimmune bullous disorders. Only so can tissue-bound autoim- mune reactants be demonstrated. The location of the biopsy site is of key importance to achieve best possible sensitivity. As immunoglobulins and complement factors are degraded by the inflammatory reaction and are thus no longer detectable directly in the blister, the biopsy should be taken from normally appearing skin in the immedi- ate vicinity of a fresh blister (Figure 6). The tissue specimen for direct immunofluo- rescence microscopy should also not be fixed in formalin, but be frozen in native form or stored in physiologic saline solution or what is termed Michel’s solution [3]. The specific type and location of the tissue-bound autoantibodies results in charac- teristic fluorescence patterns that frequently allow for an initial diagnostic classifica- tion (Figure 2). 1.2.1 Direct immunofluorescence microscopy in pemphigus diseases All diseases of the pemphigus group demonstrate intercellular (= net-like) deposits in the epidermis in direct immunofluorescence. While an accentuation of the suprabasal epidermis is seen in pemphigus vulgaris, accentuation of the subcorneal epidermis is found in pemphigus foliaceus. In paraneoplastic pemphigus additional band-like deposits are detected in the dermo-epidermal junction zone. The class of autoantibody is also of diagnostic relevance. In pemphigus vulgaris, pemphigus foli- aceus as well as paraneoplastic pemphigus mainly deposits of IgG as well as comple- ment deposits (C3) are present; in IgA pemphigus deposits of IgA predominate. 932 Academy JDDG | 11˙2011 (Band 9) © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2011/0911 In dermatitis hepetiformis papillary abscesses are pathognomonic. Direct immunofluorescence microscopy is considered the gold standard in the diagnostics of autoimmune bullous disorders. For direct immunofluorescence mi- croscopy the biopsy should be taken from normally appearing skin in the im- mediate vicinity of a fresh blister. The tissue specimen for direct immuno- fluorescence microscopy should be frozen in native form or stored in physio- logic saline solution or Michel’s solution. Pemphigus diseases demonstrate in- tercellular deposits in the epidermis in direct immunofluorescence microscopy. Figure 3: Diagnostic algorithm for autoimmune bullous skin diseases (abbreviations: IB: immunoblot, IP: immunoprecipitation).
- 7. Academy 933 © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2011/0911 JDDG | 11˙2011 (Band 9) Figure 4: Diagnostic algorithm in cutaneous and mucosal involvement (abbreviations: DEJ: dermo-epidermal junction zone; Dsg: desmoglein; LAD-1: soluble ectodomain of BP180; SH: mucous membrane). 1 In paraneoplastic pemphigus additionally linear deposition along the DEJ. 2 In suspected case of paraneoplastic pemphigus indirect immunofluorescencemicroscopy on plakin-rich substrates, e.g. monkey or rat bladder. 3 In linear IgA bullous dermato- sis dermal staining of salt-split skin possible. 4 Dermal staining can also be found in anti-laminin ␥1 (anti-p200)-pemphigoid. Figure 5: Diagnostic algorithm in exclusive cutaneous involvement (abbreviations: DEJ: dermo-epidermal junction zone; Dsg: desmoglein; LAD-1: solu- ble ectodomain of BP180; SH: mucous membrane). 1 In linear IgA bullous dermatosis dermal staining of salt-split skin possible. 2 Dermal staining can also be found in anti-laminin ␥1 (anti-p200) pemphigoid.
- 8. 1.2.2 Direct immunofluorescence microscopy in diseases with subepidermal loss of adhesion Autoimmune bullous disorders with subepidermal loss of adhesion are characterized in direct immunofluorescence microscopy in most cases by linear deposits along the dermo-epidermal junction zone. In bullous pemphigoid, pemphigoid gesationis, mucous membrane pemphigoid, lichen planus pemphigoides, anti-laminin ␥1 pem- phigoid as well as epidermis bullosa acquisita deposits of complement C3 as well as IgG predominate. In rare cases deposits of IgM and IgA have also been reported. In lichen planus pemphigoides “cytoid bodies” are also seen in the dermo-epidermal junction zone just as in lichen planus. Linear IgA dermatosis is characterized by lin- ear deposits mainly of IgA. In dermatitis herpetiformis fine granular deposits of IgA and C3 are found focally at the tips of the papillae or in a granular linear pattern along the dermo-epidermal junction zone as well as along dermal blood vessels (Figure 2). 1.3 Indirect immunofluorescence microscopy While direct immunofluorescence microscopy detects tissue-bound antibodies, indi- rect immunofluorescence microscopy serves to detect circulating autoantibodies in patient serum. In most cases monkey esophagus is employed as substrate. To detect autoantibodies in plakin-rich tissue, e. g. in paraneoplastic pemphigus, monkey or rat urothelium or guinea pig esophagus is used in addition. The patterns in indirect immunofluorescence microscopy usually resemble those in indirect immunofluores- cence microscopy. The lower sensitivity must, however, be taken into consideration. For example in IgA pemphigus circulating intercellular IgA autoantibodies can be detected in only about 50 % of cases. Dermatitis herpetiformis represents a peculiar- ity. Indirect immunofluorescence microscopy using monkey esophagus reveals IgA reactivity with the endomysium of smooth muscle cells. For the group of autoimmune bullous dermatoses with subepidermal loss of adhe- sion indirect immunofluorescence on salt-split human split-thickness skin provides for another diagnostic tool in the algorithm (Figure 3). Incubation of human skin in 1 M NaCl solution results in an artificial split at the level of the lamina lucida of the dermo-epidermal junction zone. This split-skin examination allows for the differen- tiation between bullous pemphigoid, and epidermocylysis bullosa acquisita as well as anti-laminin ␥1 pemphigoid depending on the location of the autoantigens. In bullous pemphigoid linear fluorescence is seen on the epidermal side of the split, while in epi- dermolysis bullosa acquisita, but also anti-laminin ␥1 pemphigoid linear fluorescence is seen on the dermal side (Figure 1). Mixed fluorescence both on the epidermal as 934 Academy JDDG | 11˙2011 (Band 9) © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2011/0911 In linear IgA dermatosis linear de- posits of IgA are observed in direct im- munofluorescence. Dermatitis herpetiformis demonstrates fine granular deposits of IgA focally at the tips of the papillae or in a granular- linear pattern. Indirect immunofluorescence mi- croscopy serves to detect circulating autoantibodies in patient serum. In paraneoplastic pemphigus plakin- rich tissue (e.g.urothelium) is used. In dermatitis herpetiformis indirect immunofluorescence microscopy re- veals IgA reactivity with endomysium. In bullous pemphigoid linear fluores- cence is found on the epidermal side, in epidermolysis bullosa acquisita and anti-laminin ␥1 pemphigoid on the dermal side of the split in salt-split skin. Figure 6: Optimal site for diagnostic biopsy. Histopathological examinations: In an extensive bulla parts of the blister as well as unaffected skin should be taken, a small blister should be taken completely. Direct immunofluorescence microscopy: taking of perilesional skin.
