Anti-p200 pemphigoid is a rare autoimmune subepidermal blistering disease. Clinical presentation is similar to standard bullous pemphigoid (BP) but mucous membranes and cephalic lesions are more frequent. Histology and direct immunofluorescence (IF) are identical to BP but indirect IF discloses linear deposits of immunoglobulin G (IgG) on the dermal side of artificial salt-split skin. Specific diagnosis is based on western immunoblotting that shows circulating IgG recognizing a 200-kDa protein localized on the dermal extract. The 200-kDa antigen was recently identified as laminin γ1. Anti-p200 pemphigoid should be considered before all atypical or topical steroid-resistant bullous disease, as well as mucous membranes pemphigoid or epidermolysis bullosa acquisita. Dapsone appears to be the most effective treatment and should be used as the first option in combination with topical steroids. In this report, we describe the case of a patient with a typical clinical and immunopathological anti-p200 pemphigoid, responding to a combination of topical steroids and dapsone

Audrey Lasek

Fabienne Jouen

Laura Van Lerberghe

Philippe Modiano

Pierre Gosset

Dermatologica Sinica

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Anti-p200 pemphigoid responding to dapsone

AbstractAnti-p200 pemphigoid is a rare autoimmune subepidermal blistering disease. Clinical presentation is similar to standard bullous pemphigoid (BP) but mucous membranes and cephalic lesions are more frequent. Histology and direct immunofluorescence (IF) are identical to BP but indirect IF discloses linear deposits of immunoglobulin G (IgG) on the dermal side of artificial salt-split skin. Specific diagnosis is based on western immunoblotting that shows circulating IgG recognizing a 200-kDa protein localized on the dermal extract. The 200-kDa antigen was recently identified as laminin γ1. Anti-p200 pemphigoid should be considered before all atypical or topical steroid-resistant bullous disease, as well as mucous membranes pemphigoid or epidermolysis bullosa acquisita. Dapsone appears to be the most effective treatment and should be used as the first option in combination with topical steroids. In this report, we describe the case of a patient with a typical clinical and immunopathological anti-p200 pemphigoid, responding to a combination of topical steroids and dapsone

