STUDY

A Comparison of Oral Methylprednisolone

Plus Azathioprine or Mycophenolate Mofetil
for the Treatment of Pemphigus
Stefan Beissert, MD; Thomas Werfel, MD; Uta Frieling, MD; Markus Böhm, MD; Michael Sticherling, MD;
Rudolf Stadler, MD; Detlev Zillikens, MD; Berthold Rzany, MD; Nicolas Hunzelmann, MD; Michael Meurer, MD;
Harald Gollnick, MD; Thomas Ruzicka, MD; Hans Pillekamp, MD; Volker Junghans, MD; Thomas A. Luger, MD

Objective: To investigate the safety and efficacy of oral
methylprednisolone combined with azathioprine sodium
or mycophenolate mofetil for the treatment of pemphigus.
Design: A prospective, multicenter, randomized, non-
blinded clinical trial to compare 2 parallel groups of pa-
tients with pemphigus (pemphigus vulgaris and pem-
phigus foliaceus) treated with oral methylprednisolone
plus azathioprine or oral methylprednisolone plus my-
cophenolate mofetil.
Settings: Thirteen departments of dermatology in Ger-
many.
Patients: We included patients with pemphigus vul-
garis (n=33) or pemphigus foliaceus (n = 7) evidenced
by clinical lesions suggestive of pemphigus, intraepider-
mal blistering on histological analysis of skin biopsy speci-
mens, intercellular deposition of IgG within the epider-
mis, and immunoblot analysis findings for antidesmoglein
3 and/or antidesmoglein 1 autoantibodies.
Main Outcome Measures: The cumulative total meth-
ylprednisolone doses and rate of remission. Secondary
outcome measures were safety profiles and duration of
remission.
Results: In 13 (72%) of 18 patients with pemphigus re-
ceiving oral methylprednisolone and azathioprine, com-
plete remission was achieved after a mean±SD of 74±127
days compared with 20 (95%) of 21 patients receiving
oral methylprednisolone and mycophenolate mofetil in
whom complete remission occurred after a mean±SD of
91±113 days. The total median cumulative methylpred-
nisolone dose used was 8916 mg (SD, ±29 844 mg) in
the azathioprine group compared with 9334 mg (SD,
±13 280 mg) in the mycophenolate group. In 6 (33%) of
18 patients treated with azathioprine, grade 3 or 4 ad-
verse effects were documented in contrast to 4 (19%) of
21 patients who received mycophenolate mofetil.
Conclusion: Mycophenolate mofetil and azathioprine
demonstrate similar efficacy, corticosteroid-sparing ef-
fects, and safety profiles as adjuvants during treatment
of pemphigus vulgaris and pemphigus foliaceus.
Arch Dermatol. 2006;142:1447-1454

Author Affiliations are listed at
the end of this article.
P
EMPHIGUS IS AN ACQUIRED
bullous autoimmune disor-
der of the skin and mucous
membranes in which auto-
antibodies against keratino-
cyte antigens lead to a loss of cell-cell ad-
hesion, resulting in erosions and blister
formation. The autoantibodies are di-
rected against epidermal cadherins, a fam-
ily of calcium2⫹-dependent cell-cell adhe-
sion molecules.1,2 According to clinical
lesion appearance and autoantibody reac-
tivity, pemphigus can be further classi-
fied into different subtypes, each with a
characteristic intraepidermal loss of cel-
lular attachments. By histological classi-
fication, the 2 major subtypes, pemphi-
gus vulgaris and pemphigus foliaceus, are
distinguished by the level of cleavage
within the epidermis.3,4 Blister formation
is more superficial in pemphigus folia-
ceus compared with pemphigus vulgaris.
Pemphigus vulgaris accounts for about two
thirds of all pemphigus cases and prob-
ably constitutes the most common bul-
lous autoimmune disorder in the eastern
countries of Eurasia. In the West, pem-
phigus vulgaris is less common.5
The major pemphigus vulgaris auto-
antigen is desmoglein 3 (Dsg3), a desmo-
somal cadherin.1,2 Anti-Dsg3 autoantibod-
ies bind to the extracelluar domain of the
NH2 region of Dsg3, which is proposed to
have a direct effect on the adhesive func-
tion of Dsg3. Accordingly, experimental
injection of anti-Dsg3 autoantibodies into
newborn mice induced epidermal blister
formation similar to pemphigus vul-
garis.6 The relevance of Dsg3 for the ad-
herence of keratinocytes is demonstrated

