ARTICLE
Auteur(s) : Emanuele Cozzani1, Konstantina
Christana1, Alessandro Mastrogiacomo2, Paolo
Rampini1, Massimo Drosera1, Massimo
Casu3, Giovanni Murialdo3, Aurora Parodi1
1Section of Dermatology, University of Genoa, Viale
Benedetto XV, n. 7, 16132 Genova Italy
2Laboratory of Molecular and Cell Biology, Istituto
Dermopatico dell’Immacolata IRCCS, Rome, Italy
3Section of Endocrinology, University of Genoa,
Italy
accepté le 30 Mai 2007
Pemphigus vegetans (PVeg) is an uncommon variant of pemphigus
vulgaris, comprising less than 1-2% of all cases of pemphigus,
characterized by vegetating lesions primarily localised to flexural
areas [1]. Clinically two subtypes are recognized: Neumann PVeg and
Hallopeau PVeg [2, 3]. The first subtype was described in 1876 by
Neumann as a disease characterized by bullae that extend and
coalesce, evolving to vegetating masses. In time, the vegetations
become dry, hyperkeratotic and fissured. The second subtype was
described in 1889 by Hallopeau as a new skin disease characterized
by a polycyclic eruption of pustules that form firm pink papillomas
which progressively flatten and change to dark brown plaques.
Involvement of the oral mucosa is almost invariable in both
subtypes. Hallopeau PVeg has a relatively benign course and
spontaneous remission is possible. The Neumann subtype is more
common, it develops extensive lesions and is often refractory to
therapy. We describe 2 patients in whom the clinical and
histological features and the disease course were typical of PVeg
Neumann subtype. These patients presented antibodies directed to
desmoglein (Dsg) 3 and 1 and to Dsg3, respectively. In addition,
both patients had circulating autoantibodies against a 190 kDa
protein co-migrating with periplakin.
Case reports
Case 1. A 72-year-old man, affected by diabetes mellitus type II,
presented with a 1.5-year history of vegetating, malodorous,
violaceous plaques in the axillary and inguinal folds (figure 1A) and erosions of
the oral mucosa, tongue and perioral area. The cutaneous lesions
started with vesicles and bullae that extended peripherally,
forming later the vegetating lesions. Laboratory routine tests were
within normal limits except for glycated haemoglobin that was
elevated (7.3%, normal value 4.3-5.8%). A skin biopsy showed
hyperplasia of the epidermis with suprabasal acantholysis and an
inflammatory dermal infiltrate composed of lymphocytes, eosinophils
and neutrophils (figure
2). Direct immunofluorescence (DIF) showed the deposition
of IgG in intercellular spaces of the epidermis and granular
deposits of C3 at the basal membrane zone (BMZ). Circulating
pemphigus autoantibodies (Ab) were found at a titre of 1:1280 using
both monkey oesophagus and rat bladder as substrates.
Immunoblotting (IB) analysis with epidermal extracts from normal
human skin demonstrated bands at 130 kDa antigen (Dsg3) and 190
kDa, the latter comigrating with an anti-periplakin polyclonal
antibody (C-20, Santa Cruz Biotechnology, Santa Cruz, USA) (figure 3). Anti-Dsg
enzyme-linked immunosorbent assay (ELISA) was positive for
anti-Dsg1 (187,44 U/L; cut-off < 20) and anti-Dsg3 (199,60 U/L;
cut off < 20).
Case 2. A 77-year-old woman came to our observation with a
1-year history of itchy, vegetating, violaceous plaques, confined
to the intertriginous regions (figure 1B) and preceded by
vesicles and bullae. The patient also presented erosions on the
palate and hemorrhagic crusts on the lips and nasal nostrils. A
skin biopsy showed epidermal hyperplasia with acantholysis and a
dermal infiltrate of eosinophils, neutrophils and monocytes. DIF
examination revealed deposition of IgG and C3 in the intercellular
spaces of the epidermis and linear deposits of C3 along the BMZ.
Circulating pemphigus Ab binding to monkey oesophagus and rat
bladder epithelium were found at a titre of 1:640. IB demonstrated
a band at 130 kDa antigen (Dsg3) and a faint band at 190 kDa,
comigrating with an anti-periplakin polyclonal antibody. Dsg ELISA
was positive for anti-Dsg3 (248 U/L; cut-off < 20) but negative
for anti-Dsg1.
In both patients, evaluation for an associated malignancy
including chest radiography, abdomen echography, full blood count
and serum tumour markers (carcinoembryonic antigen and cancer
antigens 19-9, 15-3 and 125) failed to reveal any occult solid
tumour or lymphoproliferative disorder over a 2-year follow-up.
