ARTICLE
Auteur(s) : Noriko
Fukiwake1, Yoichi Moroi1, Kazunori
Urabe1, Norito Ishii2, Takashi
Hashimoto2, Masutaka Furue1
1Department of Dermatology, Kyushu University
Hospital Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan
2Department of Dermatology, Kurume University, School of
Medicine Asahi-machi 67, Kurume, Fukuoka, 830-0011, Japan
accepté le 20 Decembre 2006
It is well known that autoantibodies play a crucial role in
autoimmune bullous diseases such as pemphigus vulgaris, pemphigus
foliaceus, and bullous pemphigoid. Autoantibodies circulate in the
blood and bind to specific cutaneous components, leading to bulla
formation. Several proteins have been identified as the target
proteins of autoantibodies. Anti-desmoglein (Dsg) 1 or Dsg3
antibodies are detected in the sera of all the patients with
pemphigus [1], and an in vivo study using neonatal mice revealed
that the circulating autoantibodies have pathogenic activity in
blister formation [2]. Autoantibodies in the sera of patients with
bullous pemphigoid react with 230 kDa and 180 kDa proteins, which
are recognized as the antigens BP230 and BP180, respectively [3-5].
Desmoplakin (DP) I and II are located in desmosomes, and
autoantibodies to these proteins were detected in patients with
paraneoplastic pemphigus [6, 7].Foedinger et al. [8] detected
autoantibodies to DP I and II in seven out of 10 patients with
erythema multiforme (EM) major and in none of the patients with EM
minor. The authors suggested that these autoantibodies define a
subset of patients with EM. Here we describe a patient who
presented with chronic erosions and ulcers of the oral mucosa
without other skin and mucosal lesions, and autoantibodies to DP I
and II were detected.
Case report
A 73-year-old woman with a 20-year history of erosions and ulcers
of the tongue and oral mucosa was referred to our department. The
lesions were resistant to many treatments including oral
prednisolone and topical application of antibiotics. Although
repeated exacerbations and regressions of the mucosal
manifestations were observed, the symptoms never disappeared. She
did not have a history of skin and mucosal erythema, bullae or
erosions at other sites at any time during her clinical course. In
spite of repeated serum chemistry studies and biopsies at other
institutions, a final diagnosis had not been made. The patient did
not have a past history of malignancies.
On examination, erosions and ulcers were seen in the lateral
parts of the tongue and lower oral mucosa (figure 1). The lips and
gingivae were not affected. Laboratory examination and serum
chemistry panel did not reveal any abnormalities. Microscopic
examination of mucosal coats did not reveal any evidence of Candida
albicans infection. Biopsy specimens of the oral mucosa showed the
infiltration of inflammatory cells, which mainly consisted of
lymphocytes and plasma cells in the upper area of the submucosa
(figure 2A).
There were several necrotic cells in the mucosal epithelium (figure 2B). No
definite blisters were seen in either the intramucosal or
submucosal tissues.
Anti-Dsg1 and Dsg3 antibodies were not detected in the serum of
the patient by ELISA. By indirect immunofluorescence (IIF) using
normal human skin sections, circulating autoantibodies reactive
with keratinocyte cell surfaces were detected at a titer of x160
(figure 3A). IIF
using monkey esophagus as a substrate also showed anti-keratinocyte
cell surface antibody (figure 4). On
immunoblotting using protein extracts of normal human epidermis,
the patient’s serum was found to contain autoantibodies to 250 kDa
and 210 kDa proteins, indicating the presence of autoantibodies to
DP I and II (figure
5). The patient was negative for anti-envoplakin and
anti-periplakin antibodies.
Based on these results, we diagnosed the patient as having
erythema multiforme. The patient was treated with oral
administration of minocyclin, 100 mg/day, and topical
dexamethasone for 3 months. The erosions decreased in size,
although they still exist.
Discussion
To our knowledge, this is the first case of EM limited to the oral
mucosa in which autoantibodies to DP I and II were detected.
EM is a disorder that has characteristic skin lesions composed
of papules, erythema, blisters or so-called iris lesions with
unknown etiology. Symmetrical involvement of the extremities is the
classical distribution of EM, although oral or other mucosal sites
are occasionally affected. EM varies widely in severity, ranging
from acute, self-limited mild cases with skin erythema to severe
types (Stevens-Johnson syndrome and toxic epidermal necrolysis)
with extensive mucocutaneous necrosis. Some EM cases involve only
the oral mucosa (oral EM).
