See related commentary on pg 1964

ORIGINAL ARTICLE

Treating Pemphigus Vulgaris with Prednisone and

Mycophenolate Mofetil: A Multicenter, Randomized,
Placebo-Controlled Trial
Stefan Beissert1, Daniel Mimouni2,3, Amrinder J. Kanwar4, Neil Solomons5, Veena Kalia5 and Grant J. Anhalt6
Non-blinded trials of pemphigus vulgaris suggest that mycophenolate mofetil (MMF) may be beneficial. In a
prospective, multicenter trial, outpatients with mild or moderate pemphigus vulgaris were randomized to MMF
(2 or 3 g day1) plus oral corticosteroids or placebo plus oral corticosteroids for 52 weeks. The primary end point
was the proportion of patients in the placebo and combined MMF groups responding to treatment (absence of
new, persistent oral or cutaneous lesions, and prednisone dose p10 mg day1 from weeks 48 to 52). Of 96
randomized patients, 94 were given treatment and 75 completed the study. Treatment responses occurred in 40
of 58 patients (69.0%) in the combined MMF group and 23 of 36 (63.9%) in the placebo group (P 0.6558, 95%
confidence interval 17.4 to 27.6). MMF-treated patients showed faster and more durable responses. In post hoc
analyses, more patients taking MMF showed sustained responses for 3 or 6 months than did placebo patients.
MMF was well tolerated. Although MMF did not show an advantage on the primary end point, there seemed to
be a beneficial treatment effect on several secondary end points, including time to response and duration of
response. Thus, MMF may be a potentially useful agent in patients with mild or moderate pemphigus vulgaris.
JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article please go to http://www.nature.com/jid/journalclub
Journal of Investigative Dermatology (2010) 130, 20412048; doi:10.1038/jid.2010.91; published online 22 April 2010

INTRODUCTION
Pemphigus is a rare, acquired, autoimmune bullous disorder
of the skin and mucous membranes. It is caused by
autoantibodies against epidermal desmogleins (DSG), resulting in loss of cell adhesion in keratinocytes (Amagai et al.,
1991). Pemphigus vulgaris accounts for approximately twothirds of pemphigus cases and affects 1 to 5 in 100,000
people, with an overall incidence of 0.1 to 0.4 in 100,000
(Toth and Jonkman, 2001).
If untreated, pemphigus vulgaris is associated with high
mortality (470%; Bystryn and Steinman, 1996; Carson et al.,
1996; Stanley, 1999). The introduction of high-dose corticosteroid therapy has reduced mortality rates to approximately 10% (Robinson et al., 1997), but the long-term use of
such treatment is limited by potentially serious adverse events
1

Department of Dermatology, University of Munster, Munster, Germany;

Department of Dermatology, Rabin Medical Center, Beilinson Campus,
Petach Tiqva, Israel; 3Sackler Faculty of Medicine, Tel Aviv University,
Tel Aviv, Israel; 4Postgraduate Institute of Medical Education and Research,
Chandigarh, India; 5Vifor Pharma Ltd (previously Aspreva), Victoria,
British Columbia, Canada and 6Department of Dermatology, Johns Hopkins
Hospital, Baltimore, Maryland, USA

Correspondence: Neil Solomons, Vifor Pharma Ltd, #1203, 4464 Markham

Street, Victoria, British Columbia, V8Z 7X8 Canada.
E-mail: Neil.Solomons@viforpharma.com
Abbreviations: AE, adverse event; DSG, desmoglein; MMF, mycophenolate
mofetil
Received 17 December 2009; revised 23 February 2010; accepted 26
February 2010; published online 22 April 2010

& 2010 The Society for Investigative Dermatology

(AEs) (e.g., hypertension, osteoporosis, diabetes mellitus/

glucose intolerance, and susceptibility to infections; Yeh
et al., 2005). In one report, more patients died from
corticosteroid-related complications than from uncontrolled
disease (Bystryn and Steinman, 1996). Disease control with
reduced corticosteroid-related toxicity is the therapeutic goal.
Steroid-sparing therapy with immunosuppressants (e.g.,
azathioprine or cyclophosphamide) is used with pemphigus
vulgaris, but is associated with long-term AEs such as
urological/gynecological or hepatic dysfunction, bone marrow suppression, and immunosuppressant-induced lymphoproliferative disorders (Ho and Zloty, 1993). According to a
recent systematic review, the optimal adjuvant steroidsparing agent has not yet been established (Martin et al.,
2009).
Mycophenolate mofetil (MMF; CellCept; Hoffmann-La
Roche, Basel, Switzerland) is a systemic immunosuppressive
agent originally developed for preventing allograft rejection
(Zwerner and Fiorentino, 2007). Several small, non-blinded
trials have suggested that MMF is beneficial in pemphigus
treatment (Enk and Knop, 1997, 1999; Nousari et al., 1999;
Chams-Davatchi et al., 2002; Mimouni et al., 2003; Baskan
et al., 2009), as have randomized, open-label trials comparing MMF with other immunosuppressants (Chams-Davatchi
et al., 2007; Esmaili et al., 2008). Randomized, placebocontrolled trials in this condition are difficult to undertake
and, to our knowledge, have rarely been performed (Amagai
et al., 2009). In this study we report the results of a
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S Beissert et al.
Pemphigus Vulgaris and Mycophenolate Mofetil