On the basis of the clinical and laboratory findings, a
diagnosis of Pveg Neumann type was made in the two patients. The
first one started treatment with prednisone (50 mg/day) and
azathioprine (50 mg/day) and the second one with prednisone
(60 mg/day). Both patients clearly improved within one month,
but both had a relapse. The first patient relapsed 6 months later
when the dosage of prednisone was 12.5 mg/day, and the second
one 7 months later while being treated with prednisone
10 mg/day. The dosage of prednisone was then increased to
25 mg/day with disease control.
Discussion
In our two PVeg patients, the IIF positivity on rat bladder
epithelium together with the presence of circulating antibodies
recognizing a 190 kDa band co-migrating with periplakin and of C3
deposits along the BMZ raised the possible diagnosis of
paraneoplastic pemphigus (PNP). However, this was excluded by the
lack of any evidence of malignancy at the time of diagnosis and
over a 2-year follow-up period. Additional findings against the PNP
diagnosis included the absence of IgG deposition along the BMZ on
DIF examination and the lack of reactivity by IB against other
proteins of the antigen complex recognized by PNP sera, in
particular envoplakin [4, 5].
PVeg patients are reported to present antibodies directed to
Dsg3 [1, 6, 7], and our patients were no exceptions. The reactivity
against Dsg1 detected by ELISA in the first patient is also not
surprising as Pveg is a clinical variant of PV in which anti-Dsg1
Ab often accompany anti-Dsg3 Ab. In addition, PVeg sera have
previously been reported to recognise Dsg1 [8]. In our patient, the
absence of reactivity against Dsg1 using IB on epidermal extracts
could probably be explained by the lower sensitivity of this
technique as compared to ELISA [9, 10]. An interesting and
unexpected finding in our PVeg cases was the presence of reactivity
against a 190 kDa protein co-migrating with periplakin. Periplakin
belongs to the plakin family of cytoplasmic molecules involved in
the link between desmosomal and hemidesmosomal components and
cytoskeleton intermediate filaments [11]. IB reactivity against
periplakin and/or envoplakin is regularly detected in PNP and has
been reported by Joly et al. to represent a highly specific feature
for this disease [4, 5]. However, in a subsequent study, Nagata et
al. [12] examined 240 non-PNP sera (pemphigus vulgaris, foliaceus,
bullous pemphigoid) by IB on epidermal extracts and found that 19%
of non-PNP sera reacted with a protein co-migrating with
periplakin. Moreover, they showed that most non-PNP sera reactive
with periplakin using epidermal extracts, also recognised
periplakin recombinant proteins. Other authors have also described
the presence of anti-periplakin circulating antibodies in pemphigus
foliaceous [13]. Therefore, the 190 kDa protein band recognised by
our PVeg sera is most likely periplakin, although we cannot rule
out the possibility that an as yet uncharacterized 190 kDa protein
is targeted in these patients. Recently, the presence of
circulating Ab recognising periplakin has also been detected by IB,
using both epidermal extracts and recombinant proteins, in the sera
of 10 out of 10 patients affected with toxic epidermal necrolysis
[14]. Furthermore, a reactivity to different antigens of the plakin
family has been described in blistering skin diseases other than
PNP. In fact, autoantibodies directed to desmoplakins were found in
two patients with pemphigus vulgaris and pemphigus foliaceus [15,
16], in three patients with mucosal dominant pemphigus vulgaris
[17], in two patients with bullous pemphigoid [18, 19] and in six
patients with erythema multiforme major [20]. Finally, in a recent
study we have shown that circulating antibodies to desmoplakins I
and II can be detected in pemphigus vulgaris sera, especially when
the cutaneous involvement is extensive [21].
The IIF positivity on rat bladder epithelium in our two PVeg
patients most probably correlates with the presence of
anti-periplakin antibodies and further confirms that rat bladder is
a sensitive substrate for detecting anti-plakin antibodies,
although not specific enough by itself to permit the diagnosis of
PNP. In fact, a positive labelling on rat bladder has been found in
some patients affected by pemphigus vulgaris presenting
anti-desmoplakin antibodies and in toxic epidermal necrolysis with
anti-periplakin antibodies [14, 17, 21].
As suggested for other pemphigus variants, anti-periplakin
antibodies in PVeg might result from an epitope spreading
phenomenon. However, the pathophysiological role of antibodies
directed against molecules other than Dsg is currently unknown.
Further studies on a larger number of PVeg patients should allow us
to verify if anti-periplakin antibodies are a marker of PVeg.
Acknowledgements
Financial support: none. Conflict of interest: none.
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