ARTICLE
Auteur(s) : Nafiseh Esmaili1, Cheyda
Chams-Davatchi1, Mahin Valikhani1, Farshad
Farshidfar1, Nima Parvaneh2, Banafshe
Tamizifar1
1Department of Dermatology, School of Medicine,
Medical Sciences – University of Tehran, Tehran, Iran
2Department of Pediatrics, School of Medicine, Medical
Sciences – University of Tehran, Tehran, Iran
accepté le 24 Octobre 2007
Pemphigus vulgaris (PV) is a rare autoimmune disease,
characterized by circulating and tissue-bound desmoglein (Dsg) 3
and/or Dsg1-specific autoantibodies, which lead to the formation of
blisters, erosions or crusts of the skin and/or mucous membranes
[1-6]. Estimation of the incidence in Iran is one patient per
100,000 of the population per year [7], which is higher than that
of other countries [8-11].
Before the introduction of corticosteroids in the early 1950s,
the mortality rate from PV was high, between 60% and 90%; however,
it dropped dramatically by 15-45% with the use of glucocorticoids,
changing the course of this fatal disease to one with a mortality
rate currently under 10% [7, 12-15]. Systemic corticosteroids in
high doses will usually suppress the disease, but in most cases
maintenance therapy must be continued indefinitely, and many
patients develop side effects from this treatment [16, 17]. The
addition of other immunosuppressive agents in different studies
improves the disease outcome and reduces the steroid dose and side
effects [7, 18-23]. Successful treatment of PV and bullous
pemphigoid has been reported for mycophenolate mofetil (MMF) in
combination with high-dose prednisolone, or as a monotherapy
[24-31].
In recent years several scoring systems have been employed to
demonstrate disease severity; however, there is no unified scoring
modality [32]. In this study, we introduce a scoring system for PV
severity that can be used for patient follow-up during treatment,
as well as predicting the response to such therapy. We also
describe our experience in the management of 31 PV patients with
the adjuvant use of MMF as an initial treatment. We evaluate the
efficacy and safety of MMF combined with prednisolone in this
cohort.
Methods
Patients
From a cohort of over 160 new cases of PV currently under follow-up
at our center, 34 cases with active disease were selected for
therapy with MMF. PV was diagnosed on the basis of (I) clinical
criteria: flaccid skin and/or mucosal blisters; (II) histological
criteria: suprabasal acantholysis, leading to clefts and subsequent
blistering, and eosinophilic spongiosis; (III) direct
immunofluorescence: deposition of IgG, complement 3 (C3) or both on
keratinocyte membranes. All cases gave informed consent before the
initiation of therapy. Each patient file contained the following
data: age, sex, weight, persistence and degree of each mucosal
involvement, persistence, site and degree of skin involvement, nail
involvement, presenting site, total number of skin lesions,
existence of generalized disease (involvement of ≥ 4 skin areas and
≥ 2 mucosal surface areas), treatment, treatment complications, lab
test results, duration of remission and putative cause of death.
Treatment
For the initial treatment, MMF (500 mg four times per day for
one year) was administered in combination with prednisolone
(2 mg/kg/day up to 120 mg/day for two weeks). The
patients received prophylaxis against, or treatment for,
corticosteroid-induced osteoporosis. If complete or near complete
remission of the lesions was achieved, then the dose of
prednisolone was reduced slowly. If near complete remission of the
lesions was not achieved, prednisolone was continued at this dose
until complete remission. Complete remission was defined as no new
lesions and re-epithelialization of earlier lesions. Relapse was
defined as new blister formation during dosage reduction of
prednisolone. If a relapse was mild (< 3 blisters per day),
the previous corticosteroid dosage that permitted control of the
disease was given. For moderate relapses (formation of 3-5 blisters
per day), if the prednisolone dosage was at least 60 mg/d, the
previous corticosteroid dosage that permitted control of the
disease was given, and if the prednisolone dosage was less than
60 mg/d, the corticosteroid dosage was increased to
60 mg/d. For severe relapses (formation of > 5 blisters per
day), or refractory cases that relapsed despite the above changes
in prednisolone dosage, the patients were admitted and the adjuvant
drugs changed.
