The role of adjuvant therapy in pemphigus:

A systematic review and meta-analysis

Lihi Atzmony, MD,a Emmilia Hodak, MD,a,b Yael A. Leshem, MD,c Omer Rosenbaum, MD,a
Michael Gdalevich, MD, MPH,d Grant J. Anhalt, MD,e and Daniel Mimouni, MDa,b
Petach Tikva, Tel Aviv, and Beer Sheva, Israel; Portland, Oregon; and Baltimore, Maryland
Background: The assumption that adjuvant modalities have added value to oral glucocorticoids in the
treatment of pemphigus is intuitively sound but has not been conclusively proven.
Objective: We sought to compare the efficacy and safety of oral glucocorticoid treatment with or without
adjuvants for pemphigus vulgaris and pemphigus foliaceus.
Methods: We performed a systematic review and meta-analysis of randomized controlled trials. The
primary outcome was remission. Secondary outcomes were disease control, time to disease control,
relapse, time to relapse, cumulative glucocorticoid dose, withdrawal because of adverse events, and allcause death. Trials were pooled irrespective of adjuvant type evaluated.
Results: Ten trials (559 participants) were included. Adjuvants evaluated were azathioprine, mycophenolate mofetil, cyclophosphamide, cyclosporine, intravenous immunoglobulin, plasma exchange, and
infliximab; not all were included in every analysis. Although adjuvants were not beneficial for achieving
remission, they were found to collectively decrease the risk of relapse by 29% (relative risk 0.71, 95%
confidence interval 0.53-0.95).
Limitations: Different adjuvants were pooled together.
Conclusion: Adjuvants have a role in pemphigus treatment, at least in reducing the risk of relapse.
Further randomized controlled trials of other promising modalities are warranted. ( J Am Acad Dermatol
2015;73:264-71.)
Key words: adjuvant; glucocorticoids; meta-analysis; pemphigus; pemphigus vulgaris; systematic review;
therapy.

emphigus comprises a group of rare autoimmune mucocutaneous bullous disorders.

Glucocorticoids (GCs) have been the mainstay
of treatment of pemphigus since their introduction in
the 1950s,1 reducing mortality from 75% to less than
10%.2 However, because of the chronicity of the
disease, prolonged therapy is necessary, leading to
the development of a wide spectrum of GC-related side
effects, some severe. Indeed, most pemphigus-related
deaths today are a result of treatment complications.2

From the Department of Dermatology, Rabin Medical Center,

Beilinson Hospital, Petach Tikvaa; Sackler Faculty of Medicine,
Tel Aviv Universityb; Department of Dermatology, Oregon
Health and Science Universityc; Faculty of Health Sciences,
Ben-Gurion University of the Negev and South District Health
Office, Ministry of Health, Beer Shevad; and Department of
Dermatology, Johns Hopkins University, School of Medicine,
Baltimore.e
Funding sources: None.

264

Abbreviations used:
CI:
GC:
HR:
IVIG:
MMF:
PF:
PV:
RCT:
RR:

confidence interval
glucocorticoid
hazard ratio
intravenous immunoglobulin
mycophenolate mofetil
pemphigus foliaceus
pemphigus vulgaris
randomized controlled trial
relative risk

Conflicts of interest: None declared.

Accepted for publication April 17, 2015.
Reprint requests: Daniel Mimouni, MD, Department of Dermatology,
Rabin Medical Center, Beilinson Hospital, 39 Jabotinski St, Petach
Tikva, Israel 49100. E-mail: mimouni@post.tau.ac.il.
Published online June 15, 2015.
0190-9622/$36.00
2015 by the American Academy of Dermatology, Inc.
http://dx.doi.org/10.1016/j.jaad.2015.04.038

