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Objective: To investigate the safety and efficacy of oral outcome measures were safety profiles and duration of
methylprednisolone combined with azathioprine sodium remission.
or mycophenolate mofetil for the treatment of pemphigus.
Results: In 13 (72%) of 18 patients with pemphigus re-
Design: A prospective, multicenter, randomized, non- ceiving oral methylprednisolone and azathioprine, com-
blinded clinical trial to compare 2 parallel groups of pa- plete remission was achieved after a mean±SD of 74±127
tients with pemphigus (pemphigus vulgaris and pem- days compared with 20 (95%) of 21 patients receiving
phigus foliaceus) treated with oral methylprednisolone oral methylprednisolone and mycophenolate mofetil in
plus azathioprine or oral methylprednisolone plus my- whom complete remission occurred after a mean±SD of
cophenolate mofetil. 91±113 days. The total median cumulative methylpred-
nisolone dose used was 8916 mg (SD, ±29 844 mg) in
Settings: Thirteen departments of dermatology in Ger-
the azathioprine group compared with 9334 mg (SD,
many.
±13 280 mg) in the mycophenolate group. In 6 (33%) of
Patients: We included patients with pemphigus vul- 18 patients treated with azathioprine, grade 3 or 4 ad-
garis (n=33) or pemphigus foliaceus (n = 7) evidenced verse effects were documented in contrast to 4 (19%) of
by clinical lesions suggestive of pemphigus, intraepider- 21 patients who received mycophenolate mofetil.
mal blistering on histological analysis of skin biopsy speci-
mens, intercellular deposition of IgG within the epider- Conclusion: Mycophenolate mofetil and azathioprine
mis, and immunoblot analysis findings for antidesmoglein demonstrate similar efficacy, corticosteroid-sparing ef-
3 and/or antidesmoglein 1 autoantibodies. fects, and safety profiles as adjuvants during treatment
of pemphigus vulgaris and pemphigus foliaceus.
Main Outcome Measures: The cumulative total meth-
ylprednisolone doses and rate of remission. Secondary Arch Dermatol. 2006;142:1447-1454
P
EMPHIGUS IS AN ACQUIRED is more superficial in pemphigus folia-
bullous autoimmune disor- ceus compared with pemphigus vulgaris.
der of the skin and mucous Pemphigus vulgaris accounts for about two
membranes in which auto- thirds of all pemphigus cases and prob-
antibodies against keratino- ably constitutes the most common bul-
cyte antigens lead to a loss of cell-cell ad- lous autoimmune disorder in the eastern
hesion, resulting in erosions and blister countries of Eurasia. In the West, pem-
formation. The autoantibodies are di- phigus vulgaris is less common.5
rected against epidermal cadherins, a fam- The major pemphigus vulgaris auto-
ily of calcium2⫹-dependent cell-cell adhe- antigen is desmoglein 3 (Dsg3), a desmo-
sion molecules.1,2 According to clinical somal cadherin.1,2 Anti-Dsg3 autoantibod-
lesion appearance and autoantibody reac- ies bind to the extracelluar domain of the
tivity, pemphigus can be further classi- NH2 region of Dsg3, which is proposed to
fied into different subtypes, each with a have a direct effect on the adhesive func-
characteristic intraepidermal loss of cel- tion of Dsg3. Accordingly, experimental
lular attachments. By histological classi- injection of anti-Dsg3 autoantibodies into
fication, the 2 major subtypes, pemphi- newborn mice induced epidermal blister
gus vulgaris and pemphigus foliaceus, are formation similar to pemphigus vul-
Author Affiliations are listed at distinguished by the level of cleavage garis.6 The relevance of Dsg3 for the ad-
the end of this article. within the epidermis.3,4 Blister formation herence of keratinocytes is demonstrated
0.8
methylprednisolone that had been taken were noted. The date
0.2
STATISTICAL ANALYSIS Mycophenolate Mofetil (n = 21)
the study were compared using the Wilcoxon rank sum test 0 100 200 300 400 500 600
>7 d (n = 17)
Rate Without Recurrence 0.8 0.8
0.4 0.4
Mycophenolate Mofetil (n = 21)
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).
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
time from the diagnosis of pemphigus to the beginning
0
of treatment. The result in Figure 5 shows that the du-
0 100 200 300 400 500 600 700 800
ration from the diagnosis to the initiation of therapy of
Time, d 7 days or less or of more than 7 days did not signifi-
cantly influence the time until a relapse of disease was
Figure 4. Duration until relapse. Kaplan-Meier graph shows the time since
noted. These findings indicate that pemphigus can be suc-
randomization until pemphigus patients developed a recurrence of disease cessfully controlled with both treatment regimens.
during the reduction phase of treatment medication (P=.59).
CUMULATIVE CORTICOSTEROID DOSES USED
in 2 patients, and contact was lost with 1 patient. Com-
plete healing of the lesions and disease remission was One of the aims of this investigation was to determine
noted in 20 (95%) of the 21 MMF group patients. One whether the corticosteroid-sparing effect of either im-
patient from this group (5%) did not achieve remission munosuppressant would be superior. Therefore, the cu-
(Figure 2). This patient was noncompliant and discon- mulative corticosteroid dose was calculated for each pem-
tinued therapy prematurely. phigus patient after the beginning of treatment and
Complete remission was achieved after a mean dura- through the documentation period for at least 720 days.
tion of 74±127 days of treatment in the AZA group. In The data in Table 2 show that pemphigus patients who
the MMF group, complete remission was noted after a were randomized to the AZA group received a median±SD
mean of 91±113 days (P⬎.05). The mean disease-free methylprednisolone dose of 8916 ± 29 844 mg. In the
interval from the time when complete remission was MMF group, the median±SD methylprednisolone dose
achieved until recurrence of lesions was 258 ± 183 days was 9334±13 280 mg. In general, these numbers are simi-
for the AZA group and 123±103 days for the MMF group lar and possibly reflect the comparable immunosuppres-
(P⬎.05). The Kaplan-Meier graph in Figure 3 shows sive potential of both drugs.
the rate without relapse in pemphigus patients over time, The results in Table 3 further demonstrate that 19
indicating that both adjuvants in the 2 treatment arms (54%) of 35 pemphigus patients received a cumulative
controlled disease equally well. methylprednisolone dose of 10 000 mg or less during the
The data in Figure 4, depicting the duration until course of treatment. Nine (26%) of 35 patients received
relapse of disease, was documented from the time of ran- 10 001 to 20 000 mg of corticosteroids. The distribution
domization. The 2 curves show a similar course and are, of the pemphigus patients to the different corticosteroid
therefore, not significantly different. In addition, the du- dose groups (Table 3) was similar for the AZA and MMF
ration until relapse was differentiated in relation to the adjuvant treatment groups. In summary, similar cumu-