Van Lerberghe, Laura

Lasek, Audrey

Gosset, Pierre

Jouen, Fabienne

Modiano, Philippe

Elsevier - Publisher Connector 

at SciVerse ScienceDirect
DERMATOLOGICA SINICA 32 (2014) 51e54Contents lists availableDermatologica Sinica
journal homepage: http: / /www.derm-sinica.comCASE REPORTAnti-p200 pemphigoid responding to dapsone
Laura Van Lerberghe 1,*, Audrey Lasek 1, Pierre Gosset 2, Fabienne Jouen 3,
Philippe Modiano 1
1Department of Dermatology, University of Lille, France
2Department of Anatomopathology, University of Lille, France
3Rouen University Hospital, Department of Immunopathology, Rouen F-76031, Francea r t i c l e i n f o
Article history:
Received: Dec 10, 2012
Revised: Mar 6, 2013
Accepted: Mar 10, 2013
Keywords:
autoimmune bullous disease
bullous pemphigoid
dapsone
immunoblotting
laminin g1Conﬂicts of interest: The authors declare that they hav
conﬂicts of interest related to the subject matter or mat
* Corresponding author. Hôpital Saint Vincent de P
63, Boulevard de Belfort, 59000 Lille, France. Tel.: þ33
87 48 05.
E-mail address: laura_vlb@hotmail.com (L. Van Le
1027-8117/$ e see front matter Copyright  2013, Ta
http://dx.doi.org/10.1016/j.dsi.2013.03.001a b s t r a c t
Anti-p200 pemphigoid is a rare autoimmune subepidermal blistering disease. Clinical presentation is
similar to standard bullous pemphigoid (BP) but mucous membranes and cephalic lesions are more
frequent. Histology and direct immunoﬂuorescence (IF) are identical to BP but indirect IF discloses linear
deposits of immunoglobulin G (IgG) on the dermal side of artiﬁcial salt-split skin. Speciﬁc diagnosis is
based on western immunoblotting that shows circulating IgG recognizing a 200-kDa protein localized on
the dermal extract. The 200-kDa antigen was recently identiﬁed as laminin g1. Anti-p200 pemphigoid
should be considered before all atypical or topical steroid-resistant bullous disease, as well as mucous
membranes pemphigoid or epidermolysis bullosa acquisita. Dapsone appears to be the most effective
treatment and should be used as the ﬁrst option in combination with topical steroids. In this report, we
describe the case of a patient with a typical clinical and immunopathological anti-p200 pemphigoid,
responding to a combination of topical steroids and dapsone.
Copyright  2013, Taiwanese Dermatological Association.
Published by Elsevier Taiwan LLC. All rights reserved.Introduction
Anti-laminin g1 pemphigoid is a recently-described autoimmune
subepidermal bullous disease that has been characterized by
autoantibodies against a 200-kDa protein (p200) of the dermale
epidermal junction (DEJ).
Here, we describe the typical clinical, histopathological, and
immunopathological features in a patient with anti-p200 pem-
phigoid and his favorable response to treatment with dapsone.Case report
A 74-year-old man presentedwith a blistering pruriginous eruption
evolving for 3 months. Skin lesions were mainly localized on palms
and soles with erythematous plaques and vesicles or tense blisters
(Figure 1A). Oral and genital mucosae were involved with large
painful erosions (Figure 1B). The trunk and limbs showed poly-
morphic erythematous plaques (Figure 1C). The patient was treatede no ﬁnancial or non-ﬁnancial
erials discussed in this article.
aul, Service de Dermatologie,
3 20 87 75 76; fax: þ33 3 20
rberghe).
iwanese Dermatological Associatiofor several years with nebivolol and amlodipine for hypertension.
There was no new medication introduced. A personal history for
cutaneous disease was negative. Standard blood analysis showed
no speciﬁcity and particularly no hypereosinophilia.
Histopathological analysis of the lesional skin revealed a slight
dermaleepidermal separation and a neutrophilic and eosinophilic
inﬁltrate in the dermal papillae (Figure 2A). Direct immunoﬂuo-
rescence (IF) showed the presence of linear immunoglobulin G (IgG)
and complement 3 (C3) at the DEJ (Figure 2B). Diagnosis of bullous
pemphigoid (BP) was established and the patient was successfully
treated by clobetasol propionate 0.05% cream 40 g daily. However,
skin lesions reappearedwhen the treatmentwas tapered. Because of
this steroid resistance, new analyses were realized. Secondary his-
topathological analysis and direct IF conﬁrmed the diagnosis of BP.
Indirect IF disclosed circulating antibodies at a titer of 1:10, which is
not signiﬁcant. Those antibodies reacted with the ﬂoor of an artiﬁ-
cial blister created by the salt-split skin technique (Figure 3).
Enzyme-linked immunosorbent assay (ELISA)with basalmembrane
zone proteins of 230 kDa (BP230) and 180 kDa (BP180) were nega-
tive. Western immunoblot analysis using a dermal extract showed
the reactivity of circulating IgG4 antibodies with the 200-kDa an-
tigen, suggesting the diagnosis of anti-p200 pemphigoid (Figure 4).
The patient was successfully treated by combining clobetasol
propionate 0.05% cream 30 g daily and dapsone 100 mg daily, with
a progressive healing of erosions without scarring and milian. Published by Elsevier Taiwan LLC. All rights reserved.
Figure 1 Clinical characterization of a patient with anti-p200 pemphigoid. (A) Tense blisters and erythematous plaques on the sole of the foot. (B) Mucous membrane lesions and
tense blister on the ﬁnger. (C) Pruriginous polymorphic eruption on the trunk and limbs. (D) Complete healing after 2 weeks of topical clobetasol propionate 30 g and dapsone
100 mg daily.
L. Van Lerberghe et al. / Dermatologica Sinica 32 (2014) 51e5452formation (Figure 1D). His disease is currently controlled with
dapsone 100 mg daily and without the use of corticosteroids.
Discussion
In 1996, Zillikens et al1 described the ﬁrst case of a new sub-
epidermal immunobullous disease called anti-p200 pemphigoid.
Approximately 70 cases of anti-p200 pemphigoid mediated by
IgG antibodies have been reported in the literature to date,2 and
only one was associated exclusively with immunoglobulin A (IgA)
antibodies.3 In 2009, Dainichi et al4 identiﬁed the 200-kDa pro-
tein as laminin g1 and renamed the disease anti-laminin g1
pemphigoid.
Anti-p200 pemphigoid usually occurs at a younger age than that
observed in patients with BP and appears to be more frequent in
male patients.5 The presentation is rather heterogenous and mayFigure 2 (A) Histological analysis: hematoxylineeosin staining of the lesional skin (20) sho