Randomized
N=96

Placebo
n=37

Completed
treatment period
n=29

Did not receive

study drug
n=1

MMF 3 g/day
n=37

MMF 2 g/day
n =22

Completed
treatment period
n =18

Withdrawn n =7
Could not decrease
steroid dose (2)

Did not receive

study drug
n=1

Completed
treatment period
n=28

Withdrawn n=3
AE (2)
Lost to follow-up (1)

AE (1)
Lost to follow-up (1)
Other (2)
Death (1)

Withdrawn n =9
Could not decrease
steroid dose (1)
Had >5 new lesions
lasting >4 weeks (1)
AE (1)
Withdrew consent (3)
Lost to follow-up (1)
Other (2)

Figure 1. Patient disposition. AE, adverse event; MMF, mycophenolate mofetil.

randomized, placebo-controlled trial of MMF as steroidsparing therapy in active pemphigus vulgaris.

RESULTS
Eligible patients were recruited from 1 June 2004 to 22 May
2007; the last patient completed the study on 18 October
2008. A total of 96 patients were randomly assigned to
treatment, with 28 before the protocol amendment (Figure 1).
Of the total, 94 patients were given study medication as 1
patient withdrew consent and 1 was excluded because of an
incorrect laboratory measurement. Of the 94 treated patients,
21 received MMF 2 g day1, 37 received MMF 3 g day1, and
36 received placebo. In all, 75 patients completed the study.
There were no major protocol violations leading to withdrawal; however, non-major protocol violations existed.
Treatment groups were demographically comparable,
although there were some differences in race, sex, and
weight (Table 1). Placebo-treated patients tended to have
milder disease than those receiving MMF, as indicated by the
lower mean daily dose of prednisone before and at baseline.
The study was completed by 18 of 21 patients (85.7%)
receiving MMF 2 g day1, 28 of 37 (75.7%) receiving MMF
3 g day1, and 29 of 36 (80.6%) receiving placebo (Figure 1).
The actual prescribed mean daily doses of MMF in the 2
and 3 g day1 groups were 2.0 and 2.9 g, respectively. The
meanstandard deviation duration of treatment in the placebo,
MMF 2 g day1, and MMF 3 g day1 groups was 315.2120.5,
333.085.4, and 308.8115.2 days, respectively.
Efficacy

Out of 58 patients, 40 (69.0%) in the combined MMF group

were classified as responders, compared with 23 of 36
(63.9%) in the placebo group (P 0.6558, difference 5.1%,
95% confidence interval 17.4 to 27.6). The response rate
was higher in the group receiving MMF 2 g day1 than those
receiving 3 g day1 (17/21 (81.0%) vs. 23/37 (62.2%),
P 0.1558, Fishers exact test).
Compared with patients receiving placebo, those receiving either dose of MMF achieved a response more quickly
(Figure 2a), maintained the response for longer (Figure 2b),
2042 Journal of Investigative Dermatology (2010), Volume 130

and had a longer time to relapse (Figure 2c). The median time
to initial response in the placebo group was 31.3 weeks,
compared with 24.1 weeks in the combined MMF group
(P 0.0512 by log-rank test).
Time to relapse after the initial response was delayed for
MMF versus placebo patients; the relapse rate at 24 weeks
was 44.5% in the placebo group versus 21.8% in the
combined MMF group (hazard ratio (MMF/placebo) 0.44,
95% confidence interval 0.200.97, P 0.0343, log-rank
test). Time to sustained response occurred sooner for MMFtreated patients compared with placebo-treated patients. The
median time to sustained response was 32 weeks for MMF
patients and 46 weeks for placebo patients (hazard ratio
(MMF/placebo) 1.85, 95% confidence interval 1.023.34,
P 0.0390, log-rank test).
In post hoc analyses, MMF-treated patients also showed
significantly higher rates of response lasting 3 or 6 months when
compared with placebo-treated patients (3 months: 67.2 vs.
44.4%, P 0.0337, Fishers exact test; 6 months: 43.1 vs.
22.2%, P 0.0472, Fishers exact test). Efficacy results for the
MMF 2 and 3 g day1 groups were similar (data not shown).
Steroid-sparing