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in mice with a spontaneous mutation in Dsg3 and in
knockout animals with a disrupted Dsg3 gene induced
by homologous recombination.7 Pemphigus vulgaris
serum samples may also contain autoantibodies to
desmocollins and Dsg1, the pemphigus foliaceus anti-
gen.8-10 Dsg3 expression is restricted to the basal and im-
mediate suprabasal layers of the epidermis, whereas Dsg1
is expressed in the superficial layers.11
There is no standard treatment of pemphigus fulfill-
ing the criteria of evidence-based medicine, and there are
few, if any, controlled studies on individual therapeutic
strategies in pemphigus. Before the therapeutic use of cor-
ticosteroids, pemphigus was almost invariably a fatal dis-
ease with a mortality of more than 70%.12,13 Ever since,
the high mortality could be reduced to less than 10%. Ac-
cordingly, even today, corticosteroids remain the main-
stay treatment of pemphigus. However, the relatively high
doses and long duration of treatment often required to
control the disease lead to a variety of adverse effects, many
of which are serious. Today, corticosteroids are usually
given in combination with adjuvant immunosuppres-
sant therapy to reduce the cumulative corticosteroid dose
and adverse effects. Nevertheless, most patients who die
of pemphigus today die of complications from the treat-
ment. Therefore, the search for safe and effective treat-
ment regimens is of particular practical interest. Among
the different immunosuppressants, azathioprine so-
dium has been widely used since the late 1960s to con-
trol disease in patients with pemphigus (hereafter re-
ferred to as pemphigus patients). 14 More recently,
pemphigus was successfully treated with a combination
therapy using mycophenolate mofetil.15-17 Therefore, we
were interested in investigating and comparing the safety
and efficacy of azathioprine vs mycophenolate mofetil,
each in combination with oral methylprednisolone, for
the treatment of pemphigus. We herein present the re-
sults of a national randomized multicenter study ad-
dressing this issue.
METHODS
STUDY PATIENTS
Thirteen dermatologic departments in Germany participated
in this prospective, randomized investigation. The study pro-
tocol was approved by the ethics committee of the University
of Münster, Münster, Germany, and written informed consent
was obtained from each patient. Consecutive patients with pem-
phigus vulgaris or pemphigus foliaceus were eligible for entry
if they met the following criteria: clinical lesions suggestive of
pemphigus, intraepidermal blistering on histological analysis
of skin biopsy specimens, intercellular deposition of IgG within
the epidermis, and detection of anti-Dsg3 and/or anti-Dsg1 auto-
antibodies by immunoblot analysis. Exclusion criteria were treat-
ment with oral or topical corticosteroids and other immuno-
suppressive drugs during the previous 4 weeks.
STUDY DESIGN
This multicenter, randomized, nonblinded clinical trial com-
pared 2 parallel groups of patients with pemphigus vulgaris and
pemphigus foliaceus treated with oral methylprednisolone in
combination with azathioprine or mycophenolate mofetil. Be-
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cause complete healing of the lesions, as defined by a com-
plete reepithelization of all previous lesions, was the first pri-
mary outcome measure, blinding was not regarded as necessary.
The second primary outcome measure was the cumulative oral
corticosteroid dose used until complete remission, allowing com-
parison of the corticosteroid-sparing effects of the 2 alterna-
tive immunosuppressants. Secondary outcome measures were
duration of remission and safety profiles of the 2 treatment arms.
Randomization was stratified according to the clinical center
and performed centrally with the use of random numbers of
3 for each stratum. Patients were randomly assigned, irrespec-
tive of severity of disease, to receive 2 mg/kg of methylpred-
nisolone once daily (Urbason; Aventis Pharma Deutschland
GmbH, Bad Soden, Germany) with 2 mg/kg of azathioprine so-
dium (Imurek; GlaxoSmithKline GmbH & Co KG, Munich, Ger-
many) or 2 mg/kg of methylprednisolone once daily with 1000
mg of mycophenolate mofetil (CellCept; Hoffmann-La Roche
AG, Grenzach-Wyhlen, Germany) given twice daily (2 g/d). The
initial dosage was maintained until blister formation ceased,
crusts and erosions disappeared, and reepithelialization of pre-
vious lesions started. The corticosteroid dosage was subse-
quently reduced to 40 mg/d. Afterward, the corticosteroid dos-
age was sequentially reduced by 10 mg/d every 2 weeks until a
dosage of 20 mg/d was reached, followed by reductions in 5-mg
steps every 2 weeks until 10 mg/d was reached and in 2.5-mg
steps every 2 weeks until discontinuation of treatment. After
discontinuation of corticosteroid therapy, azathioprine or my-
cophenolate dosages were maintained at the initial dosage as
monotherapy for an additional 12 weeks. Subsequently, aza-
thioprine sodium was reduced by 0.5 mg/kg every 4 weeks to
a dosage of 100 mg/d. Thereafter, the azathioprine sodium dos-
age was tapered in 25-mg steps every 4 weeks until discon-
tinuation of treatment. Mycophenolate mofetil therapy was re-
duced in 500-mg/d steps every 4 weeks to 1000 mg/d. Afterward,
the mycophenolate mofetil dosage was decreased in 250-mg steps
every 4 weeks until discontinuation of treatment.
If new blisters developed 7 days after the initiation of therapy,
the methylprednisolone dosage was increased by 1 mg/kg ev-
ery 7 days until blister development ceased.
Relapse was defined as new blister formation during dos-
age reduction of methylprednisolone or immunosuppres-
sants. If a relapse was noticed when the methylprednisolone
dosage was at least 40 mg/d, the previous corticosteroid dos-
age that permitted control of the disease was given. If a relapse
was noticed when the methylprednisolone dosage was less than
40 mg/d, including the phase of immunosuppressant mono-
therapy or its reduction, the corticosteroid dosage was in-
creased to 40 mg/d and the initial immunosuppressant dosage
was given.
BASELINE AND FOLLOW-UP EVALUATIONS
At baseline, each patient underwent physical examination fol-
lowed by a complete blood cell count, liver function tests,
blood pressure evaluation, fecal occult blood test, and urine
analysis. In addition, abdominal ultrasonography, chest radi-
ography, electrocardiography, quantitative computed tomog-
raphy for determination of bone density, and ophthalmologi-
cal evaluation to measure inner eye pressure and to determine
cataract status were performed. The extent and location of
blisters and erosions were documented by a physician who
was not otherwise involved in the study. At each follow-up
visit (on days 7, 14, 30, 60, 90, 120, 150, 180, 270, 360, 540,
and 720), the patient underwent physical examination, com-
plete blood cell count, liver function tests, blood pressure
evaluation, and stool and urine analysis, and the extent and
location of blisters and erosions and the cumulative dose of
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 Table 1. Baseline Characteristics of the Patients
47 Assessed for Eligibility