Safety assessment
In this open study, all patients were monitored twice weekly in the
first two weeks, then weekly in the first two months, followed by
monthly intervals for 12 months to assess clinical disease control
and the possibility of complications. Patients were questioned at
each visit regarding adverse events. Safety assessment included
routine biochemical and hematological monitoring with special focus
on leukocyte counts. We monitored CBC with differential at weekly
intervals for the first month, twice monthly for the second month
and at monthly intervals thereafter. In addition, patients were
checked for the side effects of systemic corticosteroid therapy
using fasting blood glucose, lipid profiles, liver and renal
function tests and blood pressure checks every month, with
bone-mineral density assessments every six months.
Assessment of efficacy
Clinical disease severity was assessed on the first visit according
to a four-point scoring system as shown in table
1. For each patient, the scores were determined for each
skin area/mucosal surface and the scores were summed at baseline
and then at monthly intervals thereafter (table
2).
During follow-up, the patients were divided into two groups
according to the following criteria:
- 1) Response group: initial complete or near complete
remission of lesions, no severe relapses, not refractory during the
follow-up period, completed the study without any side effects
related to MMF, and in remission had a clinical score of <
2.
- 2) Failure group: did not meet the above mentioned
criteria.
The success of the role of MMF as an adjuvant immunosuppressive
agent would need to be reflected in a significant reduction in
corticosteroid requirements. Daily prednisolone doses were modified
at each visit according to disease activity.
Table 1 Pemphigus vulgaris lesion severity score
|
Skin lesions
|
Mucosal lesions
|
|
Areas of the body
|
Score*
|
Involved mucosa
|
Score*
|
|
Face
|
Nil: 0
|
Oral
|
Nil: 0
|
|
Scalp
|
Mild:1-2
|
Nasal
|
Mild: 1
|
|
Nose skin
|
Moderate: 3-5
|
Larynx
|
Moderate: 2-3
|
|
Breast
|
Severe: > 6
|
Conjunctiva
|
Severe: > 4
|
|
Axillary
|
|
Genitalia
|
|
|
Groin
|
|
Urethra
|
|
|
Thorax
|
|
|
|
|
Abdomen
|
|
|
|
|
Limbs
|
|
|
|
Table 2 Relationship between means of severity scores
and failure of treatment
|
Location of lesions
|
Means of severity scores
|
Significance (p-value)
|
|
Response group
|
Failure group
|
|
Scalp skin
|
0.081
|
1.10
|
0.070
|
|
Facial skin
|
0.33
|
1.00
|
0.030
|
|
Thoracic skin
|
0.95
|
1.90
|
0.034
|
|
Abdominal skin
|
0.38
|
0.90
|
0.130
|
|
Limb skin
|
0.24
|
0.80
|
0.040
|
|
Groin skin
|
0.19
|
1.10
|
0.000
|
|
Oral mucosa
|
1.86
|
2.50
|
0.059
|
|
Laryngeal mucosa
|
0.981
|
1.252
|
0.070
|
|
Nasal mucosa
|
0.52
|
0.70
|
0.426
|
|
Conjunctiva
|
0.29
|
0.30
|
0.945
|
|
Genitalia
|
0.463
|
1.033
|
0.063
|
|
Nail dystrophy
|
000
|
0.3
|
0.047
|
|
Nail paronychia
|
0.10
|
0.40
|
0.097
|
|
Generalized
|
0.05
|
1.10
|
0.000
|
|
Total sum of scores at presentation
|
7.20
|
14.10
|
0.004
|
Statistical analysis
Statistical analyses were performed using SPSS 12.0 analysis
software for Windows (SPSS Inc., 2003). Comparisons were made using
Pearson’s chi-square test and Student’s t-test for qualitative and
quantitative analyses, respectively.
Results
Patient demographic data
A total of 34 patients, including 12 men and 22 women, were
studied. Three patients (two men and one woman) were excluded from
the study because of their preference to continue their treatment
in other centers. Therefore, our analysis included 31 patients,
32.2% male and 67.7% female, with a male to female ratio of 1:2.1.