The median cumulative steroid doses were 8,727.5 mg for

placebo and 7,617.5 mg for combined MMF, with 7,880 and
7,442.5 mg as the respective median cumulative doses for the
MMF 2 and 3 g day1 groups (see Supplementary Table S1
online). The time that patients were maintained on prednisone doses of p10 mg day1 while having no new
persistent lesions was longer with MMF (median 186 days
for combined MMF) than with placebo (median 136.5 days;
P 0.0337, Wilcoxon test). The values for individual MMF
dosing groups were 185 and 187 days for the MMF 2 and
3 g day1 groups, respectively (Supplementary Figure S1).
Analysis of total prednisone dose from weeks 12 to 52, which
represents the period after steroid tapering, showed that
patients in the combined MMF groups (with median dose of
3,220 mg) received significantly less steroid than did those
receiving placebo (with median 4,449.5 mg dose; P 0.0280,
Wilcoxon test). The median prednisone dose during the week

S Beissert et al.
Pemphigus Vulgaris and Mycophenolate Mofetil

Table 1. Demographic characteristics and disease history

Placebo
(n=36)

MMF 2 g day1
(n=21)

MMF 3 g day1
(n=37)

MMF
combined
(n=58)

Total
(n=94)

Men

12 (33%)

7 (33%)

19 (51%)

26 (45%)

38 (40%)

Women

24 (67%)

14 (67%)

18 (49%)

32 (55%)

56 (60%)

White

21 (58%)

7 (33%)

26 (70%)

33 (57%)

54 (57%)

Black1

1 (3%)

Race

Hispanic
Asian

0
14 (39%)

1 (3%)

1 (2%)

1 (1%)

8 (22%)

22 (38%)

36 (38%)

14 (67%)

1 (1%)

Asian (Pacific)

1 (3%)

1 (2%)

1 (1%)

Other

1 (3%)

1 (2%)

1 (1%)

Median age (years)

46

40

46

44.5

45.5

Median weight (kg)

65

62

72

70

69

45.0

39.0

46.0

42.5

45.0

6.5

6.0

2.0

3.5

4.0

Disease history
Median age at onset of PV symptoms (years)
Median duration of PV symptoms (months)
Median prednisone dose before baseline (mg per day)

27.9

35.0

50.0

41.8

37.5

Median baseline prednisone dose (mg per day)

65.0

60.0

70.0

67.5

65.0

0.7

1.1

0.7

0.9

0.8

39 (42%)

Median duration of previous prednisone dose (months)

Body surface area involvement at baseline

o3%

18 (50%)

7 (33%)

14 (38%)

21 (36%)

310%

14 (39%)

12 (57%)

19 (51%)

31 (53%)

45 (48%)

4 (11%)

2 (10%)

4 (11%)

6 (10%)

10 (11%)

41020%

Disease severity at baseline

Mild2

14 (38.9%)

7 (33.3%)

10 (27.0%)

17 (29.3%)

31 (33.0%)

Moderate3

22 (61.1%)

14 (66.7%)

27 (73.0%)

41 (70.7%)

63 (67.0%)

Abbreviations: MMF, mycophenolate mofetil; PV, pemphigus vulgaris.

Not Hispanic.
2
Mild was defined as 15 lesions lasting 41 week or o3% of body surface involvement.
3
Moderate was defined as 640 lesions lasting 41 week or 320% of body surface involvement.
Percentages may add up to 4100% due to rounding.
1

1252 interval for the MMF 2 and 3 g day1 groups was the same
as for the combined MMF group.

groups during the course of the study (data not shown); there
was no meaningful difference in the quality-of-life measures
between groups.

Antibody titers

DSG-1 and DSG-3 antibody titers decreased in both placeboand MMF-treated patients (Supplementary Figure S2), with
DSG-1 titers decreasing to a similar extent in the placebo and
combined MMF groups, but DSG-3 titers decreasing to a
greater extent in the placebo group.
Quality of life

Scores for the 36-Item Short Form questionnaire in all

domains increased in both the placebo and combined MMF

Safety

AEs were reported in 31 of 36 (86.1%) of placebo-treated

patients and in 20 of 21 (95.2%) and in 32 of 37 (86.5%) of
patients receiving MMF 2 and 3 g day1, respectively (Table 2),
with treatment-related AEs occurring in 30.6, 38.1 and 43.2%
patients, respectively. The most common AEs were infections, which occurred in 13 of 36 patients (36.1%) receiving
placebo, 11 of 21 (52.4%) receiving MMF 2 g day1, and 23 of
37 (62.2%) receiving MMF 3 g day1 (P 0.0356 vs. placebo;
www.jidonline.org 2043

S Beissert et al.