Characteristic Finding 7 Excluded

4 Did Not Meet
Age, mean ± SD, y 56.5 ± 13.4 Inclusion Criteria
Sex, No. M/F 16/23 3 Refused to Participate
Days between diagnosis and randomization, mean ± SD 129 ± 325
No. with pemphigus vulgaris/pemphigus foliaceous 33/7 40 Randomized
Previous treatment of pemphigus, No. (%)
Yes 5 (13)
19 Allocated to Azathioprine Sodium 21 Allocated to Mycophenolate Mofetil
No 34 (87) and Received Allocated Treatment
18 Received Allocated Treatment
Body surface involvement, No. (%) (n = 37) 1 Did Not Receive Allocated
0 1 (3) Treatment (Patient Withdrew
⬍5% 16 (43) Written Consent)
⬍10% 11 (30)
⬍20% 2 (5) 18 Analyzed 21 Analyzed
ⱖ20% 7 (19)
Oral mucosa involvement, No. of patients (n = 35)
Yes 28 Figure 1. Flow diagram of the trial profile showing randomization of 40
patients to treatment with oral methylprednisolone combined with adjuvant
No 7
azathioprine sodium or mycophenolate mofetil.
Presence of circulating antibodies against
keratinocyte surface antigens, No. of patients
Yes 30
No 9 1.0

0.8
methylprednisolone that had been taken were noted. The date

Rate Without Remission

of any relapse was also noted. Any adverse effects of treatment
were assessed, and their severity was graded as 1 for mild ef- 0.6
fects, 2 for moderate effects, 3 for severe effects, or 4 for life-
threatening effects, according to the standard criteria of the 0.4
World Health Organization. Azathioprine (n = 18)