- 9. well as on the dermal side has been reported in mucous membrane pemphigoid (laminin 332) and in linear IgA dermatosis. 1.4 Serological confirmatory tests (ELISA, immunoblot, immunoprecipitation) As a final and in many cases definitive step in the diagnostic algorithm of autoim- mune bullous dermatoses serological confirmatory tests in the form of ELISA, immunoblot or immunoprecipitation are available. Due to the increasing availabili- ty of epidermal extracts of cultivated keratinocytes or recombinant autoantigens, the diagnostic spectrum of autoimmune bullous skin diseases has been expanded consid- erably in recent years and has gained both in sensitivity as well as specificity. In the meantime various test systems, among others, to detect IgG or IgA autoantibodies against desmoglein 1, desmoglein 3, BP180, BP230, tissue transglutaminase (e. g. MBL, Japan, and Euroimmun, Lübeck, Germany) as well as against envoplakin (e. g. Euroimmun, Lübeck, Germany) and laminin ␥1 (e. g. USCN Life Science Inc., Wuhan, China) are available commercially. The laminin ␥1 ELISA must yet be vali- dated clinically. 1.4.1 Serological confirmatory tests in pemphigus diseases Diseases of the pemphigus group ares characterized by the occurrence of autoanti- bodies against desmosomal structure proteins (Figure 1). By identification of their autoantigens the diseases of the pemphigus group can be classified more closely not only on the basis of the clinical phenotype but also on the basis of the specific anti- body profile [2]. In pemphigus vulgaris with exclusive mucosal involvement desmoglein 3 autoantibodies can be detected, while in the mucocutaneous variety of pemphigus vulgaris both desmoglein 3 as well as desmoglein 1 autoantibodies can be detected [4]. As the autoantibody titer usually correlates with clinical activity, desmoglein 1 and desmoglein 3 ELISA are particularly suited for follow-up. It also could be shown that in acute disease autoantibodies of the IgG4 as well as IgE class predominate, while in chronic disease both IgG4 as well as IgG1 autoantibodies against desmoglein 3 can be detected [5]. At present analysis of autoantibody sub- types has not yet entered routine clinical practice. Further, acetylcholine receptors have been reported as autoantigens in pemphigus vulgaris, but these, nonetheless, possess unclear pathogenetic relevance. In pemphigus foliaceus with exclusive involve- ment of cornified skin autoantibodies against desmoglein 1, but not against desmoglein 3 or against plakins can be detected, with the latter also having an unclear pathogenic role. In pemphigus erythematosus in many cases antinuclear antibodies are present in addition. In atypical pemphigus characteristically despite detection of intercellular fluorescence in direct and indirect immunofluorescence microscopy no IgG autoantibodies against the “classical” desmosomal structure proteins desmoglein 1 and/or 3 can be detected, but usually against desmocollin 1 and/or desmocollin 3 [6]. In paraneoplastic pemphigus in most cases IgG autoantibodies against desmoglein 3 and 1 are found. In addition, autoantibodies against desmosomal proteins of the plakin family, such as e. g. desmoplakin I and II, envoplakin and periplakin, are pres- ent [7–9]. Further autoantibodies are targeted against plektin and desmocollins as well as against a 170 kDa antigen that was identified by Schepens et al. as the pro- tease inhibitor alpha-2 macroglobulin-like1 (A2ML1) [10]. IgA pemphigus is characterized by detection of IgA autoantibodies against desmoglein 1 and desmoglein 3 (= intraepidermal neutrophilic dermatosis) or also against desmocollin 1 (= subcorneal pustular dermatosis) (Table 1 and Figure 1). 1.4.2 Serological confirmatory tests in diseases with subepidermal loss of adhesion In diseases with subepidermal loss of adhesion in immunoserology autoantibodies against structure proteins of the hemidesmosomes or the dermo-epidermal junction zone as well as against epidermal or tissue transglutaminase can be detected (Figure 1). Bullous pemphigoid is characterized by autoantibodies against both hemidesmosomal structure proteins collagen XVII (= BP180) and BP230 (Figure 1). In most cases autoreactivity is targeted against the NC16A domain of BP180 [11]. In contrast to anti-BP230 IgG, the serum levels of autoantibodies against BP180 NC16A correlate with disease activity [12–14]. In the event of detection of autoantibodies against Academy 935 © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2011/0911 JDDG | 11˙2011 (Band 9) Laminin 332-positive mucous mem- brane pemphigoid and linear IgA der- matosis demonstrate mixed fluores- cence both on the epidermal as well as on the dermal side in salt-split skin. Pemphigus diseases are characterized by the occurrence of autantibodies against desmosomal structure proteins. Pemphigus vulgaris with exclusive mu- cosal involvement exhibits desmoglein 3 autoantibodies, in mucocutaneous involvement both desmoglein 3 as well as desmoglein 1 autoantibodies are found. The autoantibody titer usually corre- lates with clinical activity. Pemphigus foliaceus exhibits autoanti- bodies against desmoglein 1, but not against desmoglein 3. In pemphigus erythematosus autonu- clear antibodies are present in addition in many cases. In atypical pemphigus no IgG autoanti- bodies against the classical desmoso- mal structure proteins can be detected. In paraneoplastic pemphigus usually IgG autoantibodies against desmoglein 3 and 1, plakins, plektin and desmo- collins as well as A2ML1 can be identi- fied. IgA pemphigus possesses IgA autoan- tibodies against desmoglein 1 and desmoglein 3 or desmocollin 1. In bullous pemphigoid autoantibodies against collagen XVII (= BP180) and BP230 are found.
- 10. BP230 and/or BP180 it must be taken into consideration that a considerable propor- tion of older patients with polymorphic pruritic skin diseases also possess IgG autoantibodies against BP230 and BP180 [15]. Therefore, the diagnosis of bullous pemphigoid cannot be made solely on the basis of detection of IgG against BP230 and/or BP180 without the identification of tissue-bound antoantibodies in direct immunofluorescence microscopy. ELISA test systems for the detection of IgG against BP180 NC16A as well as BP230 are available commercially in the meantime. In pemphigoid gestationis also predominantly autoantibodies against the BP180 NC16A domain are detectable, rarely against BP230 in the course. The rele- vant autoantibodies belong to the IgG3 and IgG1 class and possess a high potential for activating complement [16]. These autoantibodies are usually also found in chorionic and amniotic epithelium. Mucous membrane pemphigoid, too, is associated with IgG autoantibodies against BP180; in addition, autoantibodies against laminin 332 (= laminin 5), ␣6 and 4- integrin as well as occasionally against BP230 are found. Corresponding to the loca- tion of the structure proteins in the dermo-epidermal junction zone (Figure 1), in laminin 332-positive mucous membrane pemphigoid linear fluorescence is observed on the dermal side of the split in indirect immunofluorescence microscopy (human salt-split skin). When autoantibodies against laminin 332 are detected, a search for a tumor should be conducted. Autoantibodies against ␣6-intergrin are associated pre- dominantly with oral involvement, autoantibodies against 4-integrin with ocular involvement [17]. The autoantigen of linear IgA dermatosis is a 120 kDa large extracellular cleavage product of the BP180 ectodomain, which is degraded into a 97 kDa protein (LAD-1) [18]. In laminin ␥1 pemphigoid (formerly anti-p200 pemphigoid) Hashimoto and cowork- ers identified the ␥1 chain of laminin as autoantigen [19]. Epidermus bullosa acquisita is characterized by autoantibodies against collagen VII. Collagen VII is the main component of the anchoring fibrils of the dermo-epidermal junction zone (Figure 1). Besides in epidermolysis bullosa acquisita collagen type VII autoantibodies can be detected in bullous systemic lupus erythematosus. Test systems are currently available only for scientific research (e. g. MBL, Japan) or are performed in various university departments of dermatology in Germany (among others, Marburg, Lübeck, Würzburg). Epidermal transglutaminase has been identified as the autoantigen of dermatitis herpetiformis [20]. Pathogenetically there is a complex interaction between genetic factors (HLA association) and environmental factors (gluten-rich food). After oral gluten exposition IgA autoantibodies against a complex consisting of gluten and tissue transglutaminase in the epithelium of the small intestine are produced in gluten-sensitive persons. The autoantibodies cross-react with epidermal transglutam- nase, which participates as an isoenzyme in keratinocyte differentiation. Immune complexes of IgA and epidermal tansglutaminase are found as diagnostic markers in the papillary dermis. The proof of pathogenetic relevance for the development of the characteristic signs and symptoms is still lacking. At present, a commercial ELISA with tissue transglutaminase is available. This is diagnostically helpful due to the high degree of homology of both atuoantigens in dermatitis herpetiformis. Further, ELISA employing gliadin-analogous multimeric fusion proteins are available (Euroimmun, Lübeck, Germany). 2 Therapy 2.1 General therapy measures The therapy of autoimmune bullous diseases is usually oriented towards the severity of clinical findings. Trigger factors, e. g. drugs such as penicillamine, furosemide, van- comycin, rifampicin, nonsteroidal antiinflammatory drugs, cephalosporines, ACE inhibitors and thiazide diuretics should be discontinued. Further, consistent sun pro- tection should be ensured. In the event of oral mucous membrane involvement spicy and hot food or that of a hard consistency should be avoided and soft or liquid meals be given. In extensive involvement of the skin reverse isolation should be observed. In case of immobility decubitus prevention should be performed as well as positioning on Metalline® foil is essential as well as protection from cold. To avoid cachexia the 936 Academy JDDG | 11˙2011 (Band 9) © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2011/0911 The serum levels of autoantibodies against BP180 NC16A correlate with disease activity. In mucous membrane pemphigoid IgG autoantibodies against BP180, laminin 332 (= laminin 5), ␣6- and 4-integrin as well as occasionally against BP230 are found. The autoantigen of linear IgA dermato- sis is a cleavage product of the BP180 ectodomain. Epidermolysis bullosa acquisita ex- hibits autoantibodies against collagen VII. Epidermal transglutaminase is the au- toantigen of dermatitis herpetiformis.