The age range at the onset of the disease was 15-63 years (mean,
36.29 ± 13.753 years). The mean age was 31.72 ± 9.2 years for men
and 38.8 ± 15.34 years for women. There was no statistical
relationship between the mean age of men versus that of women. Four
patients were younger than 20 years of age. The mean time interval
between the onset of the disease and the definite diagnosis by
positive histopathology and DIF tests was 5.77 ± 5.614 months.
Clinical presentations
The majority of patients presented with both mucosal and skin
involvement (21 patients), compared to eight and two patients with
isolated mucosal or skin involvement, respectively. The mean period
between the onset of symptoms to the diagnosis was eight months.
Oral mucosa was the most common site of onset of symptoms (71%),
followed by scalp (16%) and trunk (6.4%). During the follow-up
period, the frequency of oral involvement increased to 93.5% (29
patients), and the larynx was involved in 16 (51.6%) patients,
nasal mucosa in 17 (54.8%) patients, genitalia in 11 (35.5%)
patients and conjunctiva in 8 (1.6%) patients. However, a large
percentage of these were mild, with a few moderately severe
involvements: larynx – four (12.9%) patients, genitalia – two
patients, and nasal mucosa and conjunctiva – one patient each.
Response to treatment
A total of 21 (67.7%) patients were designated as the response
group, of which 17 were female and four male. The remaining 10
patients (four females and six males) were placed in the failure
group. For one patient, who had a very poor response to treatment,
we had to discontinue MMF before week 6 because of the development
of bone marrow suppression due to MMF. The mean cumulative dose of
prednisolone was 79.003 mg for responders and 97.837 mg
for non-responders. In the responders, the daily prednisolone dose
was reduced to 7.5 mg, at which point it was maintained. MMF
was discontinued following the successful control of PV for one
year.
Factors predictive of response
Several factors were related to the treatment outcome (tables 1 and 2), each of which was assessed, as
was the total severity score for each of the involved skin/mucosal
surfaces. Women responded better to the treatment, with only 19% of
the women in the failure group versus 60% of the men (p < 0.05).
Furthermore, patients with generalized disease (involvement of ≥ 4
skin areas and ≥ 2 mucosal surfaces) appear to have a poor response
to MMF (p < 0.001). A higher failure rate was also observed in
the groups of patients who had moderately severe involvement of the
groin (p < 0.001), chest (p = 0.03), face (p = 0.03), limbs (p =
0.04) and those with nail dystrophy (p = 0.047). A higher sum of
the severity scores for groups with both skin and mucosa is
associated with a poor response rate (p = 0.004).
A total of five patients had sterile nail paronychia, four mild
and one moderate, with three of these five patients in the failure
group (p = 0.097). Patient age, marital status, disease type at
onset or at presentation, and the length of time from the onset to
initiation of MMF were not related to the outcome. Disease severity
on the scalp, nose skin, breast, axilla, conjunctiva, nasal mucosa,
larynx, genitalia, and abdomen at the baseline, as well as the
total number of the lesions, were not shown to be associated with
the response rate.
The patient who experienced bone marrow suppression had
generalized disease with moderate involvement of the oral mucosa
and severe involvement of face, groin, chest, limbs and abdomen.
Other side effects, mainly due to prednisolone, ameliorated after
dose reduction (table 3).
Table 3 Side effects of the treatment regimen
|
Complications
|
Number of patients
|
|
Candidial infections requiring oral antifungal agents
|
14
|
|
Morbid obesity, steroid and Cushingoid facies
|
8
|
|
Recurrent herpes labialis
|
5
|
|
Systemic bacterial infections including sepsis, requirement for
systemic antibiotics
|
4
|
|
Gastritis
|
2
|
|
Warts
|
1
|
|
Bone pain
|
1
|
|
Bone marrow suppression (severe lymphopenia and
thrombocytopenia)
|
1
|
Discussion
PV is a potentially life-threatening skin disease in which
autoantibodies against Dsg3/Dsg1 cause a loss of cell-cell
adhesion, with resultant epidermal blisters [33-37].
Early use of corticosteroids with or without immunosuppressive
drugs is the rule; untreated disease is fatal. Current first-line
therapy in Western countries as well as in Iran generally consists
of a combination of corticosteroids and azathioprine [7, 21-23]. In
India, pulsed-intravenous cyclophosphamide and corticosteroids are
often used [18-20].