0.2
STATISTICAL ANALYSIS Mycophenolate Mofetil (n = 21)

Cumulative corticosteroid dosages as the primary endpoint of 0

the study were compared using the Wilcoxon rank sum test 0 100 200 300 400 500 600

for independent observations. All other analyses presented herein Time, d

are of a descriptive or a hypothesis-generating nature. Dichoto-
mous and ordered categorical data were analyzed with the Fisher
exact test and a corresponding exact permutation version of
the Mantel-Haenszel test, respectively. Event-related data, such
as the time to achieve a remission or the time to recurrence,
were estimated according to the Kaplan-Meier method and even-
tually compared using the log-rank test. All event or censor-
ing times were calculated from the time of randomization. All
P values reported are 2 sided. Unless otherwise indicated, data
are expressed as mean±SD.
RESULTS
PATIENTS
Between October 1997 and October 2000, 47 patients with
pemphigus underwent assessment for eligibility
(Table 1). Three patients declined to provide written
consent. Use of other medication effective against pem-
phigus (in 2 patients), diagnosis of another bullous au-
toimmune disorder (in 1 patient), and severe cardiac in-
sufficiency (in 1 patient) were other reasons for exclusion.
Of the remaining 40 patients, 33 had pemphigus vul-
garis and 7 had pemphigus foliaceus. The 40 patients were
randomly assigned to receive the methylprednisolone-
azathioprine combination (AZA group; n = 18) or the
methylprednisolone–mycophenolate mofetil combina-
tion (MMF group; n = 21) (Figure 1). After randomiza-
Figure 2. Rate and duration until clinical remission. Pemphigus patients
were randomized to receive azathioprine sodium (n = 18) or mycophenolate
mofetil (n = 21) as adjuvant treatments in combination with oral
methylprednisolone. Kaplan-Meier graph shows the rate without remission
over time (P = .75).
tion, 1 patient withdrew written consent. Thirty-four pa-
tients (87%) were newly diagnosed as having pemphigus,
whereas 5 (13%) had been previously treated for their
disease. The mean duration of follow-up among the pem-
phigus patients was 438 days for the AZA group and 438
days for the MMF group.
DISEASE CONTROL AND RELAPSE
In all 18 pemphigus patients who were assigned to the
AZA group (15 with pemphigus vulgaris and 3 with
pemphigus foliaceus) and in all 21 pemphigus patients
who were assigned to the MMF group (17 with pemphi-
gus vulgaris and 4 with pemphigus foliaceus), disease
progression was inhibited by day 30±7 days. Complete
healing of the lesions and remission was achieved in 13
(72%) of the 18 AZA group patients (Figure 2).
Among the other 5 patients with incomplete healing
(28%), 2 did not respond to treatment with the methyl-
prednisolone-azathioprine combination, treatment
had to be discontinued owing to severe adverse effects

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 1.0 1.0

>7 d (n = 17)
Rate Without Recurrence 0.8 0.8

Rate Without Recurrence

0.6 0.6 ≤7 d (n = 22)

0.4 0.4
Mycophenolate Mofetil (n = 21)

0.2 Azathioprine (n = 18) 0.2

0 0
0 100 200 300 400 500 600 700 0 100 200 300 400 500 600 700 800
Time, d Time, d

Figure 3. Disease-free interval. Kaplan-Meier graph shows that the rate Figure 5. Effects of the length of time from the diagnosis to the initiation of
without recurrence of disease after remission was achieved in pemphigus treatment on the recurrence of disease. Kaplan-Meier graph shows the rate
patients treated with azathioprine sodium (n=18) or mycophenolate mofetil without recurrence of pemphigus over time in patients treated for 7 days or
(n = 21) as adjuvants (P =.69). less or for more than 7 days after the diagnosis of pemphigus (P =.97).

1.0 Table 2. Total Cumulative Corticosteroid Doses

Used to Control Pemphigus
0.8
Drug No. (%) of Patients Median ± SD Dose
Rate Without Remission

Azathioprine (n = 18)
Azathioprine sodium 18 (51) 8916 ± 29 844
0.6
Mycophenolate mofetil 17 (49) 9334 ± 13 280
Pemphigus 35 (100) 9334 ± 23 049
0.4 Mycophenolate Mofetil
(n = 21)