- 11. administration of sufficient calories and fluids should be guaranteed. The risk of sec- ondary infection can be reduced by close control of wounds and catheters; antibiotic or antiviral prophylaxis to avoid bacterial superinfections or herpes infections can also be considered. Blisters of the skin should be opened in a sterile manner and be drained leaving the roof of the blister as protection from infections. In addition, consistent antiseptic or antibiotic topical measures such as the application of silver sulfadiazine 1 % should be performed. Further, antiseptic topical therapy with, for example, prod- ucts containing clioquinol or triclosan is recommendable; to perform atraumatic change of dressing additional wound gauzes may be applied. In involvement of the oral mucosa the necessity of forced local hygiene to reduce col- onization by pathogens should not be underestimated. Due to the usually existing severe painfulness prior application of anesthetizing adhesive creams or solutions should be performed. Further, antiinflammatory topical therapy with a corticosteroid adhesive cream, e. g. with triamcinolone acetonide, can be carried out. Further, com- binations of agents for easier application such as mouthwashes with corticosteroids and dexpanthenol as well as anesthetizing and antiseptic additives are possible. An example of such a compounded prescription is: chlorhexamed fluid 939461 solution 200.0 g, hydrocortisonum aceticum 1.0 g, tetracainum hydrochloricum 2.0 g. Ol. menthae pip 0.3 g, panthenol 5 % Lichtenstein solution 40.0 g, propylene glycolum 37.0 g and aqua purificata plus surcharge 4.7 g. Further, consistent candida prophy- laxis, for example, with nystatin or amphotericin B should be performed. In the event of conjunctival involvement consistent eye hygiene should be ensured to avoid the development of symblepharon. Corticosteroids can be applied in the form of ocular ointment, cyclosporine in form of eyedrops. In the event of secondary conjunctival involvement close monitoring by an ophthal- mologist is mandatory. 2.2 Systemic immunosuppressive therapy 2.2.1 General considerations Table 2 provides an overview of currently practiced immunosuppressive therapy of autoimmune bullous dermatoses. Systemic immunosuppressive agents are employed initially in most cases for therapy of autoimmune bullous dermatoses. In common for all is an increased risk of opportunistic infections by bacteria, viruses as well as yeasts and protozoa; due to therapeutic immunosuppression infections can take severe or even fatal courses. Before initiating immunosuppressive therapy chronic infections (bacterial infections, HIV, hepatitis B and C, tuberculosis) should be excluded in order to assess the dan- ger of possible reactivation of latent infections during immunosuppression. Frequent opportunistic infections are candidal infections of the mucous membranes (especially oral candidiasis) as well as skin infections with herpes viruses (herpes sim- plex, varicella zoster). Rarer infections are nocardiosis, histoplasmosis and Cryptococcus mycosis as well as cytomegalovirus infections. Very rarely have cases of progressive multifocal leukencephalopathy in association with the use of rituximab for non-Hodgkin lymphomas and chronic lymphocytic leukemia, but also in rheumatoid arthritis and other autoimmune disorders (e. g. systemic lupus erythe- matosus, vasculitis) been reported. In the majority of these cases rituximab was administered in combination with chemotherapy or within the context of a hematopoietic stem cell graft, and the infections were associated with a high degree of iatrogenic immunosuppression. Further, during systemic immunosuppression (particularly during high-dose immunosuppressive combination or long-term thera- py) an increased risk of development of lymphoproliferative diseases and malignant tumors, especially skin tumors, but also solid organ tumors, exists. To prevent malig- nant skin tumors it is recommended to limit exposure to the sun or UV irradiation, wear protective clothing and ensure regular skin inspections. Further, teratogenic potential is reported for numerous immunosuppressive agents, so that during therapy for a certain time period after the end of therapy contraceptive measures (see pre- scribing information) should be undertaken. During immunosuppressive medication vaccinations with live viral vaccines are con- traindicated, as severe complications can result. Vaccinations with inactive vaccines can be performed, but are usually considerably less successful. Academy 937 © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2011/0911 JDDG | 11˙2011 (Band 9) Generaltherapymeasuresincludeelim- ination of trigger factors, protection from cold and administration of suffi- cient calories and fluids. To avoid superinfections antiseptic or antibiotic topical measures, perhaps even systemic prophylaxis should be undertaken. Antiinflammatory topical therapy is performed with topical corticosteroids. In the event of conjunctival involve- ment consistent eye hygiene should be ensured to avoid the development of symblepharon. Initially, usually systemic immunosup- pressive agents are employed for therapy of autoimmune bullous der- matoses.This results in an increased risk of opportunistic infections. During systemic immunosuppression there is an increased risk of develop- ment of lymphoproliferative diseases and malignant disorders.
- 12. 938 Academy JDDG | 11˙2011 (Band 9) © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2011/0911 Table 2: Immunosuppressive therapy in autoimmune bullous skin diseases (abbreviations: PV: pemphigus vulgaris; PF: pemphigus foliaceus; BP: bullous pemphigoid; MMP: mucous membrane pemphigoid; LAD: linear IgA bullous dermatosis; EBA: epidermolysis bullosa acquisita; DHD: dermatitis herpetiformis, +: effective; +/–: questionably effective, effective for individual endpoints or unclear data; –: ineffective or lack of data). 1 Evidence level of clinical trials: I: prospective, randomized study; II: non-randomized case-control study; III case series or descriptive study; IV: single case report/expert opinion. 2 Dosage at start of therapy. 3 Only the most common side effects are listed. For additional information concerning side effects and drug interactions please refer to the medication guide. 4 Dapsone is also given in refractory pemphigus foliaceus. Paraneoplastic pemphigus: Similar to PV, partial response to systemic corticosteroids cyclosporine, cyclophosphamide and rituximab. IgA-pemphigus: Treatment with dapsone or retinoids combined with prednisolone, PUVA. Continued Drug PV/PF BP MMP LAD EBA DH Dosage 2 Side effects 3 Peculiarities 3 Systemic corticos- teroids + I 1 + I + III +/– IV + III +/– IV PV/PF 0,5–1 mg/d orally BP 0,5–0,75 mg/kg Cutaneous atrophy, osteoporosis, glaucoma, gastrointestinal ulcers, Cushing syndrome, edema, diabetes mellitus, hypertension In high dosages or long-term thera- py: osteoporosis prophylaxis, antacids, candida prophylaxis Topical corticosteroids (clobetasol propionate) +/– IV + I +/– IV +/– IV +/– IV +/– IV 10–30 g clobetasol daily topically Local side effects: atrophy, striae, telangiec- tases, steroid acne, folliculitides, ecchymoses, perioral dermatitis, hypertrichosis, systemic effects possible (see systemic corticosteroids) Long-term use difficult (compliance, cutaneous atrophy) Azathioprine + I +/– III +/– III +/– III +/– III – 1–2,5 mg/kg/d oral- ly (depending on TPMT activity) Pancytopenia, gastrointestinal disturbances, hepatotoxicity, nephropathy, toxic myelosup- pression in TPMT deficiency Immunosuppressant of first choice onset of action after 2–3 months exclude TPMT deficiency before start of therapy control blood count and liver function parameters no combination with allopurinol contraception until 3 months after the end of therapy Mycophenolate mofetil/ sodium mycophenolate + I +/– III +/– IV +/– IV +/– IV +/– IV 1–2 g/d orally Gastrointestinal disturbances, pancytopenia, hepatopathy, electrolyte disturbances, renal insufficiency In case of gastrointestinal distur- bances switch to sodium mycophe- nolate, blood count controls (BEWARE: neutropenia) Cyclophosphamide +/– I +/– IV +/– III +/– IV +/– IV – 100–200 mg/d oral- ly or i.v. pulse ther- apy Gastrointestinal disturbances, myelosuppres- sion, alopecia, hepato- and nephropathy, neuro- and cardiotoxicity, stomatitis, hemor- rhagic cystitis, sterility, teratogenic Administration of antiemetics, oral hygiene and care, control blood count prophylaxis of urotoxicity (Uromitexan ® ), contraception until 6 months after end of therapy