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Atzmony et al 265

VOLUME 73, NUMBER 2

Therefore, researchers have sought adjuvant

Primary outcome
agents/modalities to increase the efficacy of GCs
Proportion of patients achieving rewhile reducing their toxicity. However, the data
mission. Remission was defined as absence of
emerging from these efforts are confusing. Some
cutaneous and oral lesions or presence of 3 or fewer
cohort studies and case series reported better
transient lesions that healed within 1 week while the
efficacy of GCs with adjuvants compared with
patient was on minimal therapy or off therapy.
GCs alone,3-5 whereas randomized controlled triMinimal therapy was defined as a daily dose of 10
als (RCTs) did not necesmg or less of prednisolone
sarily corroborate these
(or equivalent), continued
CAPSULE SUMMARY
findings.6 Systematic readjuvant therapy, or both.
views focused on individual
Multiple adjuvant treatments have been
adjuvants and were thereSecondary outcomes
studied in pemphigus, but only a few
d Proportion of patients
fore limited by the paucity
appear to be effective, mainly in their
of evidence and small samachieving disease consteroid-sparing effect.
ple sizes.6,7
trol. Disease control was
We performed a systematic review and
To resolve some of these
defined as the cessation
meta-analysis of randomized controlled
issues, we conducted a sysof new lesion formation
trials and found that adjuvant treatments
tematic review and metaand onset of healing of
do not increase the remission rate but
analysis of the comparative
established lesions. The
may decrease the number of relapses.
effectiveness of oral GCs
complete absence of cutawith all possible adjuvants
neous and oral lesions
Combination of specific adjuvant
versus oral GCs alone or
while on doses of GCs
modalities and oral glucocorticoids for
with placebo in the treatment
higher than those defining
the treatment of pemphigus should be
of patients with pemphigus
remission ([10 mg daily
considered.
vulgaris (PV) and pemphigus
prednisone or equivalent)
foliaceus (PF).
was considered disease
control as well.
d Time to disease control.
METHODS
d Proportion of patients with relapse. Relapse
The systematic review and meta-analysis were
was defined as the appearance of new lesions or
conducted and reported in accordance with the
the extension of established lesions after either
8
PRISMA statement. The review protocol was regisremission or disease control. In cases where a
tered on PROSPERO and can be accessed at: www.
participant had several relapses, only the first was
crd.york.ac.uk/PROSPERO/display_record.asp?ID=
counted.
CRD42014014160.
d Time to relapse.
Only studies that met the following criteria were
d Mean total cumulative GC dose. The mean total
included in the analysis:
cumulative GC dose was used as a surrogate for
d RCTs of combined GC plus adjuvant treatment for
adverse events caused by prolonged GC therapy.
PV, PF, or both compared with oral GCs alone or
d Rate
of withdrawal because of adverse
with a placebo.
events.
d Inclusion of patients of any age with PV or PF
d Proportion of all-cause deaths. We conducted
diagnosed according to clinical features, histopaa comprehensive search to identify all relevant
thology, and immunofluorescence studies.
studies regardless of language, publication status,
d Report of at least 1 of the predefined outcomes.
or year of publication. Two reviewers (L. A. and O.
For purposes of this review, the agents/modalities
R.) independently searched the Cochrane Central
considered adjuvant treatment for pemphigus were
Register of Controlled Trials (inception to May
immunomodulators, immunosuppressants, or both.
2014) using the term pemphigus, and PubMed
The primary and secondary outcomes were
(1889 to September 2014) and the Latin American
selected according to the Consensus Statement
and Caribbean Health Science Information datafor Definitions of Disease, End Points, and
base (LILACS) (1983 to September 2014) using the
Therapeutic Response for Pemphigus by the
term pemphigus combined with the Cochrane
International Pemphigus Committee9 published in
Highly Sensitive Search Strategy for RCTs.10 The
2008. However, permissive definitions of these outsearch strategy for PubMed is shown in Appendix
comes were used to allow for the inclusion of trials
1. In addition, the ongoing trials registry of the US
conducted before this publication.
National Institutes of Health (www.clinicaltrials.
d

