ARTICLE
Auteur(s) : Sachiko Takeichi1, Yoshiaki
Kubo1, Seiji Arase1, Takashi
Hashimoto2, Shin-ichi
Ansai1
1Department of Dermatology, Institute
of Health Biosciences, University of Tokushima Graduate
School, 3-18-15, Kuramoto-cho, Tokushima, 770-8503, Japan
2Department of Dermatology, Kurume University
School of Medicine, Japan
accepté le 20 Mars 2009
Bullous pemphigoid (BP) is an autoimmune subepidermal bullous
disease usually affecting the limbs and trunk [1, 2]. The localized
form is an unusual variant of BP that occurs in 5-30% of BP
patients [1]. Localized BP (LBP) is known to be divided into two
different types [1, 3]. One, designated as pretibial localized
pemphigoid, is usually limited to the lower extremities and
responds well to treatment. This type of LBP may progress to the
generalized form. The other form, termed Brunsting-Perry type LBP,
is considered to be a variant of cicatricial pemphigoid (CP), and
the lesions are localized to the scalp or face with scarring [3].
The pathogenesis of these two variants of BP remains unclear.
We report a case of LBP on the face of a patient who received
peritoneal dialysis, and whose lesions were possibly triggered by
furosemide administration and sunlight.
Case report
A 56-year-old male visited the outpatient clinic of the Department
of Dermatology, Tokushima University Hospital, in May, 2007,
complaining of numerous erosive erythemas on his forehead and
cheeks for over one month. His mother was receiving treatment for
pemphigus vulgaris. He had been receiving peritoneal dialysis and
furosemide administration due to chronic renal failure of uncertain
etiology, for four years.
Clinical presentation at the first visit revealed irregular
shaped atrophic erythematous plaques with blood crust, erosion,
pigmentation, and depigmentation on the forehead, bilateral cheeks,
and ear lobes (figure
1). No lesions were found in the oral mucosa.
Histopathological findings of a specimen taken from erythema on the
cheek exhibited slight vacuolar changes in the keratinocytes of the
basal layer of the epidermis and perivascular infiltration of
lymphocytes and eosinophils in upper portion of dermis (figure 1). Direct
immunofluorescence examination using a specimen taken from the
cheek exhibited linear depositions of IgG and C3 in the basement
membrane zone (BMZ) (figure 1). Indirect
immunofluorescence examination using serum and 1 M NaCl
split skin revealed linear depositions of IgG on the epidermal side
of the BMZ (figure
1). Laboratory examinations revealed eosinophilia (11.5% in
7,600/μL of white blood cells), a positive fluorescent test for
antinuclear antibodies (×40) and high serum blood urea nitrogen (50
IU/mL, normal: < 17 IU/mL) and creatinine
(12.61 mg/dL, normal: 0.4-0.9 mg/dL) levels caused by
chronic renal failure. Other laboratory data were all normal. Other
autoantibodies, such as anti-SS-A, anti-SS-B, anti-Sm, and Anti-ds
DNA were all negative.
The titre of antibodies against the recombinant NC16a-domain of
BP180 was within normal limits by ELISA (4.39: normal < 15),
though that of BP230 ELISA was high (75.36: normal < 9).
Immunoblotting using extracts of normal human epidermis showed that
IgG class autoantibodies reacted with BP180 and BP230 (figure 2), but not with
desmoglein 1, desmoglein 3, envoplakin, or collagen type VII.
Patient’s serum reacted with 190 kDa periplakin, but this reaction
was thought to be non-specific, because it is also seen in normal
controls. On the other hand, IgG class autoantibodies to
recombinant proteins of the C-terminal domain of BP180 were
detected by immunoblotting (figure 2) but those to
recombinant proteins of the NC16A domain could not be detected.
Antibodies to the 120 kDa LAD-1 also could not be detected by
immunoblotting using the concentrated culture supernatant of HaCaT
cells.
From these findings, a diagnosis of LBP was made. The patient
initially responded well to oral administration of prednisolone
10 mg daily, soon after the diagnosis was made. Eruptions on
the face disappeared with superficial scars. Prednisolone was
tapered and stopped; then several eruptions recurred. Oral
administration of prednisolone 10 mg daily was started again,
and furosemide administration was discontinued. Eruptions
disappeared soon thereafter. The patient is being maintained with
topical tacrolimus without recurrence for more than 15 months.
The minimum erythematous dose (MED) of UVA was low
(2.1 J/cm2) under furosemide administration;
however, the dose was normalized (10.5 J/cm2) nine
months after discontinuation. Autoantibodies to BP230 were detected
by ELISA and immunoblotting and antibodies against the recombinant
protein of BP180 by immunoblotting after eruptions disappeared;
however, the titer of autoantibodies to recombinant protein of
BP230 by ELISA was impaired (29.37).