- 13. Academy 939 © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2011/0911 JDDG | 11˙2011 (Band 9) Table 2: Continued. Drug PV/PF BP MMP LAD EBA DH Dosage 2 Side effects 3 Peculiarities 3 Methotrexate +/– III +/– III +/– IV +/– IV +/– IV – 10–20 mg/week oral- ly or s.c. Pancytopenia, stomatitis, hepato- and nephropathy, gastrointestinal disturbances, exanthemas, cephalgia, alopecia, interstitial pneumonitis, infertility, teratogenic Control blood count, liver and renal parameters Ciclosporine +/– II +/– IV +/– IV +/– IV +/– IV +/– IV 2,5–5 mg/kg/d orally Arterial hypertension, nephrotoxicity, hyper- lipidemia, hyperuricemia, cephalgia, hyper- trophic gingivitis, hypertrichosis, gastroin- testinal disturbances, hepatopathy, myalgia, paresthesia Contraindicated in hyperuricemia and hyperkalemia no combination with other calcineurin inhibitors control of blood pressure and serum creatinine as well as cyclosporine serum levels Dapsone +/– 4 IV +/– III + IV + IV +/– IV + III 1–2 mg/kg/d orally Methemoglobinemia, hemolytic anemia, cephalgia, gastrointestinal disturbances, cyanosis, agranulocytosis, hepato- and nephropathy, dapsone syndrome Determine glucose-6-phosphate dehydro- genase activity before the start of therapy control blood count and methemoglobin Intravenous immunoglobulins (IVIG) + I +/– IV +/– IV +/– IV +/– IV – 2 g/kg every 4 weeks i.v. Anaphylactic reaction, shivering, fever, cephalgia, hypotension, gastrointestinal dis- turbances, aseptic meningitis, hyperviscosity with increased risk of thrombembolic events, acute renal failure, hemolysis, exan- thema BEWARE: hypersensitivity reaction in selective IgA deficiency, premedication and careful monitoring of patients, positive serological test results (Coombs test) due to transient passive transfer of antibodies Immunoadsorption +/– III +/– IV +/– IV +/– IV +/– IV – 3–4 x/week in 3–4 week intervals Anaphylactic reaction, hypogammaglobu- linemia Combination of adjuvant immunoad- sorption and immunosuppressive basic therapy for more rapid disease control Rituximab + III +/– IV + III – + IV – 2 ⫻ 1 g i.v. day 1 and 15 or 375 mg/m2 body surface area day 1, 8, 15 and 22 Anaphylaxis, gastrointestinal disturbances, cardiac insufficiency, arrhythmia, pancytope- nia, neuropathy, very rarely: progressive multifocal leukencephalopathy (PML) Intravenous administration with available emergency drugs, complete B-cell deple- tion over 8–12 months, blood count con- trols Tetracyclines/ nicotinamide – +/– III – +/– IV – +/– IV 2–4 ⫻ 500 mg/d oral- ly 0.2–1.2 g/d orally Gastrointestinal symptoms, hepatopathy, light sensitivity No use in children
- 14. 940 Academy JDDG | 11˙2011 (Band 9) © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2011/0911 A further option for therapy-refractory pemphigus vulgaris is immunoadsorp- tion. In addition to the side effects of systemic immunosuppressive therapy described above (opportunistic infections, increased risk of malignancy) various peculiarities must be considered in the therapy of autoimmune bullous dermatoses. Due to the rarity of these diseases controlled therapy studies with sufficiently large numbers of patients are difficult to realize. In many cases, therefore, evidence-based therapy can- not be instituted; this results in frequently costly treatment methods or off-label use of drugs [21]. Causal therapy is not yet available. Therefore, the goal of each treat- ment is the quickest possible control of disease activity and achievement of long-last- ing remissions. 2.2.2 Therapy of the pemphigus diseases Systemic corticosteroids play a central role in the therapy of pemphigus vulgaris due to their rapid effects and their resulting significant improvement of the mortality rate [22]. The initial dose is usually equivalent to 0.5–1 mg prednisolone/kg daily. Systemic corticosteroids are usually combined with other immunosuppressive agents to allow for rapid reduction of the corticosteroid dose. As adjuvant immunosuppres- sive agents azathioprine, mycophenolate mofetil, cyclophosphamide and methotrex- ate as well as cyclosporine and chlorambucil are employed [21, 23], with azathioprine being the agent of first choice. Due to the delayed onset of effects of azathioprine it is frequently administered initially in combination with systemic corticosteroids. In order to minimize the risk of toxic myelosuppression, the pheno- or genotypic deter- mination of the activity of thiopurine methyltransferase (TPMT) should be per- formed before the start of therapy [24]. It could be shown that azathioprine in addi- tion to its steroid-sparing effect leads to more rapid clinical remissions than corticos- teroid monotherapy [25]. A steroid-sparing effect could also be demonstrated for mycophenolate mofetil; fur- ther, positive effects with respect to time and duration of the clinical response could be seen for adjuvant therapy with mycophenolate mofetil [26]. Mycophenolate mofetil and azathioprine were comparable as adjuvant therapies in comparison to corticosteroid monotherapy [27]. In the event of substantial gastrointestinal side effects a switch-over to mycophenolate mofetil can be successful [28]. Cyclophosphamide as intravenous pulse therapy is employed in therapy-refractory cases of pemphigus vulgaris [22, 29]. Its action profile resembles that of azathioprine and mycophenolate mofetil and the steroid-sparing effect is comparable [25]. As opposed to oral administration intravenous pulse therapy can possibly reduce the risk of development of secondary malignancies [30]. In younger patients who desire to have children, cyclophosphamide is obsolete, as it often leads to sterility. Cyclosporine is also utilized in the therapy of pemphigus vulgaris. It is employed both as systemic therapy and also for topical application to oral mucous membrane lesions [22]. Success in the therapy of pemphigus vulgaris has also been reported for methotrexate [31]. For both drugs the data are not sufficient to date to access effica- cy objectively. There is evidence of a steroid-sparing effect for the use of diamin- odiphenylsulfone (dapsone) [32]. Due to the increasing understanding of the pathogenesis of autoimmune bullous der- matoses several targeted therapies are available in the meantime that have not yet been licensed for this indication. The efficacy of high-dose, intravenous immunoglob- ulins as an adjuvant therapy option has been demonstrated in numerous retrospec- tive case studies in therapy-refractory pemphigus. Both a decline in disease activity as well as improved response to subsequently administered immunosuppressants such as e. g. rituximab could be demonstrated for immunoglobulin therapy [33, 34]. A Japanese prospective study showed that the one-time administration of high-dose immunoglobulins led to an improved clinical response to an already established immunosuppressive therapy [35]. A consensus paper summarizes the recommenda- tions for the use of immunoglobulins for bullous dermatoses in Germany [34]. A further option for therapy-refractory pemphigus vulgaris is immunoadsorption. While plasmapharesis unspecifically removes plasma protein, in immunoadsorption immunoglobulins and immune complexes are removed specifically from plasma. In general, clinical findings improve rapidly after immunoadsorption; in some cases this may, however, be of only short duration. The combined administration of systemic corticosteroids, adjuvant immunotherapy as well as immunoadsoprtion appears to In the therapy of bullous autoimmune dermatoses evidence-based therapies are usually not available. Therapeutic goal is control of disease activity and long-lasting remissions. In the therapy of pemphigus vulgaris systemic corticosteroids are adminis- tered in an initial dosage equivalent to 0.5–1 mg prednisolone/kg daily. Asadjuvantimmunosuppressiveagents in pemphigus vulgaris azathioprine (agent of first choice), mycophenolate mofetil, cyclophosphamide and methotrexate as well as cyclosporine and chlorambucil are employed. Before the administration of azathio- prine thiopurine methyltransferase (TPMT) activity should be determined. In younger patients who desire to have children,cyclophosphamide is obsolete. In therapy-refractory pemphigus high- dose intravenous immunoglobulins represent an adjuvant therapy option.