The concept of oral EM is still controversial [9], although many
authors recognize this entity [10-12]. Clinically, bullae,
erosions, or ulcers appear in the mucosa of the oral cavity. The
course of oral EM may be self-limiting or episodic. Occasionally,
chronic lesions exist. Among 95 EM patients with oral involvement,
cutaneous involvement was seen in 25% of the patients [13]. The
diagnosis of oral EM is made after the exclusion of other diseases
such as pemphigus, cicatrical pemphigoid, chronic ulcerative
stomatitis and lichen planus (LP) that present erosions or
ulcerations of the oral mucosa [14].
LP is a common inflammatory disorder that occasionally affects
oral mucosa. Clinical manifestations of oral LP are composed of
reticular, erythematous and erosive forms. Reticular lesions are
the most recognized form of oral LP, and reticular lesions have
been observed alone or with erythematous and erosive lesions in
almost all cases of oral LP [15]. Although hypotheses about
pathogenesis of LP include virus infections, and cellular immune
dysregulation such as T cells and mast cells [16], the etiology
remains unknown. The typical histological findings in LP are
composed of superficial band-like lymphocyte infiltration, basal
cell liquefaction degeneration. Jagged rete ridges and Civatte
bodies may also be observed [17].
Chronic ulcerative stomatitis has been described as new disease
entity. It displays the chronic, erosive or ulcerative lesions in
lingual, buccal or gingival mucosa. The histopathologic findings of
this disease are not distinctive. Stratified epithelium-specific
antinuclear antibody is a disease marker and this autoantibody is
detected in patient’s sera [18].
To make a diagnosis in the present case, we excluded the
possibility of autoimmune bullous diseases. On an IIF, the
patient’s serum reacted with keratinocyte cell surfaces, which
ruled out the diagnosis of bullous pemphigoid. Negative ELISA
results for Dsg1 and Dsg3 excluded the possibility of pemphigus
vulgaris and pemphigus foliaceus. The detection of anti-DP I and II
without anti-envoplakin or anti-periplakin antibodies, and the fact
that there is no evidence of coexisting malignancy excluded the
diagnoses of paraneoplastic pemphigus. Chronic ulcerative
stomatitis was denied by the autoantibody profile. We rejected the
possibility of LP because there were no features of basal layer
liquefaction degeneration in the histopatholgical findings. The
histopathological findings, which were composed of necrotic cells
in mucosal layer and submucosal cell infiltration, led us to the
diagnosis of oral EM.
DP I and II exist in cytoplasmic attachment plaques of
desmosomes and bind directly to the keratin intermediate filaments.
In paraneoplastic pemphigus, the antigen complex consists of DP I,
DP II, BP230, envoplakin, periplakin, plectin and unknown antigen
p170 [6]. Anti-DP antibodies have also been detected in some
patients with bullous pemphigoid [19], pemphigus foliaceus [20] and
pemphigus vulgaris [21]. Besides these cases, Oyama et al. [22]
reported a case of oral and genital erosions with circulating DP I
and DP II antibodies histopathologically which demonstrated
lichenoid reactions. In this case, clinical features are different
from usual LP because of a persistent ulcer of the hard palate. DP
I and DP II turned out to be positive 2 years after the onset of
mucosal ulceration [22].
Seven out of 10 cases with EM major have also been reported
positive for anti-DP I and II autoantibodies. In the positive
cases, an IIF revealed autoantibodies bound to the plasma membrane
of epidermal keratinocytes, and immunoblotting showed
autoantibodies reactive with polypeptides of 250kDa and 210kDa,
which were DP I and II. In contrast, no autoantibodies were
detected in the 8 patients with EM minor [8]. Foedinger et al. [23]
reported that histological changes consistent with EM were observed
in the skin of experimental mice after subcutaneous injection of
anti-DP antibodies from the sera of patients with EM major,
however, it is not fully understood whether anti-DP antibodies have
a pathogenic role in mucocutaneous manifestations or they appeared
by the mechanism of epitope spreading [22].
Systemic corticosteroids have occasionally been used to treat
continuous oral EM. Considering the age of our patient and
potential side effects, we selected topical steroid therapy for our
patient.
This is the first case of oral EM that was positive for
autoantibodies to DP. These antibodies are not specific to patients
with paraneoplastic pemphigus, but have also been detected in
patients with other blistering or ulcerative diseases. An
immunofluorescence, immunoblotting or ELISA of Dsg1 and Dsg3 should
be performed for the differential diagnosis between oral EM that is
positive for autoantibodies and other autoimmune bullous
diseases.
Acknowledgment
We thank Ernst H. Beutner, PhD (Beutner Laboratories, Buffalo, New
York) for providing non-fixed monkey esophagus section. This work
has been supported by National Institute of Health grant RR00163 to
the Oregon Primate Research Center.
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