Proportion of patients with initial response

Pemphigus Vulgaris and Mycophenolate Mofetil

0.9
0.8
0.7
0.6
0.5
0.4
0.3
P=0.0512 MMF combined vs. placebo
P =0.1592 MMF 2 g d 1 vs. placebo
P=0.0507 MMF 3 g d 1 vs. placebo

0.2
0.1
0.0

Weeks
Placebo n=
MMF 2 g d 1 n =
MMF 3 g d 1 n=
MMF combined n=
Proportion of patients sustaining response

during the study as a result of cardiac insufficiency. This

death was not considered to be related to study treatment.

1.0

10

15

20

25

30

35

40

45

50

55

36
21
37
58

33
21
35
56

32
21
34
55

32
21
32
53

29
15
26
41

22
9
13
22

16
7
9
16

10
5
5
10

5
2
3
5

3
1
2
3

2
0
1
1

0
0
0
0

1.0
0.9
P=0.0390 MMF combined vs. placebo
P=0.0557 MMF 2 g d 1 vs. placebo
P=0.0763 MMF 3 g d 1 vs. placebo

0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0

Weeks
Placebo n=
MMF 2 g d 1 n=
MMF 3 g d 1 n=
MMF combined n=

10

15

20

25

30

35

40

45

50

55

36
21
37
58

33
21
35
56

32
21
34
55

32
21
32
53

31
17
26
43

26
12
20
32

22
10
16
26

18
8
12
20

16
6
11
17

15
5
9
14

15
4
8
12

0
0
0
0

Proportion of patients relapsing

1.0
0.9

P=0.0343 MMF combined vs. placebo

P=0.0584 MMF 2 g d 1 vs. placebo
P=0.1143 MMF 3 g d 1 vs. placebo

0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0

Weeks
Placebo n=
MMF 2 g d 1 n=
MMF 3 g d 1 n =
MMF combined n=

10

15

20

25

30

35

40

28
18
30
48

21
15
25
40

17
15
25
40

15
14
21
35

13
11
19
30

6
7
14
21

1
5
9
14

0
2
4
6

0
0
0
0

Figure 2. KaplanMeier plots. (a) Time to initial response (n represents the

number of subjects remaining in the study who have not yet had a response);
(b) length of sustained response (n represents the number of subjects
remaining in the study who have not yet had a sustained response); and
(c) time to relapse in patients receiving mycophenolate mofetil (MMF) 2 or
3 g day1 or placebo (n represents the number of subjects in the cohort after
initial response who are still relapse free). All P-values were obtained using
the log-rank test.

Fishers exact test). The most commonly reported infections

are reported in Supplementary Table S2. The incidence of
serious AEs was lower in the MMF groups than in the placebo
group (Table 2). One patient in the placebo group withdrew
because of AEs, compared with three patients in the MMF
combined group (Table 2). One placebo-treated patient died
2044 Journal of Investigative Dermatology (2010), Volume 130

DISCUSSION
This trial, with its low attrition rate, has provided important
information about conducting phase III trials in this rare
condition. Although the study did not meet the primary end
point, results suggest that MMF does have clinically relevant
effects in terms of faster and more prolonged improvements
compared with placebo.
There may be several reasons why the primary end point
was not achieved. The response rate in the placebo group
was higher than that expected from previous experience.
Despite randomization, there was an imbalance between
groups, with placebo-treated patients having milder disease.
It may be that corticosteroid-treated patients with milder
pemphigus vulgaris do not require additional immunosuppressive therapy. More important, the primary end point
captured only the last 4 weeks of treatment, which may have
been too insensitive given the fluctuating nature of pemphigus vulgaris. Hence, there was no difference in response rates
at the end of the trial. Secondary and post hoc analyses
showed that MMF-treated patients responded sooner,
relapsed later, and sustained a response for longer than
placebo-treated patients, indicating a more durable therapeutic outcome.
Minimization of steroid use is a key goal in the
development of new treatments for pemphigus vulgaris. In
this study, patients receiving MMF achieved an initial
response more quickly and were maintained on low-dose
prednisone for a median of 50 days longer than placebotreated patients, in the absence of disease activity. In
addition, overall steroid exposure was slightly lower in the
MMF group. This difference was more marked when the time
period after protocol-defined steroid tapering was analyzed
(weeks 1252). Although some of the differences were not
statistically significant, when viewed together they give the
impression that MMF is an effective steroid-sparing agent in
this disease.
MMF was well tolerated, and the AE profile was consistent
with previous experience (Yeh et al., 2005). MMF is known to
increase patients susceptibility to viral infections, and the
nature of the infections observed in this study was in
accordance. Saha et al. (2008) reported an incidence of
16.4% for herpes zoster in 55 patients with pemphigus who
had received MMF for 7 years. As might be expected, DSG-1
titers decreased to a similar extent in both the MMF
combined and placebo groups. However, the antibody
response to DSG-3 seemed to differ, with persistently higher
titers in the combined MMF group compared with the
placebo group at study end. Such a discrepancy between
DSG-1 and DSG-3 antibody responses has also been reported
with the monoclonal antibody rituximab in severe pemphigus
(Joly et al., 2007). The fact that anti-DSG-3 antibodies
persisted in both groups despite clinical improvement
suggests that there may not be such a good correlation
between antibody levels and clinical remission. Abasq et al.
(2009) suggested that anti-DSG-1 correlates well with the