J AM ACAD DERMATOL

266 Atzmony et al

gov) was screened for additional trials that published results using the term pemphigus. Reference lists of the included trials were screened for
additional eligible publications.
Two reviewers (L. A. and O. R.) independently
screened the titles and abstracts of all the retrieved
articles, followed by the full texts of the articles
considered potentially eligible for the study. They
independently extracted the data into predefined
forms that were then consolidated. Disagreements
were resolved by discussion with a third reviewer
(D. M). Authors were contacted for missing data and
clarifications.
Every study was evaluated for risk of bias arising
from each of the following domains: allocation
sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome
reporting, and extreme imbalance at baseline characteristics. Grades (high, low, or unknown risk) were
assigned according to the criteria suggested in the
Cochrane Handbook for Systematic Reviews of
Interventions, v.5.1.0.10 Publication bias was not
formally assessed owing to the small number of studies.
For dichotomous data, we calculated the relative
risk (RR), and for continuous data, we calculated the
absolute mean difference with 95% confidence
intervals (CIs). For time-to-event outcomes, we
calculated the log hazard ratio (HR) with SE. We
applied intention-to-treat analysis when data were
adequate, and available case analysis when they
were not. Quantitative analyses were conducted using
Review Manager (RevMan) [computer program].
Version 5.3. (The Nordic Cochrane Centre, The
Cochrane
Collaboration,
2014,
Copenhagen,
The Netherlands). Interventions were pooled for
meta-analysis irrespective of type of adjuvant
modality, dose, or route of administration. Analyses
were performed using the random effects model.
Heterogeneity of the trial results was assessed by
visually examining the forest plot to detect nonoverlapping CIs, using the x 2 test of heterogeneity (with
P \ .1 indicating statistical significance) and the I2
statistic of inconsistency (with 30%-60% denoting
moderate levels of heterogeneity). We expected that
heterogeneity might stem from the different therapeutic effects of the included adjuvants and from our use
of permissive definitions of the outcome measures.
Although we had planned to perform a predefined
subgroup analysis for each included adjuvant, this
proved unfeasible because some of the trials
compared more than 1 treatment arm with oral GCs.
Instead, when any heterogeneity was observed, we
sought the source by performing additional analyses
of each adjuvant separately relative to oral GCs alone.

AUGUST 2015

To determine the effect of our using a permissive

definition of disease control and remission, we
performed a sensitivity analysis, excluding trials that
did not adhere to the consensus statement definitions
of those outcomes. When the conditional outcome
relapse (which is dependent on a previous disease
response) was reported, a modified intention-to-treat
analysis was applied, using a composite outcome of
relapse after response (remission or disease control)
or inability to achieve response.

RESULTS
The literature search yielded 261 titles and abstracts (Fig 1). Eleven trials fulfilled the eligibility
criteria, including 10 original publications11-20 and 1
follow-up report of an already included trial combined with the initial trial data.11,21 Characteristics of
included trials are detailed in Table I. They included
a total of 559 patients, 516 with PV and 43 with PF. All
study patients were adults; 54% to 72% were female.
Six trials included patients with newly diagnosed
disease,11-13,15,17,19 1 trial included patients with
newly diagnosed or recurrent disease,15 and 3 trials
did not specify disease duration.16,18,20 Reported
baseline disease severity ranged from mild to severe,
but it was assessed by different instruments.
The regimens for the initial oral GC dose and dose
escalation and tapering differed among the studies.
The adjuvant agents that were investigated in combination with oral GCs against oral GCs alone or
combined with placebo were azathioprine in 2 trials,
mycophenolate mofetil (MMF) in 3, cyclophosphamide in 3, cyclosporine in 2, and intravenous immunoglobulin (IVIG), plasma exchange, and infliximab
in 1 trial each.
The risk of bias assessment is depicted in Table I.
The baseline characteristics of the study arms were
relatively balanced in 8 trials11-14,17-20 and were not
specified in 2.15,16 Only 4 trials were blinded
(participants, personnel, and outcome assessment),
and the rest were open-label. The risk of bias varied
among the studies.
Outcomes
Remission. Remission was reported in 6
trials11-15,17 including 378 patients treated with oral
GCs and MMF (n = 112), azathioprine (n = 58),
cyclophosphamide (n = 40), or cyclosporine (n =
24) or oral GCs alone (n = 144). The addition of
adjuvants was not associated with an increase in the
proportion of patients achieving remission (Fig 2).
Excluding trials that did not report remission according to the consensus statement definition did
not alter these findings (RR 1.05, 95% CI 0.87-1.26).

J AM ACAD DERMATOL
VOLUME 73, NUMBER 2

Fig 1. Study flow chart. CENTRAL, Cochrane Central

Register of Controlled Trials; IVIG, intravenous immunoglobulin; LILACS, Latin American and Caribbean Health
Science Information database MMF, mycophenolate mofetil; ref, references.

Disease control. Disease control was reported

in 8 trials12,13,15-20 including 190 patients treated
with azathioprine (n = 28), MMF (n = 24), cyclophosphamide (n = 44), IVIG (n = 41), cyclosporine (n =
24), plasma exchange (n = 19), or infliximab (n = 10)
compared with 149 patients treated with oral GCs
alone. The addition of adjuvants was not associated
with an increase in the proportion of patients
achieving disease control (Fig 3).

