ARTICLE
Auteur(s) : Hiroshi Koga, Norito Ishii, Takahiro Hamada,
Tadashi Karashima, Takekuni Nakama, Shinichiro Yasumoto, Takashi Hashimoto
Department of Dermatology, Kurume University School
of Medicine, 67 Asahimachi, Kurume, Fukuoka 830-0011,
Japan
accepté le 21 F�vrier 2010
Mycophenolate mofetil (MMF), a 2-morpholino-ethyl ester of
mycophenolic acid, is a relatively new systemic immunosuppressive
agent and its use is rapidly increasing in various fields of
dermatology, including treatment for autoimmune bullous diseases
such as pemphigus vulgaris (PV), pemphigus foliaceus, and bullous
pemphigoid [1]. Moreover, MMF has been reported to be effective in
patients with paraneoplastic pemphigus [2], linear IgA disease [3],
linear IgA bullous dermatosis of childhood [4], cicatricial
pemphigoid [5] and epidermolysis bullosa acquisita [6].
We treated four patients with mucocutaneous type PV. In all
cases, the diagnosis was confirmed by routine histopathology,
direct and indirect immunofluorescence, and by detecting
circulating antibodies to desmoglein 1 (Dsg1) and Dsg3 by
enzyme-linked- immunosorbent assay (ELISA). The patients were
refractory to various treatments including systemic
corticosteroids, plasmapheresis, and immunosuppressive agents such
as mizoribine and azathioprine. Patients were treated with a
combination of MMF and prednisolone, and the skin and oral mucosal
lesions quickly improved without any MMF-attributable side
effects.
Case reports
Case 1
A 54-year-old Japanese male patient suffered from PV and was
treated with prednisolone (20 mg/day). The patient had
extensive erosions over his whole body and oral mucosa at the first
visit. Upon hospitalization, the patient underwent intravenous
immunoglobulin therapy. Although the lesions improved, new lesions
gradually appeared. The patient was treated with a combination of
prednisolone (30 mg/day) and mizoribine (150 mg/day)
without success. Then, mizoribine was replaced with azathioprine,
but new lesions continued to appear (figure 1A). An X-ray
revealed lesions in the lung and the patient was diagnosed with
non-tuberculous mycobacterial infection. Therefore, we tapered the
corticosteroid treatment. We decided thereafter to start a
combination therapy with prednisolone (30 mg/day) and MMF
(2 g/day), and the appearance of new blisters significantly
decreased (figure 1B). Although
the prednisolone dosage was decreased from 30 mg/day to
25 mg/day without a reduction in the MMF dose 6 months
after the initiation of the MMF therapy, the patient was free from
blisters for the following 10 months and his lung lesions were
not exacerbated.
Case 2
A 44-year-old Japanese male patient developed blisters and erosions
on his entire body and in the oral mucosa, and visited us. The
patient was diagnosed with PV and was treated eight times with
plasmapheresis and prednisolone (60 mg/day), which decreased
new lesions. However, the lesions recurred, and combination
therapies of prednisolone with mizoribine (150 mg/day),
azathioprine (100 mg/day), and cyclosporine (200 mg/day)
were performed without success. Therefore, we started a combination
therapy with prednisolone (25 mg/day) and MMF (2 g/day).
The appearance of new active lesions ceased within 10 days.
The prednisolone dosage was first reduced by 2.5 mg/day every
2 weeks to 7.5 mg/day without relapse. Thereafter, the
MMF dosage was reduced by 250 mg every month. At the
administration of 7.5 mg/day prednisolone and 1.5 g/day
MMF 5 months after the initiation of MMF therapy, however, new
lesions appeared, and the MMF dosage was restored. The patient was
then treated with MMF (2 g/day) and a low dose of
prednisolone, and had no relapse for 8 months.
Case 3
A 58-year-old Japanese female patient suffered from mucocutaneous
type PV and was treated with prednisolone (50 mg/day) and
mizoribine (150 mg/day) without benefit. Although
plasmapheresis was performed seven times, the patient's skin
lesions worsened (figure
1C). We started a combination therapy with prednisolone
(40 mg/day) and MMF (2 g/day). The appearance of new
active lesions ceased within 2 weeks. The prednisolone dosage
was gradually reduced by 2.5 mg/day to 7.5 mg/day without
relapse. Thereafter, the MMF dosage was reduced by 250 mg
every month. Finally, MMF was stopped 15 months after the MMF
therapy started (figure 1D). The
patient is now free from any skin lesions.
Case 4
A 39-year-old Japanese male patient suffered from PV and was
treated with prednisolone (60 mg/day) and mizoribine
(150 mg/day) without benefit. Although plasmapheresis was
performed eight times and azathioprine (100 mg/day) and
cyclosporine (200 mg/day) were administered, the patient's
lesions worsened. We began treatment with a combination therapy of
prednisolone (20 mg/day) and MMF (2 g/day). The
appearance of new active lesions ceased within 3 weeks.
However, the ELISA index for circulating anti-Dsg3 antibodies
did not decrease. The prednisolone dosage was gradually reduced by
2.5 mg every month, while the MMF dose (2 g/day) was
maintained. MMF was well-tolerated by the patient without any side
effects for 8 months. The prednisolone dosage was reduced to
12.5 mg/day 8 months after the initiation of MMF therapy,
and the patient was free from blisters at that time.