Both cellular and humoral immune systems are thought to play a
critical role in the pathogenesis of PV [38, 39]. Moreover,
circulating CD56+ CD3– NK cells and CD69+ activated NK cells are
increased in PV patients compared to healthy controls [40]. MMF is
an immunosuppressive drug that inhibits inosine monophosphate
dehydrogenase with secondary decreases in guanine nucleotides, DNA
synthesis and inhibition of natural killer cell activity [41-43].
In patients treated with MMF, the percentages of CD38+ B cells,
activated T cells, CD4+/CD25+ Tregs and HLA-DR-expressing NK cells
were reduced during therapy with MMF [44].
Case series of immunobullous diseases suggest that MMF may have
a role in the management of pemphigus [24-31, 45] (table 4). Enk et al. [25] published their
experience treating 12 cases of PV with MMF. Eleven of the 12 cases
responded to 2 g MMF daily combined with prednisolone
(2 mg/kg/d) and showed no relapse of their disease even after
tapering of the steroid dose. However, they did relapse while
undergoing treatment with azathioprine (1.5-2 mg/kg/d) and
prednisolone (2 mg/kg/d).
After administration of MMF to five patients with severe PV or
bullous pemphigoid, Grundmann-Kollmann et al. [27] suggested that
MMF monotherapy may be effective for such patients.
Chams-Davatchi et al. [46] conducted an open trial using
2 g/d MMF for six months combined with systemic steroids given
to ten patients with resistant and severe disease that did not
respond to conventional therapy. They found that nine of the ten
patients responded to treatment and showed complete clearance of
lesions within 6 to 16 weeks of therapy with few side effects.
After discontinuation of MMF, five of the nine patients
relapsed.
Mimouni et al. [47] published a study of 31 PV patients who had
relapses during prednisolone tapering or had clinically significant
adverse effects from previous drug therapy. They found that
remission was achieved with MMF in 22 (71%) of the patients.
Powell et al. [45] designed a study in which patients with
active, refractory pemphigus were treated with MMF. Of the 12 cases
of PV they studied, MMF benefited eight of the patients.
Recently Beissert et al. [48] reported the results of a
prospective, multicenter, randomized, clinical trial to compare two
parallel groups of patients with pemphigus (PV and pemphigus
foliaceus) treated with oral methylprednisolone plus azathioprine
or oral methylprednisolone plus MMF. In 13 (72%) of 18 patients
receiving oral methylprednisolone and azathioprine, complete
remission was achieved after a mean of 74 ± 127 days compared with
20 (95%) of 21 patients receiving oral methylprednisolone and MMF,
in whom complete remission occurred after a mean of 91 ± 113 days.
The total median cumulative methylprednisolone dose used was
8,916 mg in the azathioprine group compared with 9,334 mg
in the MMF group. In six (33%) of 18 patients treated with
azathioprine, grade 3 or 4 adverse effects were documented in
contrast to four (19%) of 21 patients who received MMF.
Our study is a part of a greater clinical trial, to be published
in the near future, in which new patients with verified PV were
selected and randomly put in four treatment regimens: prednisolone
alone; prednisolone plus azathioprine; prednisolone plus
cyclophosphamide and prednisolone plus MMF. In the present series
of 31 cases of PV, the administration of MMF for 12 months has been
of definite benefit to 21 cases (67.7%). When we excluded patients
with generalized PV, only four patients were included in the
failure group, increasing the response rate to 83.3%. We found
that, in the response group, MMF permitted a reduction in
prednisolone dosage without disease relapse.
Whether a patient will achieve partial or complete clinical
response is determined, in part, by certain baseline
characteristics. We observe that generalized disease, groin
involvement and the larger total sums of severity scores at
presentation appear to be associated with MMF treatment failure. In
our clinical scoring system (tables 1 and
2), the total scores are significantly different between
the response and failure groups. All of the patients in the failure
group had a score of 6 or greater (6-24) and the means were 14.10
in non-responders compared to 7.20 in responders. The total number
of lesions was not shown to be associated with the response rate,
generalized disease or initial severity score. A poorer response to
MMF was also found when the skin on the chest, face and limbs was
more severely involved, and in patients with nail dystrophy. In
this study, involvement of the groin was highly predictive of
failure to respond. None of the patients with groin involvement
showed the pemphigus vegetans variety; however, long-term follow-up
is necessary. To the best of our knowledge, these predictive
characteristics of the disease at presentation have not yet been
mentioned and are useful for creating an effective pemphigus
severity score system.