0.2
0
0 100 200 300 400
Time, d
Figure 4. Duration until relapse. Kaplan-Meier graph shows the time since
randomization until pemphigus patients developed a recurrence of disease
during the reduction phase of treatment medication (P=.59).
in 2 patients, and contact was lost with 1 patient. Com-
plete healing of the lesions and disease remission was
noted in 20 (95%) of the 21 MMF group patients. One
patient from this group (5%) did not achieve remission
(Figure 2). This patient was noncompliant and discon-
tinued therapy prematurely.
Complete remission was achieved after a mean dura-
tion of 74±127 days of treatment in the AZA group. In
the MMF group, complete remission was noted after a
mean of 91±113 days (P⬎.05). The mean disease-free
interval from the time when complete remission was
achieved until recurrence of lesions was 258 ± 183 days
for the AZA group and 123±103 days for the MMF group
(P⬎.05). The Kaplan-Meier graph in Figure 3 shows
the rate without relapse in pemphigus patients over time,
indicating that both adjuvants in the 2 treatment arms
controlled disease equally well.
The data in Figure 4, depicting the duration until
relapse of disease, was documented from the time of ran-
domization. The 2 curves show a similar course and are,
therefore, not significantly different. In addition, the du-
ration until relapse was differentiated in relation to the
time from the diagnosis of pemphigus to the beginning
of treatment. The result in Figure 5 shows that the du-
500 600 700 800
ration from the diagnosis to the initiation of therapy of
7 days or less or of more than 7 days did not signifi-
cantly influence the time until a relapse of disease was
noted. These findings indicate that pemphigus can be suc-
cessfully controlled with both treatment regimens.
CUMULATIVE CORTICOSTEROID DOSES USED
One of the aims of this investigation was to determine
whether the corticosteroid-sparing effect of either im-
munosuppressant would be superior. Therefore, the cu-
mulative corticosteroid dose was calculated for each pem-
phigus patient after the beginning of treatment and
through the documentation period for at least 720 days.
The data in Table 2 show that pemphigus patients who
were randomized to the AZA group received a median±SD
methylprednisolone dose of 8916 ± 29 844 mg. In the
MMF group, the median±SD methylprednisolone dose
was 9334±13 280 mg. In general, these numbers are simi-
lar and possibly reflect the comparable immunosuppres-
sive potential of both drugs.
The results in Table 3 further demonstrate that 19
(54%) of 35 pemphigus patients received a cumulative
methylprednisolone dose of 10 000 mg or less during the
course of treatment. Nine (26%) of 35 patients received
10 001 to 20 000 mg of corticosteroids. The distribution
of the pemphigus patients to the different corticosteroid
dose groups (Table 3) was similar for the AZA and MMF
adjuvant treatment groups. In summary, similar cumu-