Discussion
In this case, there were two interesting findings. One was linear
depositions of IgG and C3 in the BMZ by direct immunofluorescence
and the detection of autoantibodies to the C-terminal domain of
BP180 by immunoblotting and BP230 by both ELISA and immunoblotting.
The other was photosensitivity probably induced by furosemide
administration, because MED normalized after the cessation of
furosemide administration.
Immunopathological and immunoblotting findings indicated that
this case was BP or CP. The clinical findings of this patient were
compatible with Brunsting-Perry type LBP. The pathogenic antigen of
Brunsting-Perry type LBP has not been fully elucidated [3, 4], and
Brunsting-Perry type LBP has been considered to be a variant of CP
[3]. CP is divided into two different subtypes according to the
target antigen of the autoantibodies. The target antigen in one
type is laminin 5 [5, 6] and that in the other is the C-terminal
domain of BP180 [7-9]. Daito and colleagues reported a case of
Brunsting-Perry type LBP associated with autoantibodies to the
C-terminal domain of BP180, as in the present case [10]. These
cases support the view that Brunsting-Perry type LBP is a variant
of CP. These two cases with Brunsting-Perry type LBP revealed only
IgG class autoantibodies to the C-terminus of BP180, but not IgA
class. Murakami and colleagues reported that only 4% of CP sera
exhibited IgA class autoantibodies to recombinant protein of the
C-terminal domain of BP180 [7]. On the other hand, several other
reports indicate that Brunsting-Perry type LBP is a variant of
epidermolysis bullosa acquisita (EBA) from immunohistological
findings [11-13]. Furthermore, Demitsu and colleagues reported a
case of Brunsting-Perry type LBP with antibodies against the
NC16a-domain of BP180 [4]. In the present case, indirect
immunofluorescence examination using serum and 1M NaCl split skin
revealed linear depositions of IgG on the epidermal side of BMZ and
antibodies against 290 kD collagen type VII were not detected by
immunoblotting using extracts of normal human dermis. And
autoantibodies against the NC16a-domain of BP180 were not detected
by immunoblotting and ELISA. These data may indicate that
Brunsting-Perry type LBP includes several diseases that are
associated with different target antigens of autoantibodies.
Local irritations, such as burn injury, trauma, operations,
radiation, and ultraviolet irradiation, and drugs such as
furosemide, spironolactone, sulfasalazine, penicillin, and
D-penicillamine, have been reported to induce BP [1]. The present
patient showed UVA photosensitivity induced by furosemide and
exhibited lesions only on sun-exposed areas. Furosemide is known to
provoke not only drug induced BP, but also drug induced
photosensitivity. However, there have been no reports of cases of
furosemide-induced BP limited to sun exposed area or cases of
furosemide-induced photosensitivity that have been identified on
the basis of immunohistological or immunoblotting examinations.
Cases with similar immunoprofiles to the present case may be
contained in those diagnosed as furosemide-induced
photosensitivity.
Bastuji-Garin and colleagues reported that diuretics and
neuroleptics were used more frequently by BP patients than control
patients and the association with diuretics was only linked to
aldosterone antagonists, but not to furosemide [14]. Their data is
indirect evidence of the involvement of some drugs in sideration of
BP. Actually, there has been a report of a case of BP induced by
furosemide administration [15]. After complete clearing with
prednisone therapy, bulla formation was observed by
re-administration of furosemide in that case. In the present case,
from the distribution of lesions and clinical course, the
combination of furosemide administration and sun exposure had
probably triggered BP. Therefore, we do not think that there is no
relation between furosemide administration and BP.
Two target antigens of autoantibodies were detected in the
present patient. They were BP230 and the C-terminal domain of
BP180. Murakami and colleagues reported that 28% of CP sera samples
exhibited autoantibodies to BP230 by immunoblotting using extracts
of normal human epidermis [7]. The significance of autoantibodies
to BP230 in this disease is still unclear. As Daito and colleagues
reported [10], only autoantibodies to the C-terminal domain of
BP180 may be responsible for inducing Brunsting-Perry type LBP.
However, photosensitivity due to furosemide may have caused the
destruction of basal keratinocytes in sun-exposed areas, and when
BP230, which is an intracellular protein of keratinocytes, was
exposed, the lesions might be enhanced. This speculation is
supported by the finding that the lesions were controlled only by
topical tacrolimus and the titer of anti-BP230 autoantibodies
reduced after the cessation of furosemide administration.
Acknowledgement
Financial support: none. Conflict of Interest: none
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