As 19% of the females and 60% of the males were in the failure
group, there appears to be an association between gender and
response to treatment. Interestingly, although most patients in the
failure group were male, patients with generalized disease at
presentation were primarily female (5 of 7 patients); therefore,
this cannot explain the male predominance in the failure group. We
cannot, at present, illustrate an etiology for this finding.
Despite the mention of a higher incidence of PV in females in most
literature reviews [7, 9, 49-51], there was no relationship between
response to treatment and gender in the reviewed studies. Because
of the loose association (p = 0.048) between response to treatment
and gender in the present cohort, it seems that a larger study is
needed to confirm this relationship.
In the current study, eight patients presented with only mucosal
involvement versus 21 patients with involvement of both mucosa and
skin. A larger PV study from this center, which followed the
patients for the mean of 3.8 years, associates a worse prognosis
for patients with both oral and skin forms [7]; however, we failed
to substantiate this result with our one-year follow up.
Powell et al. [45] revealed that, in 17 patients treated with
MMF, the length of time between the onset of the disease and
initiation of MMF influenced the outcome. In our cohort, this
period of time did not appear to affect the response rate. Then
again, Powell et al. evaluated only patients with resistant disease
that had not responded to the other treatment regimens. Therefore,
this longer duration may be a marker for disease severity and not
delayed treatment with MMF per se.
Neither the site of disease initiation (mucosa or skin), nor the
location of the lesions on the body surface, appeared to predict
the response to the drug. We conclude that, in patients with PV,
MMF can be used safely and effectively as a first line treatment,
especially in patients without generalized disease.
Table 4 Review of studies on the effect of MMF in the
treatment of PV
|
Study
|
Total No. of patients
|
Drug regimen
|
No. of improved patients
|
Side effects
|
Considerations
|
|
Enk et al. [25]
|
12
|
2 g/day MMF plus 2 mg/kg prednisolone
|
12 (100%)
|
- Mild lymphopenia (9 /11)
- Moderate GI symptoms (5/11) transient rises in transaminase
(3/11)
|
All had a poor response to azathioprine plus prednisolone
|
|
Grundmann-Kollmann et al. [27]
|
5
|
Varied
|
5 (100%)
|
Mild lymphopenia in 1 case
|
Results of MMF monotherapy in severe PV and BP*
|
|
Chams-Davatchi et al. [46]
|
10
|
2 g/day MMF plus 2 mg/kg prednisolone
|
9 (90%)
|
Few
|
5 of 9 patients relapsed after drug discontinuation
|
|
Mimouni et al. [47]
|
31
|
35 to 45 mg/kg MMF per day
|
22 (71%)
|
Side effects in 23% of the patients
|
Patients with relapse or complications with conventional drugs
|
|
Powell et al. [45]
|
12
|
Started with 500 mg/day MMF and increased as tolerated
|
8 (66%)
|
- Lymphopenia, in 10 cases.
- Asthenia (2 cases),
- Opportunistic infection: 2 cases of herpes zoster, 1 case of
cutaneous atypical Mycobacterium infection
- Myalgia (1 case)
|
All cases had refractory disease.
|
|
Beissert et al. [48]
|
21
|
2 g/day MMF plus 2 mg/kg prednisolone
|
20 (95%)
|
Grade 3 or 4 adverse effects in 4 of 21 patients
|
Compared 2 parallel groups of pemphigus patients treated with
methylprednisolone plus azathioprine or methylprednisolone plus
MMF.
|
|
Present study
|
31
|
2 g/day MMF plus 2 mg/kg prednisolone
|
21 (67%)
|
- Lymphopenia in 1 case
- Viral infections (HPV,
- HSV) in 6 cases
- Candidiasis in 14 cases
- Bacterial infections in 4 cases
|
- MMF started as first line drug regimen.
- Evaluation of the associated factors.
|
Acknowledgements
Financial support: none. Conflict of interest: none.
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