- 15. result in sustained control of disease activity. To date the positive effect of immunoadsorption has been demonstrated in several retrospective, monocenter studies. A consensus paper summarizes the recommendations on the use of immunoadsorption in bullous dermatoses in Germany [36]. In January 2011 a Germany-wide multicenter study on the efficacy of immunoadsorption in pemphi- gus diseases was initiated. A third, highly effective therapy approach is based on the depletion of peripheral B cells with rituximab, a monoclonal antibody against CD20 [33, 37]. Administration of rituximab in many cases results in complete or partial remission of pemphigus that correlates well with a long-lasting depletion of peripheral B cells. Two prospective studies show that rituximab in combination with corticosteroids or immunosuppressants or as monotherapy leads to clinical remission in over 80 % of cases. Further, the combination of rituximab with immunoadsorption or high-dose immunoglobulins has been reported. The recommendations for the use of rituximab for bullous dermatoses in Germany were summarized in a consensus paper in 2008 [38]. At present a multicenter phase III study comparing the efficacy of rituximab in comparison to systemic corticosteroids as first-line therapy of pemphigus is under way in France. In pemphigus foliaceus the same therapeutic measures are employed as in pemphigus vulgaris. Despite improved overall prognosis for survival due to the lack of mucous membrane involvement, pemphigus foliaceus not infrequently takes a therapy-refrac- tory course which in our experience requires a similarly rigorous immunosuppressive therapy as pemphigus vulgaris. In these cases the additional administration of dap- sone has proven to be effective [39]. As dapsone can cause increased hematological side effects in the presence of glucose-6-phosphate dehydrogenase deficiency, before initiation of systemic therapy glucose-6-phosphate dehydrogenase should be deter- mined. For prevention of hemolytic anemia folic acid can be administered. In paraneoplastic pemphigus most cases are characterized by a fatal course, so that it represents a particular therapeutic challenge. Remissions can usually be attained only by complete healing of the associated malignancy; thus the prognosis of para- neoplastic pemphigus depends primarily on the underlying malignancy. In general therapy approaches for paraneoplastic pemphigus resemble those for pemphigus vulgaris, with good therapeutic response to rituximab being reported in individual cases [40]. In IgA pemphigus dapsone is therapy of choice; further, systemic retinoids (acitretin) as well as PUVA therapy are employed [41]. 2.2.3 Therapy of diseases with subepidermal loss of adhesion In general bullous pemphigoid takes a milder course than diseases of the pemphigus group. Due to the high age of the patients as well as numerous comorbidities bullous pemphoid possesses a higher total mortality, so that in general milder therapeutic measures should be employed. In the meantime topical therapy with highly potent corticosteroids (initially 30 g clobetasol propionate daily) is viewed as therapy of choice on the basis of the results of two multicenter studies [42, 43]. Nonetheless, in routine practice topical therapy cannot always be realized. Systemic corticosteroids in the comparative arm demonstrate equal efficacy but distinctly higher mortality, even though topical therapy also results in systemic resorption. In therapy-refractory cases systemic corticosteroids, usually in lower dosage than in pemphigus vulgaris, are employed often in combination with other adjuvant immunosuppressive agents (e. g. azathioprine, mycophenolate mofetil, methotrexate or chlorambucil). Mycophenolate mofetil and azathioprine as adjuvant therapy proved comparable to corticosteroid monotherapy, with less hepatic toxicity of mycophenolate mofetil. Dapsone is an effective adjuvant; further, success has been reported for therapy with tetracyclines in combination with nicotinamide [44]. In the therapy of pemphigoid gestationis as first-line therapy mild antipruritic therapy with oral antihistamines in combination with topical corticosteroids is recommended. In severe cases systemic corticosteroids may be administered for a short term. Immunoadsorption or administration of intravenous immunoglobulins has demon- strated effectiveness in individual cases. Systemic immunosuppressive therapy should be avoided if possible in pemphigoid gestationis [45]. Academy 941 © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2011/0911 JDDG | 11˙2011 (Band 9) With rituximab, a monoclonal antibody against CD20,in many cases a complete or partial remission of pemphigus is achieved. In pemphigus foliaceus the same thera- peutic measures are employed as in pemphigus vulgaris. In paraneoplastic pemphigus the prog- nosis depends primarily on the underly- ing malignancy. In IgA pemphigus dapsone is therapy of choice. In bullous pemphigoid topical therapy with highly potent corticosteroids is viewed as therapy of choice in the meantime. In therapy-refractory courses of bullous pemphigoid systemic corticosteroids are employed, often in combination with adjuvant immunosuppressive agents. Oralantihistaminesincombinationwith topical corticosteroids are usually em- ployed for therapy of pemphigoid ges- tationis.
- 16. Mucous membrane pemphigoid frequently takes a chronic course and is resistant to ther- apy. Especially in the event of ocular involvement despite high-dose immunosuppres- sive therapy there can be rapid progression. Usually systemic corticosteroids are admin- istered in high doses initially, mostly in combination with adjuvant immunosuppres- sive agents. In severe cases cyclophosphamide is employed; in therapy-refractory cases intravenous immunoglobulins may be administered [17]. A recent study demonstrat- ed astonishing success with rituximab in oral and ocular manifestation [46]. In linear IgA dermatosis dapsone is the agent of first choice, often in combination with topical corticosteroids. In the event of intolerance of dapsone, sulfapyridine or sulfasalazine can be used. In most cases additional initial administration of systemic corticosteroids is advisable, but in comparison to pemphigus vulgaris or bullous pem- phigoid therapy response is poorer in linear IgA dermatosis. Immunoglobulins and immunoadsorption have also been reported to be effective [34]. Epidermolysis bullosa acquisita is markedly resistant to therapy in many cases. Especially the course of the mechanobullous form of epidermolysis bullosa acquisita can frequently only moderately be influenced positively by immunosuppressive ther- apies. Besides systemic corticosteroids adjuvant azathioprine and mycophenolate mofetil are employed successfully for the inflammatory variety of epidermolysis bul- losa acquisita. The effectiveness of dapsone, colchicine, cyclophosphamide and cyclosporine has also been reported. In therapy-refractory cases the (combined) administration of intravenous immunoglobulins, rituximab or immunoadsorption procedures may be effective [47–49]. Beyond this marked, often characteristically persistent skin fragility with secondary atrophy can be approached with appropriate wound dressings and physiotherapy. In dermatitis herpetiformis beyond the skin disease the always simultaneaously pres- ent enteropathy must be taken into consideration, so that a gluten-free diet must be adhered to by the patient. This also prevents the secondary occurrence of intestinal lymphomas. The effect of a gluten-free diet becomes manifest only after several months. Should this measure be insufficient or not be performed consistently, dap- sone is agent of choice; typically the often agonizing pruritus ceases within a few days. In case of intolerance of dapsone, sulfapyridine or sulfasalazine can be used. Typically, dermatitis herpetiformis responds poorly to systemic corticosteroids. As dapsone does not therapeutically impact the underlying enteropathy, the significance of a gluten-free diet must repeatedly be explained to the patient [50]. <<< Conflicts of interest None. Correspondence to Dr. Andrea Kneisel Prof. Dr. Michael Hertl Department of Dermatology and Allergy University Clinic Marburg Baldinger Straße D-35043 Marburg, Germany Tel.: +49-6421-586-5727 Fax: +49-6421-586-2902 E-mail: kneisel@med.uni-marburg.de 942 Academy JDDG | 11˙2011 (Band 9) © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2011/0911 Therapy of mucous membrane pem- phigoid is initially performed usually with systemic corticosteroids and ad- juvant immunosuppressive agents, further with cyclophosphamide, intra- venous immunoglobulins and rutix- imab. In linear IgA dermatosis dapsone is the agent of first choice. Epidermolysis bullosa acquisita is of- ten markedly resistant to therapy. In Epidermolysis bullosa acquisita the administration of intravenous immunoglobulins, rituximab or im- munoadsorption procedures may be effective. A gluten-free diet must be adhered to in dermatitis herpetiformis. Otherwise dapsone is considered therapy of choice.