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 Table 3. Groups of Cumulative Corticosteroid Doses Table 4. Incidence of Grade 3 and 4 Adverse Events
After the Initiation of Treatment
No. (%) of Patients
No. (%) of Patients
Azathioprine Mycophenolate No. of
Corticosteroid Sodium Mofetil Pemphigus Symptom Patients Grade 3 Grade 4
Dosage, mg (n = 18) (n = 17) (n = 35)
Azathioprine sodium
1-10 000 9 (50) 10 (59) 19 (54) adjuvant treatment
10 001-20 000 5 (28) 4 (24) 9 (26) Blood pressure 17 2 (12) 0
20 001-30 000 0 2 (12) 2 (6) Cushing syndrome 17 1 (6) 0
30 001-40 000 1 (6) 0 1 (3) Diarrhea 17 1 (6) 0
40 001-50 000 0 0 0 Hyperglycemia 18 1 (6) 0
50 001-60 001 1 (6) 1 (6) 2 (6) Infection 17 1 (6) 0
⬎75 000 2 (11) 0 2 (6) Liver-function tests 18 1 (6) 0
Myalgia/arthralgia 17 1 (6) 0
Dizziness 17 1 (6) 0
Nausea 17 2 (12) 0
lative corticosteroid concentrations were taken during Psychiatric symptoms 17 0 1
therapy in both treatment arms. Mycophenolate mofetil
adjuvant treatment
COMPLIANCE WITH TREATMENT Blood pressure 21 1 (5) 0
Cushing syndrome 21 0 0
AND ADVERSE EVENTS
Diarrhea 21 0 0
Hyperglycemia 21 3 (14) 0
One patient showed no compliance, withdrew written Infection 21 1 (5) 0
consent, and discontinued treatment. Contact was lost Liver function tests 21 0 0
with another patient. Myalgia/arthralgia 21 0 0
Overall, 17 severe (grade 3) or life-threatening (grade Dizziness 21 0 0
Nausea 21 0 0
4) adverse effects were reported in 10 patients (Table 4).
In 6 (33%) of 18 patients randomized to the AZA group,
grade 3 or 4 adverse effects were documented, com-
pared with 4 (19%) of 21 patients from the MMF group dose of prednisolone (200-400 mg) over up to 8 weeks.
(P⬎.05). The results in Table 4 demonstrate that the ad- After the healing of the lesions, the dosage should be
verse effects that are typically associated with the immu- reduced to a maintenance level of 15 mg/d. The treat-
nosuppressants used in this investigation, such as nau- ment regimen proposed by Bystryn and Steinman12 took
sea (P=.06), vomiting (P = .21), elevated liver function the variable course of pemphigus into account and rec-
test results (P = .21), and infections (P = .86), did not dif- ommended starting treatment with relatively low pred-
fer significantly between treatment arms. Together, the nisolone dosages (20 mg/d). In patients with severe
adverse effects and efficacy reported were not signifi- forms of the disease or in those who do not respond,
cantly different between the 2 treatment arms. the corticosteroid dosage is continuously increased
until the disease activity is controlled. This higher dos-
COMMENT age is maintained until most lesions are cleared and is
then reduced every 2 weeks. Another approach is to
This randomized investigation demonstrates that pem- treat pemphigus with corticosteroid megadose pulses
phigus vulgaris and pemphigus foliaceus can be con- (1 g/d).19,20 Although disease can be controlled by using
trolled equally well by methylprednisolone therapy in these different treatment regimens, many patients
combination with adjuvant azathioprine or mycopheno- develop severe complications of long-term use of corti-
late mofetil therapy. Both immunosuppressants had a simi- costeroids; in 1 report, more pemphigus patients died of
lar effect on disease activity and a similar safety profile. corticosteroid complications than of uncontrolled dis-
The cumulative corticosteroid doses used to treat dis- ease.21 Such developments sparked the hope that adju-
ease were comparable in both treatment arms, suggest- vant therapy would reduce the total cumulative cortico-
ing that the corticosteroid-sparing effect of one adju- steroid doses needed for treatment.
vant was not superior to that of the other. Also, most of The immunosuppressive drugs established for adju-
the adverse effects were equally distributed between the vant therapy of pemphigus are azathioprine and cyclo-
groups, with a slight but not statistically significant trend phosphamide. 12,14,22-30 Azathioprine has been used
in favor of mycophenolate mofetil for inducing fewer successfully for nearly 4 decades as an adjuvant in com-
grades 3 and 4 adverse events. bination with corticosteroids. The active metabolite of
Corticosteroids are the mainstay of pemphigus azathioprine is mercaptopurine, which is intracellularly
therapy to this day because they constitute the only converted to 6-thionine acid. These metabolites inhibit
treatment that is able to rapidly inhibit new blister for- lymphocyte proliferation and activation by interfering with
mation. In the past few years, several strategies for the several enzymes required for nucleotide replication, such
use of corticosteroids to treat pemphigus have been as inositol monophosphate dehydrogenase, glutamine
advocated. The original recommendation by Lever and 5-phosphoribosylpyrophosphate amidotransferase, and
Schaumburg-Lever18 was to give patients a fixed daily adenylosuccinate synthetase.31 Azathioprine and its me-