S Beissert et al.
Pemphigus Vulgaris and Mycophenolate Mofetil

Table 2. Summary of serious adverse events, adverse events leading to withdrawal, and adverse events reported by
X10% of patients
Placebo
(n=36)

MMF 2 g day1
(n=21)

MMF 3 g day1
(n=37)

MMF combined
(n=58)

All adverse events

31 (86%)

20 (95%)

32 (86%)

52 (90%)

Treatment-related adverse events

11 (31%)

8 (38%)

16 (43%)

24 (41%)

All adverse events (X10% incidence) in at least one group

Pemphigus worsening

12 (33%)

7 (33%)

11 (30%)

18 (31%)

Oral candidiasis

2 (6%)

1 (5%)

9 (24%)

10 (17%)

Headache

1 (3%)

1 (5%)

6 (16%)

7 (12%)

4 (19%)

3 (8%)

7 (12%)

Pyrexia

3 (8%)

4 (19%)

3 (8%)

7 (12%)

Cough

2 (6%)

3 (14%)

3 (8%)

6 (10%)

Hypertension

4 (11%)

3 (14%)

3 (8%)

6 (10%)

Upper respiratory tract infection

1 (3%)

1 (5%)

5 (14%)

6 (10%)

Arthralgia

1 (3%)

3 (14%)

2 (5%)

5 (9%)

Nasopharyngitis

Nausea

1 (5%)

4 (11%)

5 (9%)

Acne

1 (3%)

4 (11%)

4 (7%)

Urinary tract infection

2 (6%)

4 (11%)

4 (7%)

Patients with at least one serious adverse event

4 (11%)

1 (5%)

3 (8%)

4 (7%)

Varicella

1 (3%)

1 (2%)

Osteonecrosis

1 (3%)

1 (2%)

Cerebrovascular accident

1 (5%)

1 (2%)

Pemphigus worsening

1 (3%)

1 (2%)

Cataract

1 (3%)

Pancreatitis

1 (3%)

Duodenal ulcer

1 (3%)

Food poisoning

1 (3%)

Cardiovascular insufficiency

1 (3%)

1 (3%)1

2 (10%)

1 (3%)

3 (5%)

Total number of patients with an adverse event leading to withdrawal

Reason for withdrawal

Duodenal ulcer/pancreatitis

1 (3%)

Cerebrovascular accident

1 (5%)

1 (2%)

Pemphigus worsening

1 (5%)

1 (2%)

Lymphopenia/neutropenia

1 (3%)

1 (2%)

Abbreviation: MMF, mycophenolate mofetil.

Excludes 1 patient in the placebo group who died due to cardiovascular insufficiency; death was not considered to be related to study treatment.

clinical condition, whereas anti-DSG-3 levels do not. Our

data suggest that anti-DSG-3 levels, in particular, did not
correlate with clinical outcome.
The results suggest that MMF 2 g day1 offers a better
riskbenefit profile than MMF 3 g day1 in terms of response
and lower infection rates. MMF is not generally associated

with hepatic or renal toxicity (Zwerner and Fiorentino, 2007),

and the incidence of grade 3/4 toxicity was lower with MMF
than with azathioprine in a comparative study in this patient
group (Beissert et al., 2006).
This study has several limitations. The primary end point
may have been too insensitive for a fluctuating condition, and
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S Beissert et al.
Pemphigus Vulgaris and Mycophenolate Mofetil