in the dermal papillae. (B) Direct immunoﬂuorescence shows immunoglobulin G and compmimic BP, linear IgA dermatosis, dermatitis herpetiformis,2 or
epidermolysis bullosa acquisita (EBA).6 The BP-like type is the most
common and is characterized by itchy urticarial papules and pla-
ques and tense blisters on the trunk and extremities.5 Oral and
genital mucous membranes are affected in approximately 20% of
patients with anti-p200 pemphigoid and cephalic involvement is
common.5 Blood analysis does not disclose the hypereosinophilia
found in classic BP.
In our patient, we found acral predominance of the lesions and
considerable mucous membrane involvement. Lesions usually heal
without scarring; milia formation has been observed in three pre-
viously reported cases.7e9
Except for psoriasis in one-third of cases, no other cutaneous
disease or tumor seems to be associated with anti-laminin g1
pemphigoid. There is only one case report about penicillin-induced
anti-p200 pemphigoid.10wing slight dermaleepidermal separation and a neutrophilic and eosinophilic inﬁltrate
lement 3 deposits along the basement membrane zone.
Figure 3 Indirect immunoﬂuorescence using salted-split skin shows the presence
of circulating immunoglobulin G4 antibodies bound to the ﬂoor of an artiﬁcial blister.
L. Van Lerberghe et al. / Dermatologica Sinica 32 (2014) 51e54 53Histopathological analysis of lesional skin shows a slight
dermaleepidermal separation with neutrophilic and/or eosino-
philic inﬁltration in the superﬁcial dermis. Direct IF examination of
a perilesional skin biopsy revealed linear deposits of IgG and C3
along the DEJ. In two cases, an additional staining for IgA was
described,11,12 and one case even revealed exclusively IgA deposits.3
Indirect IF study on salt-split human skin demonstrates circulating
IgG (IgG4) autoantibodies binding to the dermal side of the artiﬁcial
split. These antibodies disappear when skin lesions improve under
immunosuppressive treatment. In four cases of anti-p200 pem-
phigoid, both dermal and epidermal sides were ﬁxed by IgG.5 ELI-
SAs with BP230 and BP180 are negative most of the time.
Immunoblot analysis reveals autoantibodies directed against a 200-Figure 4 Immunoblot analysis using the dermal extract. Lane 1: serum containing
anticollagen VII antibodies (290 kDa). Lanes 2 and 4: normal human serum showing no
reactivity. Lane 3: control serum containing anti-p200 antibodies. Lane 5: patient’s
serum showing immunoglobulin G4 (IgG4) antibodies reacting with the 200-kDa
protein.kDa antigen localized on the dermal extract that would also be
present in certain cases on the epidermal extract.2 However,
preparation of a dermal extract requires a sophisticated extraction
procedure that is not widely available, limiting the possibility of
diagnosing this disease to a few specialized laboratories. Several
research teams are trying to develop techniques to detect autoan-
tibodies against laminin g1. Groth et al13 recently developed an
ELISA test with the recombinant monomeric C-terminal fragment
of human laminin g1. This test has a high speciﬁcity of 98.7% but an
insufﬁcient sensitivity of 69%. Further studies are required to
improve detection of autoantibodies to laminin g1 for routine
diagnosis of blistering disease.
Clinically, the ﬁrst diagnoses mentioned are BP, mucous mem-
branes pemphigoid, and inﬂammatory EBA. For now, anti-p200
pemphigoid cannot be distinguished from other subepidermal
blistering disorders on the basis of histological and immunopath-
ological features alone. Diagnosis is made by western blotting and
depends entirely on the quality of the dermal extract. For this
reason, anti-p200 pemphigoid may have been underdiagnosed in
the past.
Differentiation of this disease from EBA is relevant as anti-p200
pemphigoid commonly shows a relatively benign course and can be
treated with topical clobetasol propionate alone or in association
with oral dapsone.
In 2003, Shimanovich et al14 showed that p200 is an acidic
noncollagenous N-linked glycoprotein of the lower lamina lucida.
The laminin g1 chain has recently been identiﬁed as the target
antigen in anti-p200 pemphigoid and the C-terminus was
described as an immunodominant region of laminin g1.2 Laminin
g1 is a component of different forms of laminin heterotrimers,
which contributes to dermaleepidermal adhesion outside hemi-
desmosomes. Laminin g1 is a ubiquitous protein found in the DEJ,
blood vessels, and in the extracellular matrix of several organs
including the central nervous system. It has been suggested that
laminin g1 in the DEJ may have different post-translational modi-
ﬁcations explaining the cutaneous speciﬁcity of the disease: the
antibody anti-laminin g1 should recognize a speciﬁc form present
only in the skin.2
Based on the literature, anti-p200 pemphigoid is treated with
various immunosuppressive therapies. Most of the cases required
systemic corticosteroid therapy (up to 1 mg/kg/day), alone or in
association with other immunosuppressive drugs (azathioprin,
ciclosporin, mycophenolatemofetil, methotrexate, intravenous im-
munoglobulins).5 One patient was completely healed with topical
steroids only. Most of the time, lesions reappeared when treatment
was tapered. In several cases, adjunction of dapsone permitted
remission and withdrawal of corticosteroids. The present case was
treated with a combination of topical corticosteroids and dapsone
100 mg/day, which allowed a completed remission after 1 year.
In conclusion, anti-p200 pemphigoid is probably under-
diagnosed and should be considered before every subepidermal
bullous disease that does not fulﬁll the criteria of well-known
blistering diseases, because of atypical symptoms or therapeutic
resistance. Diagnosis is conﬁrmed by immunoblotting. Dapsone
should be considered as the ﬁrst treatment choice in combination
with topical steroids.References
1. Zillikens D, Kawahara Y, Ishiko A, et al. A novel subepidermal blistering disease
with autoantibodies to a 200-kDa antigen of the basement membrane zone.
J Invest Dermatol 1996;106:1333e8.
2. Dainichi T, Koga H, Tsuji T, et al. From anti-p200 pemphigoid to anti-laminin g1
pemphigoid. J Dermatol 2010;37:231e8.
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Dermatol 2011;147:1306e10.
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