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tabolites are thereby able to block DNA replication at sev-
eral pivotal steps. Furthermore, mercaptopurine can in-
tegrate into DNA strands, leading to stable mutations. The
most common doses used for azathioprine range from
1.5 to 2.5 mg/kg, which may be increased to 3 mg/kg.
Our findings are in agreement with the reported data12,14
on the efficacy and adverse effects of azathioprine and
corticosteroid treatment in pemphigus patients. Most ad-
verse effects were graded as mild to moderate, as has been
reported before, and did not differ significantly from those
induced by mycophenolate.14,32 Only 1 severe pneumo-
nia infection, which required antimicrobial therapy, was
documented. Two patients developed severe arterial hy-
pertension and 1 developed severe diarrhea. In another
patient, corticosteroid-induced depression was diag-
nosed that resolved after reduction of the methylpred-
nisolone dosage.
One of the more recent adjuvant therapies for pemphi-
gus is mycophenolate mofetil. This drug is approved world-
wide for the prophylaxis of solid organ transplant rejec-
tions. After its approval in transplantation medicine,
mycophenolate has been successfully used in patients with
bullous pemphigoid or pemphigus vulgaris on a casuisti-
cal basis.15,16,33,34 Remission could be induced in pemphi-
gus patients who did not respond to azathioprine therapy.16
Mycophenolate mofetil is the ester of mycophenolic acid,
which is the active metabolite. Similar to azathioprine, my-
cophenolate mofetil inhibits the proliferation of lympho-
cytes by interfering with DNA replication.35 Mycophe-
nolic acid exclusively and reversibly inhibits inositol
monophosphate dehydrogenase, the essential enzyme for
the de novo guanine nucleotide synthesis.16 Additional
specificity is obtained because mycophenolic acid ap-
pears to block isoforms of inositol monophosphate dehy-
drogenase expressed primarily in proliferating lympho-
cytes. In contrast to azathioprine, mycophenolate mofetil
is nonmutagenic. Furthermore, mycophenolic acid has
been shown to abrogate B-cell proliferation, which is im-
portant in autoantibody-mediated bullous diseases, and
has a significant antitumoral effect in several experimen-
tal models.36 Accordingly, fewer malignancies were docu-
mented in transplant patients receiving mycophenolate for
longer periods.37-39
In patients with bullous autoimmune disease, myco-
phenolate mofetil was shown to be effective and well tol-
erated.36 These reports are consistent with our results,
because the methylprednisolone–mycophenolate mofetil
application was able to induce remissions in 90% of the
pemphigus patients treated. However, the time needed
to achieve disease control in 50% of the patients was about
30 days in the AZA group compared with about 75 days
in the MMF group (Figure 2). Blockade of at least 3 dif-
ferent enzymatic pathways by azathioprine compared with
the inhibition of primarily 1 pathway by mycopheno-
late mofetil may explain the slightly earlier remission af-
ter onset of therapy in the AZA group. Nevertheless, look-
ing at the rate of remission after 200 days, mycophenolate
mofetil treatment was shown to induce a 90% remission
in these patients compared with 43% in those receiving
azathioprine. This trend persisted after 600 days of treat-
ment because 20% of the pemphigus patients were still
not achieving effective control with azathioprine com-
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pared with 10% using mycophenolate mofetil. The re-
currence rate during reduction of treatment was similar
in both groups (Figure 3). After about 720 days, all pa-
tients had experienced a relapse, suggesting the benefit
of prolonging the intervals during the reduction phase
of treatment in future treatment regimens.
The profile of adverse effects of mycophenolate mofetil
was similar to that of azathioprine. However, fewer grade
3 and no grade 4 events were noted (Table 3). In one pa-
tient from the MMF treatment group, arterial hyperten-
sion was documented, which required treatment. In an-
other patient, a severe type 2 herpes simplex virus
infection occurred that was successfully controlled by vala-
cyclovir.
A key diagnostic feature in pemphigus is the anti-
Dsg1/3 autoantibody titer, which correlates with dis-
ease activity.40 Mycophenolate mofetil treatment has
been shown to reduce these titers to below detectable
levels in selected pemphigus patients.16 These data
agree with our results. Combination treatment with
mycophenolate mofetil and methylprednisolone de-
creased the serum concentration of autoantibodies in
all of the patients investigated, similar to the reduction
of autoantibody titers in all patients receiving azathio-
prine and methylprednisolone. These findings were not
significantly different between the 2 treatment arms
(data not shown). A contraindication for receiving aza-
thioprine is thiopurine methyltransferase deficiency,
which appears in 0.3% of the population.41,42 However,
we cannot completely rule out that the patients from
the AZA group who developed adverse effects had re-
duced thiopurine methyltransferase activity. Mycophe-
nolic acid plasma concentrations have been measured
in transplantation patients who were treated with my-
cophenolate mofetil. Perhaps future evaluation of my-
cophenolic acid levels in pemphigus patients will help
to determine these patients’ responsiveness to treat-
ment. Because remission was induced in 90% of our