the trial may have been too short given that pemphigus
vulgaris is a chronic condition. An extension to the trial
would have allowed further evaluation of long-term safety.
Lesions were not monitored individually and photographic
assessment was not obtained, although the same investigator
reviewed the lesions at each visit. Finally, the small sample
made analyses of subpopulations less reliable. Nevertheless,
the trial yielded good responses on secondary end points, and
the demonstrated safety profile of MMF, combined with its
steroid-sparing potential and good efficacy, suggest that it can
be an important treatment option for pemphigus vulgaris.
Owing to the scarcity of randomized controlled trials in
pemphigus vulgaris to date, many questions about the
optimal therapeutic strategy still need to be answered,
particularly with regard to the role of adjuvant medications
(Martin et al., 2009). Future studies should account for the
relapsingremitting nature of pemphigus when defining the
primary end point and study duration, and include a more
adequate assessment of the durability of treatment response.
In conclusion, results from this international, placebocontrolled study, conducted with MMF in pemphigus
vulgaris, suggest that MMF may be a clinically useful agent
in the treatment of patients with mild-to-moderate pemphigus
vulgaris.
MATERIALS AND METHODS
Setting
This prospective, randomized, placebo-controlled, parallel-group,
international multicenter study (protocol number WX17796;
ClinicalTrials.gov registration number NCT00683930) was conducted at 21 centers in eight countries (Canada, Germany, India,
Israel, Turkey, Ukraine, United Kingdom, and United States).
The primary aim was to assess the efficacy of MMF, compared
with placebo, in patients with pemphigus vulgaris who were being
treated with prednisone. The secondary objective was to assess the
safety and tolerability of MMF.

Patients
We recruited patients of either sex (aged 1870 years) if they had
received a diagnosis of pemphigus vulgaris within the previous
2 years, based on histological features of acantholysis and either
direct immunofluorescence visualization of IgG antibodies on the
surface of the affected epithelium or indirect immunofluorescence
evidence of circulating IgG antiepithelial antibodies binding to
epithelial cell surface autoantigens. All patients had mild or
moderate disease, with mild disease defined as 15 lesions lasting
41 week or covering o3% of the body surface, including oral
lesions (Mukhtar and Jones, 2003), and moderate disease defined as
640 lesions lasting 41 week or covering 320% of the body
surface, including oral lesions (Mukhtar and Jones, 2003). Another
requirement was that, in the investigators opinion, the patient could
benefit from a short course of oral prednisone, equivalent to
prednisone 12 mg kg1 day1. Principal exclusion criteria were
evidence of paraneoplastic pemphigus or other autoimmune
blistering disease, treatment for 44 weeks with MMF or other
immunosuppressive therapy for 8 weeks before randomization,
treatment with intravenous immunoglobulin therapy or plasma
exchange within 8 weeks before randomization or on a regular
2046 Journal of Investigative Dermatology (2010), Volume 130

basis, use of other pemphigus vulgaris treatments within 4 weeks

before randomization, clinically significant medical or psychiatric
illness, known hypersensitivity to MMF or corticosteroids, pregnancy, and lactation.
The protocol was approved by the institutional review boards or
independent ethics committees at each center, and the trial was
conducted in accordance with the Declaration of Helsinki principles
and the principles of the International Committee on Harmonisation
Tripartite Guideline on Good Clinical Practice. Written informed
consent was obtained from all patients before study inclusion.

Interventions
Initially, eligible patients were randomized in a 1:1 ratio to receive
MMF 3 g day1 (six tablets) or placebo for 52 weeks. The study
protocol was amended on 2 May 2005 following consultation with
the US Food and Drug Administration, and a lower-dose (2 g day1)
MMF treatment group was included. Thereafter, patients were
randomized in a 2:2:1:1 ratio to receive MMF 2 g day1 (four tablets)
or 3 g day1 (six tablets), or matching placebos. Consequently, the
number of patients in each treatment group varied depending on the
number of patients already enrolled before the protocol amendment.
Figure 3 shows the flow of patients through the study.
All patients received oral prednisone at doses tapered after an initial
daily dose of 12 mg kg1 ideal body weight. The protocol did not
specify whether prednisone doses should be divided or administered in
one dose in the morning. If the initial dose was 41 mg kg 1day1, it
was reduced to 1 mg kg 1day1 at week 2. Once tapering criteria (i.e.,
no new persistent lesions and healing of existing lesions) had been
met, doses were reduced within 4 weeks from 1 mg kg 1day1 to a dose
that was 20 mg day1 lower. When the tapering criteria were met at the
new dose, the daily prednisone dose was reduced by 10 mg within 4
weeks. If the criteria continued to be met, the daily dose was reduced
by 10 mg every 4 weeks to a minimum dose of p10 mg day1, which
was maintained until study completion. After week 2, if a patient was
unable to reduce the prednisone dose for the subsequent 1416
consecutive weeks (if the dose was 410 mg day1), then the patient
was withdrawn from the study.
Prophylactic treatment for prednisone-induced bone loss or
symptomatic treatment of gastrointestinal AEs was permitted at the
investigators discretion.