- 17. References 1 Eming R, Hertl M, Group ADW. Autoimmune bullous disorders. Clin Chem Lab Med 2006; 44(2): 144–9. 2 Hertl M, Eming R. Pemphigus vulgaris. CME Dermatol 2009; 4(2): 94–115. 3 Vaughan Jones SA, Palmer I, Bhogal BS, Eady RAJ, Black MM. The use of Michel's transport medium for immunofluorescence and immunoelectron microscopy in au- toimmune bullous diseases. Journal of Cutaneous Pathology 1995; 22(4): 365–70. 4 Amagai M, Komai A, Hashimoto T, Shirakata Y, Hashimoto K, Yamada T, Kitajima Y, Ohya K, Iwanami H, Nishikawa T. Usefulness of enzyme-linked immunosorbent assay using recombinant desmogleins 1 and 3 for serodiagnosis of pemphigus. Br J Derma- tol 1999; 140(2): 351–7. 5 Nagel A, Lang A, Engel D, Podstawa E, Hunzelmann N, de Pita O, Borradori L, Uter W, Hertl M. Clinical activity of pemphigus vulgaris relates to IgE autoantibodies against Desmoglein 3. Clin Immunol 2010; 134(3): 320–30. 6 Rafei D, Müller R, Ishii N, Llamazares M, Hashimoto T, Hertl M, Eming R. IgG au- toantibodies against desmocollin 3 in pemphigus sera induce loss of keratinocyte adhe- sion. Am J Pathol 2011; 178(2): 718–23. 7 Anhalt GJ, Kim SC, Stanley JR, Korman NJ, Jabs DA, Kory M, Izumi H, Ratrie H 3rd, Mutasim D, Ariss-Abdo L, et al. Paraneoplastic pemphigus. An autoimmune mu- cocutaneous disease associated with neoplasia. N Engl J Med 1990; 323(25): 1729–35. 8 Hashimoto T, Amagai M, Watanabe K, Chorzelski TP, Bhogal BS, Black MM, Stevens HP, Boorsma DM, Korman NJ, Gamou S, et al. Characterization of paraneoplastic pemphigus autoantigens by immunoblot analysis. J Invest Dermatol 1995; 104(5): 829–34. 9 Zimmermann J, Bahmer F, Rose C, Zillikens D, Schmidt E. Clinical and im- munopathological spectrum of paraneoplastic pemphigus. J Dtsch Dermatol Ges 2010; 8(8): 598–606. 10 Schepens I, Jaunin F, Begre N, Läderach U, Marcus K, Hashimoto T, Favre B, Borradori L. The protease inhibitor alpha-2-macroglobulin-like-1 is the p170 antigen recognized by paraneoplastic pemphigus autoantibodies in human. PLoS One 2010; 5(8): e12250. 11 Zillikens D, Rose PA, Balding SD, Liu Z, Olague-Marchan M, Diaz LA, Giudice GJ. Tight clustering of extracellular BP180 epitopes recognized by bullous pemphigoid au- toantibodies. J Invest Dermatol 1997; 109(4): 573–9. 12 Schmidt E, Obe K, Bröcker EB, Zillikens D. Serum levels of autoantibodies to BP180 correlate with disease activity in patients with bullous pemphigoid. Arch Dermatol 2000; 136(2): 174–8. 13 Hofmann S, Thoma-Uszynski S, Hunziker T, Bernard P, Koebnick C, Stauber A, Schuler G, Borradori L, Hertl M. Severity and phenotype of bullous pemphigoid relate to autoantibody profile against the NH2- and COOH-terminal regions of the BP180 ectodomain. J Invest Dermatol 2002; 119(5): 1065–73. 14 Di Zenzo G, Thoma-Uszynski S, Fontao L, Calabresi V, Hofmann SC, Hellmark T, Sebbag N, Pedicelli C, Sera F, Lacour JP, Wieslander J, Bruckner-Tuderman L, Borradori L, Zambruno G, Hertl M. Multicenter prospective study of the humoral autoimmune response in bullous pemphigoid. Clin Immunol 2008; 128(3): 415–26. 15 Feliciani C, Caldarola G, Kneisel A, Podstawa E, Pfütze M, Pfützner W, Hertl M. IgG autoantibody reactivity against bullous pemphigoid (BP) 180 and BP230 in elderly pa- tients with pruritic dermatoses. Br J Dermatol 2009; 161(2): 306–12. 16 Chimanovitch I, Schmidt E, Messer G, Döpp R, Partscht K, Bröcker EB, Giudice GJ, Zillikens D. IgG1 and IgG3 are the major immunoglobulin subclasses targeting epi- topes within the NC16A domain of BP180 in pemphigoid gestationis. J Invest Derma- tol 1999; 113(1): 140–2. 17 Chan LS, Ahmed AR, Anhalt GJ, Bernauer W, Cooper KD, Elder MJ, Fine JD, Foster CS, Ghohestani R, Hashimoto T, Hoang-Xuan T, Kirtschig G, Korman NJ, Lightman S, Lozada-Nur F, Marinkovich MP, Mondino BJ, Prost-Squarcioni C, Rogers RS 3rd, Setterfield JF, West DP, Wojnarowska F, Woodley DT, Yancey KB, Zillikens D, Zone JJ. The first international consensus on mucous membrane pemphigoid: definition, di- agnostic criteria, pathogenic factors, medical treatment, and prognostic indicators. Arch Dermatol 2002; 138(3): 370–9. Academy 943 © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2011/0911 JDDG | 11˙2011 (Band 9)
- 18. 18 Marinkovich MP, Taylor TB, Keene DR, Burgeson RE, Zone JJ. LAD-1, the linear IgA bullous dermatosis autoantigen, is a novel 120-kDa anchoring filament protein synthe- sized by epidermal cells. J Invest Dermatol 1996; 106(4): 734–8. 19 Dainichi T, Kurono S, Ohyama B, Ishii N, Sanzen N, Hayashi M, Shimono C, Taniguchi Y, Koga H, Karashima T, Yasumoto S, Zillikens D, Sekiguchi K, Hashimoto T. Anti-laminin gamma-1 pemphigoid. Proc Natl Acad Sci U S A 2009; 106(8): 2800–5. 20 Sárdy M, Kárpáti S, Merkl B, Paulsson M, Smyth N. Epidermal transglutaminase (TGase 3) is the autoantigen of dermatitis herpetiformis. J Exp Med 2002; 195(6): 747–57. 21 Hofmann SC, Kautz O, Hertl M, Sticherling M, Zillikens D, Bruckner-Tuderman L. Results of a survey of German dermatologists on the therapeutic approaches to pem- phigus and bullous pemphigoid. J Dtsch Dermatol Ges 2009; 7(3): 227–33. 22 Martin LK, Werth V, Villanueva E, Segall J, Murrell DF. Interventions for pemphigus vulgaris and pemphigus foliaceus. Cochrane Database Syst Rev. 2009(1): CD006263. 23 Martin LK, Werth VP, Villaneuva EV, Murrell DF. A systematic review of randomized controlled trials for pemphigus vulgaris and pemphigus foliaceus. J Am Acad Derma- tol 2011; 64(5): 903–8. 24 Jackson AP, Hall AG, McLelland J. Thiopurine methyltransferase levels should be measured before commencing patients on azathioprine. Br J Dermatol 1997; 136(1): 133–4. 25 Chams-Davatchi C, Esmaili N, Daneshpazhooh M, Valikhani M, Balighi K, Hallaji Z, Barzegari M, Akhyani M, Ghodsi SZ, Seirafi H, Nazemi MJ, Mortazavi H, Mirshams- Shahshahani M. Randomized controlled open-label trial of four treatment regimens for pemphigus vulgaris. J Am Acad Dermatol 2007; 57(4): 622–8. 26 Beissert S, Mimouni D, Kanwar AJ, Solomons N, Kalia V, Anhalt GJ. Treating pem- phigus vulgaris with prednisone and mycophenolate mofetil: a multicenter, random- ized, placebo-controlled trial. J Invest Dermatol 2010; 130(8): 2041–8. 27 Beissert S, Werfel T, Frieling U, Böhm M, Sticherling M, Stadler R, Zillikens D, Rzany B, Hunzelmann N, Meurer M, Gollnick H, Ruzicka T, Pillekamp H, Junghans V, Luger TA. . A comparison of oral methylprednisolone plus azathioprine or mycophe- nolate mofetil for the treatment of pemphigus. Arch Dermatol 2006; 142(11): 1447–54. 