pemphigus patients within 175 days, we believe that
routine analysis of mycophenolic acid plasma concen-
trations is not necessary.
One important aspect of adjuvant therapy is to re-
duce the total cumulative corticosteroid dose required
to achieve remission. To this end, a combination of cy-
closporine and prednisolone therapy was shown to sig-
nificantly reduce the total corticosteroid dose in pem-
phigus patients when compared with a historical
control group.43 Comparable cumulative methylpred-
nisolone doses were documented in our investigation in
both therapy arms. These results suggest that, indeed,
adjuvant therapy is able to reduce corticosteroid use.
However, in this investigation, no pemphigus patient
cohort was treated with corticosteroid-only immuno-
suppression.
Another important immunosuppressant for the treat-
ment of pemphigus is cyclophosphamide. Cyclophos-
phamide is often used as a pulse treatment in combina-
tion with prednisolone, especially in eastern Eurasia.28-30,44
By inducing DNA cross-linkage, cyclophosphamide has
a different mode of action compared with azathioprine
and mycophenolate mofetil. Cyclophosphamide treat-
ment is more effective but is related to a higher inci-
WWW.ARCHDERMATOL.COM
dence of adverse effects when compared with azathio-
prine or mycophenolate mofetil. Although azathioprine
may typically induce severe cholestatic hepatitis and
an increased long-term risk of malignancy, cyclophos-
phamide can cause hemorrhagic cystitis, bladder can-
cer, and infertility. The antitumoral effects of mycophe-
nolate mofetil observed in experimental models and
the reduced malignancy rate in transplantation patients
receiving long-term treatment favor the use of this
agent in pemphigus patients, especially because remis-
sion can be induced in a high percentage of the pa-
tients.36,39,45 To further study the clinical efficacy of dif-
ferent doses of mycophenolate mofetil in pemphigus
vulgaris, an international clinical study was initiated in
North America and Eurasia (Aspreva WX17796). Tak-
ing this together with our evidence, we find mycophe-
nolate to be an effective and safe adjuvant for the treat-
ment of pemphigus, and our findings expand the range
of the therapeutic alternatives available for patient-tai-
lored treatment.
Accepted for Publication: April 20, 2006.
Author Affiliations: Departments of Dermatology, Uni-
versity of Münster, Münster (Drs Beissert, Frieling,
Böhm, and Luger), Medical School Hannover, Han-
nover (Dr Werfel), University of Kiel, Kiel (Dr Sticher-
ling), University of Leipzig, Leipzig (Dr Sticherling),
Municipal Hospital Minden, Minden (Dr Stadler), Uni-
versity of Würzburg, Würzburg (Dr Zillikens), Univer-
sity of Lübeck, Lübeck (Dr Zillikens), Faculty of Clini-
cal Medicine Mannheim, University of Heidelberg,
Mannheim (Dr Rzany), University of Cologne, Cologne
(Dr Hunzelmann), University of Dresden, Dresden
(Dr Meurer), University of Magdeburg, Magdeburg
(Dr Gollnick), University of Düsseldorf, Düsseldorf
(Dr Ruzicka), University of Ulm, Ulm (Dr Pillekamp),
and University of Göttingen, Göttingen (Dr Junghans),
Germany; and Division of Evidenced-Based Medicine,
Department of Dermatology, Charité-Universitätsmedi-
zin, Berlin, Germany (Dr Rzany).
Correspondence: Stefan Beissert, MD, Department of Der-
matology, University of Münster, Von-Esmarch-Strasse
58, D-48149 Münster, Germany.
Author Contributions: Drs Beissert and Luger initiated
and designed the trial, had full access to all data for in-
terpretation, and had final responsibility for the deci-
sion to submit for publication. Study concept and design:
Beissert, Frieling, Zillikens, and Luger. Acquisition of
data: Beissert, Werfel, Frieling, Böhm, Sticherling,
Stadler, Zillikens, Rzany, Hunzelmann, Meurer, Goll-
nick, Ruzicka, Pillekamp, and Junghans. Analysis and
interpretation of data: Beissert and Luger. Drafting of
the manuscript: Beissert. Critical revision of the manu-
script for important intellectual content: Beissert, Werfel,
Frieling, Böhm, Sticherling, Stadler, Zillikens, Rzany,
Hunzelmann, Meurer, Gollnick, Ruzicka, Pillekamp,
Junghans, and Luger. Statistical analysis: Beissert and
Luger. Administrative, technical, and material support:
Beissert, Werfel, Frieling, Böhm, Sticherling, Stadler,
Zillikens, Rzany, Hunzelmann, Meurer, Gollnick,
Ruzicka, Pillekamp, Junghans, and Luger. Study super-
vision: Beissert and Luger.
(REPRINTED) ARCH DERMATOL/ VOL 142, NOV 2006
1453
©2006 American Medical Association. All rights reserved.
Financial Disclosure: Dr Beissert has served as consul-
tant and paid speaker for Hoffman-La Roche AG. Dr Luger
has served as consultant for Hoffman-La Roche AG.
Funding/Support: This study was supported by an un-
restricted grant from Hoffmann-La Roche AG.
Acknowledgment: We thank Jochen Dress and Axel
Hinke, PhD, of WISP Wissenschaftlicher Service Pharma,
Langenfeld, Germany, for their help with the statistical
analysis of the data and study supervision.
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ARCHIVES Web Quiz Winner

C ongratulations to the winner of our August quiz,

Mahmoud Saeed Abou-Hamedah, Shaqra Hospi-
tal, Shaqra, Saudi Arabia. The correct answer to our Au-
gust challenge was penile porokeratosis of Mibelli. For a
complete discussion of this case, see the Off-Center Fold
section in the September ARCHIVES (Perlis C, Robinson-
Bostom L, Telang G, DiGiovanna J. A thick lichenified
plaque on the ventral penile shaft. Arch Dermatol. 2006;
142:1221-1226).
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