Study end points

Assessments were performed at screening and randomization, at
weeks 2 and 4, and every 4 weeks thereafter until study end. The
primary efficacy end point was the proportion of patients who
achieved responder status in the combined MMF group, compared
with the placebo group. A response was defined as the absence of
new persistent oral or cutaneous lesions (lesions present at week 52
that had been present for at least 1 week and had not been present at
week 48), and a prednisone dose of p10 mg day1 from weeks 48 to
52. Secondary efficacy end points included the number of days a
patient maintained a prednisone dose of p10 mg day1 in the
absence of new persistent lesions, the time from initial response to
relapse (defined as the presence of at least one new persistent lesion,
a prednisone dose 410 mg day1, or both), time to initial response
(defined as the time from randomization to the point at which the
patient had no new persistent lesions and required a prednisone dose
of p10 mg day1), time to sustained response (i.e., the time that the

S Beissert et al.
Pemphigus Vulgaris and Mycophenolate Mofetil

Assessed for eligibility

(n=96)

Enrollment

Excluded (n =2)
Withdrew consent (n =1)
Other reasons (n=1)

Randomized

Allocated to placebo (n=37)

Received allocated intervention (n =36)
Did not receive allocated intervention (n=1)
Did not receive study drug (n=1)

Allocation

Allocated to MMF combined (n =59)

Received allocated intervention (n =58)
Did not receive allocated intervention (n=1)
Did not receive study drug (n=1)

Lost to follow-up (n=1)

Discontinued intervention (n=6)
Could not decrease steroid dose (n=2)
AE (n=1)
Death (n=1)
Other (n =2)

Follow-up

Lost to follow-up (n=2)

Discontinued intervention (n =10)
Could not decrease steroid dose (n =1)
Had >5 new lesions lasting >4 weeks (n =1)
AE (n =3)
Withdrew consent (n =3)
Other (n=2)

Analyzed (n=36)
Excluded from analysis (n=1)
Did not receive study drug (n =1)

Analysis

Analyzed (n =58)
Excluded from analysis (n =1)
Did not receive study drug (n =1)

Figure 3. CONSORT flowchart.

patient first showed the criteria for responder status and the
conditions were maintained through to study termination at week
52), proportion of responders in the MMF 2 and 3 g day1 groups
versus placebo, mean and median prednisone dose at study
termination, DSG-1 and DSG-3 antibody titers, and quality of life
(36-Item Short Form questionnaire; Ware et al., 2000).
Safety assessments included AEs, clinical laboratory testing,
physical examinations, vital signs, electrocardiograms, and medication use. Blood samples for measurement of antibodies to DSG-1
and DSG-3 were obtained at screening, baseline, and at weeks 12,
24, 36, and 52. Antibody titers were measured by standard methods
using ELISA (Department of Dermatology, Immunodermatology
Laboratory, University of Utah Health Sciences Center, Salt Lake
City, UT) at a central laboratory (Abasq et al., 2009).

Randomization and masking

Randomization was performed using a central telephone-based
automated interactive voice response system (IVRESS LLC, Hilton
Head Island, SC) in conjunction with double-blind packaging and using
a centralized computer-generated code. The randomization code was
generated by Chiltern International (Slough, UK). The study was double
blind with respect to treatment allocation (MMF or placebo), but open
with respect to dosing regimen (four or six tablets per day).

Statistical analysis
The final planned sample size was 92 patients, to detect a difference
in 52-week response between the placebo and combined MMF
groups, with 490% power using Fishers exact test with an a of

0.025. A 30% placebo response (G Anhalt, personal communication) and a 70% response for combined MMF (Mimouni et al., 2003)
were assumed. Primary efficacy was to be established if the null
hypotheses were rejected and each MMF group had a numerically
greater 52-week response rate than placebo.
All analyses were performed on the intent-to-treat population,
with randomized patients receiving at least one dose of study
medication. All testing was two sided. Patients withdrawn before
week 52 or because of otherwise missing data for the assessment of
the primary end point were counted as nonresponders in the primary
analysis. Sensitivity analyses used several different imputation
methods for missing data. The primary analysis was replicated in
the per-protocol population. Adjustments for age, sex, disease
severity, and prednisone dose and duration were performed using
logistic regression, and for pooled site using the CochranMantelHaenszel procedure.
The planned analysis for times to initial response and relapse was
the log-rank test with Cox hazard ratio (combined MMF/placebo)
and KaplanMeier plots. Prednisone maintenance days (with
prednisone p10 mg and no new persistent lesions) were to be
analyzed using the t-test.
Alternative analyses of the key secondary end points were
performed post hoc when statistical assumptions for the pre-planned
methods were not met (equality of variances, and normality for
t-test). Prednisone maintenance days were additionally analyzed
using the Wilcoxon test. The post hoc analysis of secondary efficacy
end points included comparisons with placebo for the MMF 2 and
3 g day1 groups.
www.jidonline.org 2047

S Beissert et al.
Pemphigus Vulgaris and Mycophenolate Mofetil

SAS version 9.1.3 (SAS Institute, Cary, NC) was used for statistical
analyses.

