ARTICLE
Auteur(s) :, Yuko Iino*,
Hiroyuki Hara, Takane Suda, Tomoyoshi Okada, Shunichi Baba,
Hiroyuki Suzuki
Department of Dermatology, Nihon University School of Medicine,
30-1 Oyaguchi-kamimachi, Itabashi-ku, Tokyo 173-0032, Japan Fax:
(+81)359 95 98 41.
accepté le 4 Juin 2004
Pemphigus vulgaris (PV) is an autoimmune blistering disease of the
skin and mucous membrane. PV is divided into two subgroups. One is
a mucosal dominant type and the other is a mucocutaneous type [1].
The mucosal dominant PV sera are positive against Dsg3, whereas
patients with mucocutaneous lesions have both anti-Dsg3 and
anti-Dsg1 antibodies [2]. Recently, an ELISA system was established
to detect and quantify anti-Dsg1 and anti-Dsg3 [3]. It has been
demonstrated that Pemphigus foliaceus (PF) is accompanied by
autoimmune thyroid diseases [4]. However, the association of PV and
Hashimoto’s thyroiditis is quite rare. It is well known that human
leukocyte antigen (HLA) might contribute to the development of
autoimmune disorders. We report a case with the mucocutaneous type
of PV in which Hashimoto’s thyroiditis proceeded to PV.
Case report
A 69-year-old Japanese woman presented to our Dermatology Clinic
with a 2-month history of painful oral erosions.
Thereafter, blisters occurred on the trunk and arms. Her past
history included Hashimoto’s thyroiditis for about two years. The
incidental thyroid function tests reveled hypothyroidism with a
thyroid stimulating hormone (TSH) of 0.02 μIU/ml (normal:
0.34-3.80). A free T3 level and a free T4 level were 1.21 pg/ml
(normal: 2.00-3.80) and 1.55 mg/dl (normal: 0.80-1.50),
respectively. Antithyoglobulin antibody was present at a titer of x
25,600 (normal: < 50) and antimicrosomal antibody at a
titer of x 3,200 (normal: < 50). Serological studies showed
a positive antinuclear antibody (ANA) titer of 1:40 in a nucleolar
pattern. She was treated with levothyroxine sodium at a dose of 100
μg/day.
Physical examination revealed extensive oral erosions from the
soft to hard palate. On the skin of the neck, chest, back and arms,
there were multiple flaccid bullae and erosions with crusts.
Nikolsky’s sign was positive.
A skin biopsy taken from a flaccid blister on the back
demonstrated an intraepidermal blister at the suprabasal layer with
acantholysis. Direct immunofluorescent analysis showed deposition
of IgG and C3 in the intercellular space in the epidermis.
Antibody titer against desmoglein 1 (Dsg1) and desmoglein 3
(Dsg3) were measured by specific enzyme-linked immunosorbent assay
(ELISA) using recombinant Dsg1 and Dsg3 as previously described [1,
3]. The patient serum was positive against both Dsg1 (index for
Dsg1, 63; cut-off value, 14.0) and Dsg3 (index for Dsg3, 192;
cut-off value, 7.0). A diagnosis of pemphigus vulgaris was
made.
Genomic DNA was extracted from the peripheral blood leukocytes
and typed for HLA-A alleles using polymerase chain reaction
(PCR)-sequencing-based typing. HLA-DR and HLA-DQ) alleles were
investigated by the method of PCR-sequence specific primers
according to a standard procedure. HLA-A (A*02011, A*2402101),
-DQA1 (DQA1*0104, DQA1*0303), -DQB1 (DQB1*0401, DQB1*05031) and
-DRB1 (DRB1*0405, DRB1*1405) were identified.
The patient was treated with oral prednisolone at a dose of 40
mg/day and then gradually tapered. The patient’s skin and mucosal
lesions were resolved 2 weeks after the initiation of prednisolone.
In spite of rapid improvement of the oral and skin lesions, the
Dsg1 and Dsg3 ELISA scores continued to show high values of 68 and
168, respectively. Three months after the initiation of treatment,
however, their scores dropped to 17 and 66, respectively. She is
now in remission with oral prednisolone at a dose of 20 mg/day ((
figure 1 )).
Discussion
The present case had PV co-existing with Hashimoto’s thyroiditis.
Hashimoto’s thyroiditis proceeded the development of PV. There was
no correlation between disease activity and Dsg1 and Dsg3 ELISAs
values. Several alleles of HLA-A, -DQA1, -DQB1 and -DRB1 loci were
determined from the patient’s peripheral blood leukocytes.
It has been demonstrated that PV is accompanied by other
autoimmune diseases such as myasthenia gravis, systemic lupus
erythematosus (SLE), rheumatoid arthritis (RA) and Grave’s disease
[5]. On the other hand, Hashimoto’s thyroiditis is also an
autoimmune disease, because there is an association with
antithyroglobulin and/or antimicrosomal antibodies. Hashimoto’s
disease is known to associate with other autoimmune diseases such
as SLE and RA and there have been several reported cases of bullous
pemphigoid and dermatitis herpetiformis in association with
Hashimoto’s thyroiditis [6-8]. Only one reported case involving the
co-existence of PV and Hashimoto’s thyroiditis has been described
in the English literature [9].
The precise mechanisms of the association between pemphigus and
autoimmune thyroid diseases are not fully understood. Although some
authors concluded that the concomitant presence of pemphigus and
autoimmune thyroid diseases might be coincidental, other authors
speculated that it might represent an expression of increased
susceptibility to autoimmune thyroid diseases [10].
Dsg1 and Dsg3 ELISA scores provide a sensitive and specific
assay for the diagnosis of patients with PV and PF. The ELISA
system shows a good correlation with disease activity [11]. The
present case had high values of both anti-Dsg3 and ant-Dsg1
antibodies by ELISA in her serum. In spite of the improvement of
the skin and mucosal lesions, however, Dsg1 and Dsg3 ELISAs
continued to have high values before and during the treatment with
prednisolone. At higher Dsg1 and Dsg3 ELISA values in mucocutaneous
types of PV, both these ELISA values become nonlinear and the
dilution curves reach a plateau [12]. In our study, the patient
sera were diluted 1:101. It is advocated that a further dilution of
the sera may be needed to detect precise values, when Dsg1 and Dsg3
ELISAs show high values [13].
It has been widely accepted that human HLA complex plays an
important role in the susceptibility to certain autoimmune
diseases. HLA class I genes and HLA class II genes have been
analyzed in several autoimmune diseases. Specific HLA classII
antigens confer a susceptibility to PV among Japanese patients.
Previous studies have shown that there was a statistical
significance in the frequencies of HLA-DRB1*04 (*0403, *0406),
DRB1*14 (*1401, *1405, *1406) and DQB1*05031 in Japanese patients
with PV [14, 15]. HLA-A*0201 and -A*2402 classified into HLA class
I alleles are also prevalent in Japanese PV patients. On the other
hand, the frequencies of HLA-A2, DB1*0403, DRB4*0101, DQA1*0102,
DQA1*03 and DQB1*0303 were significantly increased in Japanese
patients with Hashimoto’s thyroiditis [16]. In the present study,
several HLA antigens strongly associated with either PV or
Hashimoto’s thyroiditis were found. These results may indicate that
the specific HLA antigens contribute to the development of various
types of autoimmune diseases. However, we could not find the common
HLA alleles, which indicated a genetic susceptibility to both PV
and Hashimoto’s thyroiditis. More detailed analyses of the
association of HLA molecules will be necessary to determine the
susceptibility to PV and other autoimmune diseases including
Hashimoto’s thyroiditis.
References
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