Discussion
Systemic corticosteroids have been the mainstay of therapy for PV
for over fifty years and severe PV requires high dose oral steroid
therapy. However, besides including the side effects of
osteoporosis and diabetes mellitus, corticosteroids sometimes
induce severe infection and may cause death by disseminated
intravascular coagulation [7]. To avoid such severe side effects, a
lower dose of oral steroid is desirable. In Japan, prednisolone
doses over 100 mg/day are not generally prescribed [8]. For
intractable PV, combinations of corticosteroid and adjuvant
therapies are prescribed including steroid pulse therapy,
intravenous immunoglobulin therapy, plasmapheresis and
immunosuppressive agents, such as azathioprine, cyclophosphamide,
cyclosporine and MMF [9]. In addition, we frequently prescribe
mizoribine, a new azathioprine-like immunosuppressive, with benefit
as an adjuvant therapy [10].
There are several reports of patients with PV successfully
treated with MMF [11-14], as well as investigations of its efficacy
compared to other regimens [15, 16]. In the previous studies,
Beissert et al. described that MMF and azathioprine
demonstrated similar efficacy, and Chams-Davatchi et al.
concluded that azathioprine was more effective than MMF as a
corticosteroid-sparing agent. However, in the present study, three
cases were refractory to a combination therapy of azathioprine and
prednisolone prior to successful treatment with MMF. Therefore, MMF
may be a more effective immunosuppressive drug than azathioprine
for the treatment of intractable PV. Furthermore, MMF has
relatively mild side effects compared to other immunosuppressive
agents, such as azathioprine and cyclophosphamide, although it is
possible that MMF may increase the risk of infections, mainly
herpes zoster [17].
The present study reported that four Japanese patients with
intractable PV were treated successfully by MMF. In all cases,
clinical symptoms were cleared with reducing PDAI (pemphigus
disease area index) [18], after the treatment with MMF, and the
dose of prednisolone was reduced (table
1). Monitoring the levels of Dsg1 and Dsg3 ELISA
is useful, because they generally correlate with disease activity
[19]. In our cases, the levels of Dsg1 and Dsg3 as
measured by ELISA decreased, except for Dsg3 levels in one
case (figure 2).
We started MMF treatment at a dose of 2 g/day according to
previous studies [11, 12, 15, 16, 20], however, we did not observe
any gastro-intestinal symptoms due to MMF in any cases. In general,
we did not reduce the MMF dose until the dose of prednisolone was
already significantly reduced. The dose of MMF was reduced in
Patients 2 and 3, but Patient 2 relapsed after the
reduction of the MMF dose and the dose of MMF was increased back to
pre-relapse levels. Complete cessation of all medications was
achieved in a 58-year-old woman (Case 3). Interestingly, Esmaili
et al. reported that women have a better response to the
treatment with MMF [20]. Factors predictive of response to MMF
treatment provide us with useful information for treating patients
with PV who are refractory to corticosteroid therapy.
To our knowledge this is the first report describing the
treatment of Japanese PV patients with MMF. In Japan, some
considerations for MMF treatment of autoimmune bullous diseases
include high cost and that this therapy is not commonly used.
However, this study suggests that MMF may be a promising therapy
for refractory PV.
Table 1 A summary of the clinical characteristics
|
Case no.
|
Age/ sex
|
Type of PV
|
Duration of disease
|
Pretreatment
|
Mode of therapy
|
Recent status
|
Final steroid dose
|
Side effect
|
PDAI (Total Activity score/ Total damage score)
|
|
At starting MMF
|
After 2 weeks
|
At most improve
|
|
1
|
54 years/ male
|
mc
|
20 months
|
IVIG PSL+MZ,AZ
|
Predonisolone 30 mg/day + MMF 2 g/day
|
No new lesions
|
25 mg/day
|
None
|
47/ 7
|
42/ 7
|
2/ 4
|
|
2
|
44 years/ male
|
mc
|
9 months
|
Plasmapheresis PSL+MZ,AZ,CyA
|
Predonisolone 25 mg/day + MMF 2 g/day
|
No new lesions
|
25 mg/day (the lowest dose is 7.5 mg/day)
|
None
|
59/ 9
|
29/ 9
|
3/ 4
|
|
3
|
56 years/ female
|
mc
|
40 months
|
Plasmapheresis PSL+MZ
|
Predonisolone 40 mg/day + MMF 2 g/day
|
No relapse (more than 3 years)
|
None (incuding MMF)
|
None
|
51/ 7
|
20/ 7
|
0/ 0
|
|
4
|
39 years/ male
|
mc
|
108 months
|
Plasmapheresis PSL+MZ,AZ,CyA
|
Predonisolone 20 mg/day + MMF 2 g/day
|
No new lesions
|
12.5mg/day
|
None
|
45/ 8
|
45/ 8
|
5/ 4
|
Acknowlegements
We gratefully appreciate Miss Ayumi Suzuki, Miss Takako Ishikawa
and Miss Sachiko Sakaguchi for technical assistance and Miss Akiko
Tanaka and Mrs. Yasuko Nakayama for secretarial
work. We thank the patients for their participation. This work
was supported by Grants-in-Aid for Scientific Research and
Strategic Research Basis Formation Supporting Project from the
Ministry of Education, Culture, Sports, Science and Technology of
Japan, by Health and Labour Sciences Research Grants and grants for
Research on Intractable Diseases from the Ministry of Health,
Labour and Welfare of Japan. This work was also supported by
grants form the Uehara Memorial Foundation, the Nakatomi
Foundation, the Kaibara Medical Foundation, the Japan Lydia O'leary
Memorial Foundation, and the Japanese Dermatological Association
(Shiseido).
Conflict of interest: none.
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