Amagai M, Ikeda S, Shimizu H et al. (2009) A randomized double-blind trial

of intravenous immunoglobulin for pemphigus. J Am Acad Dermatol
60:595603

CONFLICT OF INTEREST

Amagai M, Klaus-Kovtun V, Stanley JR (1991) Autoantibodies against a novel

epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion.
Cell 67:86977

This trial was sponsored by Vifor Pharma Ltd (formerly Aspreva), as part of the
RocheVifor rare-diseases collaboration, which was originally conceived to
generate robust clinical data by performing prospective, randomized, clinical
studies in orphan indications. Under the RocheVifor collaboration agreement, Vifor has the rights to develop and commercialize mycophenolate
mofetil in all autoimmune disease applications. As such, Vifor was
responsible for funding and conduct of the study and was, in collaboration
with the publication committee, responsible for the authorship of the paper.
The data in this paper are original. Stefan Beissert, Daniel Mimouni, Grant
Anhalt, and four employees of the sponsor with input from the regulatory
authorities developed the concept and design of the study and/or approved
the statistical plans. The authors had full access to and interpreted the data,
wrote the paper, and were responsible for the decision to publish the paper.
Data collection was coordinated by the four employees of the sponsor. The
authors collaborated closely with a medical writer, and an employee of the
sponsor performed the statistical analysis. All authors vouched for the
accuracy and completeness of the data and the analyses. The sponsor did not
place any restrictions on the academic authors regarding the statements made
in the final paper. Stefan Beissert has received a travel grant to Berne from
Vifor Pharma Ltd. Daniel Mimouni and Amrinder Jit Kanwar have nothing to
declare. Neil Solomons and Veena Kalia are employees of Vifor Pharma Ltd.
Grant Anhalt was paid as a consultant to Vifor Pharma Ltd for his role as a
clinical expert at meetings with, and assistance in preparation of documents
for, the FDA.

ACKNOWLEDGMENTS
We thank the investigators who participated in the study: Yurly Andrashko,
Uzhgorod State National University, Uzhgorod, Ukraine; Nilgun Atakan,
niversitesi Tip Fakultesi, Ankara, Turkey; Reuvan Bergman,
Hacettepe U
Rambam Medical Center, Haifa, Israel; Zeynep Demircay, Marmara
niversitesi Tip Fakultesi, Istanbul, Turkey; Alexander Enk, UniversitatsU
Hautklinik, Heidelberg, Germany; David Fivenson, Ann Arbor, MI; Richard
Groves, St Johns Institute of Dermatology, St Thomas Hospital, London, UK;
Karen Harman, Leicester Royal Infirmary, Leicester, UK; Nisel Ilter, Gazi
niversitesi, Tip Ankara, Turkey; HR Jerajani, LTM Medical College and LTM
U
General University, Mumbai, India; Francisco Kerdel, Cedars Medical Center,
Miami, FL; Vladimir Koladenko, National Medical University, Kiev, Ukraine;
Olga Pritulo, Crimea State Medical University, Simferopol, Ukraine; Sudhir
Pujara, Municipal General Hospital, Ahmedabad, India; Vladimir Radionov,
Cathedra of Dermatology and Venereology, Lugansk, Ukraine; Rifkiye Sarica niversitesi, Istanbul, Turkey; Vinod Kumar Sharma, All
Kucukoglu, Istanbul U
India Institute of Medical Sciences, New Delhi, India; Neil Shear, DecisionLine Clinical Research Corporation, Toronto, Canada. We also thank Terry
Germanson (Germanson Statistical Associates) and Lane Senne (PRA
International), trial statistician, for data analysis and interpretation, and figure
preparation, and Nicola West (Caudex Medical, Oxford, UK, supported by
Vifor Pharma Ltd) for editorial assistance and collating author comments. This
prospective, randomized, placebo-controlled, parallel-group, international
multicenter study (protocol number WX17796; ClinicalTrials.gov registration
number NCT00683930) was conducted at 21 centers in eight countries:
Canada, Germany, India, Israel, Turkey, Ukraine, United Kingdom, and
United States.
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