28 Chan L, Mulgaonkar S, Walker R, Arns W, Ambühl P, Schiavelli R. Patient-reported gastrointestinal symptom burden and health-related quality of life following conver- sion from mycophenolate mofetil to enteric-coated mycophenolate sodium. Transplan- tation 2006; 81(9): 1290–7. 29 Pasricha JS, Thanzama J, Khan UK. Intermittent high-dose dexamethasone-cyclophos- phamide therapy for pemphigus. Br J Dermatol 1988; 119(1): 73–7. 30 Fleischli ME, Valek RH, Pandya AG. Pulse intravenous cyclophosphamide therapy in pemphigus. Arch Dermatol 1999; 135(1): 57–61. 31 Smith TJ, Bystryn JC. Methotrexate as an adjuvant treatment for pemphigus vulgaris. Arch Dermatol 1999; 135(10): 1275–6. 32 Werth VP, Fivenson D, Pandya AG, Chen D, Rico MJ, Albrecht J, Jacobus D. Multi- center randomized, double-blind, placebo-controlled, clinical trial of dapsone as a glu- cocorticoid-sparing agent in maintenance-phase pemphigus vulgaris. Arch Dermatol 2008; 144(1): 25–32. 33 Ahmed AR, Spigelman Z, Cavacini LA, Posner MR. Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin. N Engl J Med 2006; 355(17): 1772–9. 34 Enk A, Fierlbeck G, French L, Hertl M, Messer G, Meurer M, Steinbrink K, Stingl G, Volc-Platzer B, Zillikens D. Use of high-dose immunoglobulins in dermatology. J Dtsch Dermatol Ges 2009; 7(9): 806–12. 35 Amagai M, Ikeda S, Shimizu H, Iizuka H, Hanada K, Aiba S, Kaneko F, Izaki S, Tamaki K, Ikezawa Z, Takigawa M, Seishima M, Tanaka T, Miyachi Y, Katayama I, Horiguchi Y, Miyagawa S, Furukawa F, Iwatsuki K, Hide M, Tokura Y, Furue M, Hashimoto T, Ihn H, Fujiwara S, Nishikawa T, Ogawa H, Kitajima Y, Hashimoto K; Pemphigus Study Group. A randomized double-blind trial of intravenous im- munoglobulin for pemphigus. J Am Acad Dermatol 2009; 60(4): 595–603. 944 Academy JDDG | 11˙2011 (Band 9) © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2011/0911
- 19. 36 Zillikens D, Derfler K, Eming R, Fierlbeck G, Goebeler M, Hertl M, Hofmann SC, Karlhofer F, Kautz O, Nitschke M, Opitz A, Quist S, Rose C, Schanz S, Schmidt E, Shimanovich I, Michael M, Ziller F. Recommendations for the use of immunoaphere- sis in the treatment of autoimmune bullous diseases. J Dtsch Dermatol Ges 2007; 5(10): 881–7. 37 Joly P, Mouquet H, Roujeau JC, D'Incan M, Gilbert D, Jacquot S, Gougeon ML, Bedane C, Muller R, Dreno B, Doutre MS, Delaporte E, Pauwels C, Franck N, Caux F, Picard C, Tancrede-Bohin E, Bernard P, Tron F, Hertl M, Musette P. A single cycle of rituximab for the treatment of severe pemphigus. N Engl J Med 2007; 357(6): 545–52. 38 Hertl M, Zillikens D, Borradori L, Bruckner-Tuderman L, Burckhard H, Eming R, Engert A, Goebeler M, Hofmann S, Hunzelmann N, Karlhofer F, Kautz O, Lippert U, Niedermeier A, Nitschke M, Pfütze M, Reiser M, Rose C, Schmidt E, Shimanovich I, Sticherling M, Wolff-Franke S. Recommendations for the use of rituximab (anti- CD20 antibody) in the treatment of autoimmune bullous skin diseases. J Dtsch Der- matol Ges 2008; 6(5): 366–73. 39 Gürcan HM, Ahmed AR. Efficacy of dapsone in the treatment of pemphigus and pem- phigoid: analysis of current data. Am J Clin Dermatol 2009; 10(6): 383–96. 40 Borradori L, Lombardi T, Samson J, Girardet C, Saurat JH, Hügli A. Anti-CD20 mon- oclonal antibody (rituximab) for refractory erosive stomatitis secondary to CD20(+) follicular lymphoma-associated paraneoplastic pemphigus. Arch Dermatol 2001; 137(3): 269–72. 41 Bystryn JC, Steinman NM. The adjuvant therapy of pemphigus. An update. Arch Der- matol. 1996; 132(2): 203–12. 42 Joly P, Roujeau JC, Benichou J, Picard C, Dreno B, Delaporte E, Vaillant L, D'Incan M, Plantin P, Bedane C, Young P, Bernard P; Bullous Diseases French Study Group. A comparison of oral and topical corticosteroids in patients with bullous pemphigoid. N Engl J Med 2002; 346(5): 321–7. 43 Joly P, Roujeau JC, Benichou J, Delaporte E, D'Incan M, Dreno B, Bedane C, Sparsa A, Gorin I, Picard C, Tancrede-Bohin E, Sassolas B, Lok C, Guillaume JC, Doutre MS, Richard MA, Caux F, Prost C, Plantin P, Chosidow O, Pauwels C, Maillard H, Saiag P, Descamps V, Chevrant-Breton J, Dereure O, Hellot MF, Esteve E, Bernard P. A com- parison of two regimens of topical corticosteroids in the treatment of patients with bul- lous pemphigoid: a multicenter randomized study. J Invest Dermatol 2009; 129(7): 1681–7. 44 Kirtschig G, Middleton P, Bennett C, Murrell DF, Wojnarowska F, Khumalo NP. In- terventions for bullous pemphigoid. Cochrane Database Syst Rev. 2010(10): CD002292. 45 Semkova K, Black M. Pemphigoid gestationis: current insights into pathogenesis and treatment. Eur J Obstet Gynecol Reprod Biol 2009; 145(2): 138–44. 46 Le Roux-Villet C, Prost-Squarcioni C, Alexandre M, Caux F, Pascal F, Doan S, Brette MD, Soued I, Gabison E, Aucouturier F, Letestu R, Laroche L, Bachelez H. Rituximab for patients with refractory mucous membrane pemphigoid. Arch Dermatol 2011; 147(7): 843–9. 47 Niedermeier A, Eming R, Pfütze M, Neumann CR, Happel C, Reich K, Hertl M. Clinical response of severe mechanobullous epidermolysis bullosa acquisita to com- bined treatment with immunoadsorption and rituximab (anti-CD20 monoclonal an- tibodies). Arch Dermatol 2007; 143(2): 192–8. 48 Lehman JS, Camilleri MJ, Gibson LE. Epidermolysis bullosa acquisita: concise review and practical considerations. Int J Dermatol 2009; 48(3): 227–35; quiz 35–6. 49 Ishii N, Hamada T, Dainichi T, Karashima T, Nakama T, Yasumoto S, Zillikens D, Hashimoto T. Epidermolysis bullosa acquisita: what's new? J Dermatol 2010; 37(3): 220–30. 50 Bolotin D, Petronic-Rosic V. Dermatitis herpetiformis Part II. Diagnosis, manage- ment, and prognosis. J Am Acad Dermatol 2011; 64(6): 1027–33. Academy 945 © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2011/0911 JDDG | 11˙2011 (Band 9)
- 20. 946 Academy JDDG | 11˙2011 (Band 9) © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2011/0911 1.Welche Aussage trifft zu? a) Die histologische Untersuchung gilt als Goldstandard in der Dia- gnostik bullöser Autoimmunder- matosen. b) Bei unklarem klinischem Befund sollte zunächst eine ELISA-Unter- suchung zum Nachweis von Auto- antikörpern gegen die häufigsten Autoantigene bullöser Autoimmundermatosen durchge- führt werden. c) Für die histologische Untersuchung ist läsionale und periläsionale Haut gleichermaßen geeignet. d) Das bullöse Pemphigoid ist durch ein „Grabsteinmuster“ der basalen Keratinozyten charakterisiert. e) Die Dermatitis herpetiformis weist Papillenabszesse in der histo- logischen Untersuchung auf. 2.Welche Aussage trifft nicht zu? a) In der direkten Immunfluoreszenzuntersuchung lässt sich die Zusammensetzung des Entzündungsinfiltrats bestim- men. b) Die Gewebeprobe für die direkte Immunfluoreszenzuntersuchung darf nicht formalinfixiert werden. c) Beim Pemphigus vulgaris lassen sich interzelluläre IgG-Ablagerun- gen in der direkten Immunfluoreszenzuntersuchung nachweisen. d) Bullöses Pemphigoid, Pemphigoid gestationis und Schleimhautpem- phigoid zeigen in der direkten Im- munfluoreszenzuntersuchung ein ähnliches Fluoreszenzmuster. e) Die Gewebeprobe für die direkte Immunfluoreszenzuntersuchung sollte periläsional aus gesund erscheinender Haut entnommen werden. 3.Die indirekte Immunfluoreszenzuntersuchung … a) dient dem Nachweis gewebegebundener Autoantikör- per. b) wird bei Verdacht auf paraneopla- stischen Pemphigus auf plakinrei- chen Substraten (Affen- oder Rat- tenharnblase) durchgeführt. c) ermöglicht eine klare Unterschei- dung zwischen Pemphigus vulga- ris und Pemphigus foliaceus. d) wird im diagnostischen Stufenver- fahren im Anschluss an die ELISA-Untersuchung durchgeführt. e) sollte stets in Michel-Puffer trans- portiert werden. 4.Welche Aussage trifft nicht zu? a) Beim Pemphigus vulgaris lassen sich IgG-spezifische Autoantikör- per gegen Desmoglein 1 und Des- moglein 3 nachweisen. b) Die Autoantikörpertiter von Desmoglein 1 und Desmoglein 3 korrelieren in der Regel mit der klinischen Aktivität des Pemphi- gus vulgaris. c) Der atypische Pemphigus vulgaris weist in der Regel IgG-Autoanti- körper gegen Desmoglein 3 auf. d) Die Serumspiegel der Autoantikörper gegen BP180 (NC16A) korrelieren in der Regel mit der Krankheitsaktivität des bullösen Pemphigoid. e) Autoantikörper gegen BP180 finden sich beim bullösen Pemphigoid, beim Schleimhautpemphigoid, Pemphigoid gestationis und beim Lichen planus pemphigoides. 5.Welche Aussage trifft zu? a) Kollagen VII stellt die Hauptkomponente der Desmoso- men dar. b) Eine dermale Fluoreszenz in der Kochsalzspalthaut findet sich ne- ben der Epidermolysis bullosa ac- quisita und dem anti-Laminin- ␥1-Pemphigoid auch beim Schleimhautpemphigoid und der linearen IgA-Dermatose. c) Beim IgA-Pemphigus lassen sich in der indirekten Immunfluores- zenzuntersuchung lineare IgA-Ab- lagerungen entlang der dermoepi- dermalen Junktionszone nachwei- sen. d) Die lineare IgA-Dermatose ist in der direkten Immunfluoreszenzun- tersuchung durch granuläre IgA- Ablagerungen in den dermalen Pa- pillenspitzen charakterisiert. e) Aufgrund des Nachweises von IgG-Antikörpern gegen BP230 im ELISA lässt sich eindeutig die Diagnose eines bullösen Pemphi- goid stellen. 6.Welche Aussage trifft nicht zu? a) Die Applikation von Lokalanästhetika bei Mundschleimhautläsionen des Pemphigus vulgaris ist obsolet. b) Bei konjunktivaler Beteiligung bullöser Autoimmundermatosen sollte eine ophthalmologische Mitbetreuung gegeben sein. c) Bei chronischen Verläufen bullö- ser Dermatosen an der Haut muss auch an Herpesinfektionen gedacht werden. d) Vor Einleitung einer systemischen immunsuppressiven Therapie sollte das Vorliegen akuter und chronischer Infektionen ausgeschlossen werden. e) Bei Mundschleimhautbeteiligung empfiehlt sich eine Candidapro- phylaxe. 7.Welche Aussage trifft zu? a) Zur Therapie bullöser Autoimmundermatosen liegt eine Vielzahl kontrollierter klinischer Studien vor. b) Beim Pemphigus vulgaris gilt Me- thotrexat als Mittel der Wahl. c) Vor Gabe von Azathioprin muss eine Bestimmung der Thiopurin- methyltransferase-Aktivität erfol- gen. d) Mycophenolat Mofetil weist im Vergleich zu Mycophenolat- Natrium eine bessere gastrointesti- nale Verträglichkeit auf. e) Cyclophosphamid wird beim Pemphigus vulgaris auch bei Kin- derwunsch eingesetzt. Fragen zur Zertifizierung durch die DDA
- 21. Academy 947 © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2011/0911 JDDG | 11˙2011 (Band 9) 8.Welche Aussage trifft nicht zu? a) Hochdosierte, intravenöse Immunglobuline stellen eine wirksame und gut verträgliche ad- juvante Therapieoption bei thera- pierefraktärem Pemphigus dar. b) Systemische Kortikosteroide zei- gen beim Pemphigus vulgaris nur selten ein Therapieansprechen. c) Unter adjuvanter Immunadsorp- tion wurde bei therapierefraktärem Pemphigus vulgaris eine nachhaltigere Kontrolle der Krankheitsaktivität beobachtet. d) Durch die Gabe von Rituximab kommt es in vielen Fällen zu kompletten oder Teilremissionen des Pemphigus vulgaris. e) Rituximab kann auch mit intravenösen Immunglobulinen oder Immunadsorption kombiniert werden. 9.Welche Aussage trifft zu? a) Beim Pemphigus foliaceus steht die Lokaltherapie im Vordergrund, nur in schweren Fällen wird eine systemische im- munsuppressive Therapie durch- geführt. b) Nach Therapie der Grunderkran- kung kommt es beim paraneopla- stischen Pemphigus stets zur voll- ständigen Abheilung. c) Dapson wird vor allem in der Therapie der Dermatitis herpeti- formis, der linearen IgA-Derma- tose und des IgA-Pemphigus ein- gesetzt. d) Beim bullösen Pemphigoid gilt die Therapie mit hochdosierten systemischen Kortikosteroiden als Mittel der Wahl. e) Beim Pemphigoid gestationis gilt Cyclophosphamid als Therapie der Wahl. 10.Welche Aussage trifft nicht zu? a) Die Dermatitis herpetiformis zeigt unter systemischen Kortikostero- iden in der Regel eine rasche Be- fundbesserung. b) Bei therapieresistentem Schleim- hautpemphigoid können Cyclophosphamid, intravenöse Immunglobuline oder Rituximab eingesetzt werden. c) Bei der Epidermolysis bullosa ac- quisita muss häufig eine qualifizierte Wundbehandlung und Physiotherapie eingesetzt werden. d) Bei der Dermatitis herpetiformis muss eine glutenfreie Ernährung eingehalten werden. e) Beim IgA-Pemphigus können auch systemische Retinoide oder eine PUVA-Therapie eingesetzt werden. Liebe Leserinnen und Leser, der Einsendeschluss an die DDA für diese Ausgabe ist der 16. Dezember 2011. Die richtige Lösung zum Thema „Dermatologische Rehabilitation“ in Heft 7 (Juli 2011) ist: 1e, 2b, 3b, 4b, 5d, 6b, 7c, 8c, 9d, 10d. Bitte verwenden Sie für Ihre Einsendung das aktuelle Formblatt auf der folgenden Seite oder aber geben Sie Ihre Lösung online unter http://jddg.akademie-dda.de ein.