Atzmony et al 267

Owing to evidence of heterogeneity, we analyzed

each adjuvant agent/modality separately. IVIG was
the only adjuvant that independently increased disease control compared with oral GCs alone (83% vs
45%, RR 1.84, 95% CI 1.11-3.05). This effect was
exaggerated for high-dose IVIG (90.5% vs 45%, RR
2.01, 95% CI 1.21-3.33). Indeed, exclusion of IVIG
from the analysis yielded a RR of 1.04 (95% CI 0.961.13) with no heterogeneity. Excluding trials that did
not use the definition of disease control of the
consensus statement (which included the IVIG trials)
yielded a RR of 1.03 (95% CI 0.94-1.13) with no
heterogeneity.12,13,15,16
Time to disease control was calculable for 2 trials12,16
including 54 patients treated with azathioprine (n = 28)
or cyclophosphamide (n = 26) compared with 62
patients treated with oral GCs alone. There was no
difference in time to disease control when adjuvants
were added (HR 1, 95% CI 0.67-1.51). For azathioprine,
HR was 0.9 (95% CI 0.5-1.62), and for cyclophosphamide, HR was 1.11 (95% CI 0.63-1.95).
Relapse. Relapse was reported in 7 trials12-17,21
including 338 patients treated with MMF (n = 92),
cyclophosphamide (n = 57), azathioprine (n = 39), or
cyclosporine (n = 24) compared with 126 patients
treated with oral GCs alone. The addition of adjuvants
resulted in a significantly lower proportion of patients
with relapse (Fig 4). Analysis of each adjuvant
separately yielded no single one that was significantly
associated with fewer relapses (azathioprine: RR 0.65,
95% CI 0.36-1.14; MMF: RR 0.73, 95% CI 0.46-1.15;
cyclophosphamide: RR 0.77, 95% CI 0.5-1.17;
cyclosporine: RR 0.94, 95% CI 0.24-3.73). On sensitivity
analysis excluding trials that defined relapse after
remission,14 the pooled RR was 0.81 (95% CI 0.66-1).
Modified intention-to-treat analysis using the
composite outcome relapse after response or inability
to achieve response also demonstrated a lower
proportion of patients with these findings (RR 0.79,
95% CI 0.66-0.95, I2 = 0%). When this composite
outcome was analyzed for each adjuvant separately,
no individual benefit was found (data not shown).
Time to relapse was reported in 2 trials14,15
including 66 patients treated with MMF (n = 48),
cyclophosphamide (n = 10), or cyclosporine (n = 8)
compared with 38 patients treated with oral GCs
alone. No benefit in time to relapse was found when
adjuvants were added (HR 0.49, 95% CI 0.24-1).
Analysis of each adjuvant separately yielded a significant independent benefit of MMF (HR 0.44, 95%
CI 0.2-0.97).
Adverse events. Mean cumulative GC dose was
reported in 5 trials11,12,14,19,20 including 187 patients
treated with MMF (n = 88), azathioprine (n = 55),
cyclophosphamide (n = 24), plasma exchange

Study*

Amagai
et al,18 2009,
Japan

Beissert
et al,14 2010,
International

Interventiony

IVIG 400 mg/kg/d divided

over 5 d vs IVIG 200 mg/
kg/d divided over 5 d vs
placebo (1PRED $20 mg/d
in all groups)
MMF 2 g/d vs MMF 3 g/d vs
placebo (1PRED 1-2 mg/
kg/d in all groups)

No. of patients

Age, y, mean 6 SD
or range
Female, % PV,PF FU, mo

Disease severity

21 vs 20 vs 20 50.1 6 11.7 vs
57 6 14.6 vs
53.1 6 10.9

55.7

40,21

22 vs 37 vs 37 40 vs 46 vs
46 (median)

59.6

94,0

12

64

120,0

24

Mild-severe

28 vs 28

38.9 6 11.0 vs
40.6 6 14.9

58.9

56,0

12

Mild-moderate

Oral cyclophosphamide 100 mg/d 10 vs 8 vs 10

vs cyclosporine 5 mg/kg/d
(1PRED 40 mg/d in both
groups) vs PRED 40 mg/d
Guillaume et al,19 PRED 0.5 mg/kg/d 1 plasma
22 vs 18
1988, France
exchange (10 sessions over
4 wk) vs PRED 0.5 mg/kg/d
10 vs 10
Hall et al,20 2014, IV infliximab (5 mg /kg) vs
United States
placebo at wk 0, 2,
6, and 14 (1PRED $20 mg/d
in both groups)

52 (32-74)

53.6

28,0

60

Oral lesions only

53 6 14 vs
57 6 11

60

33,7

Ioannides et al,17 Cyclosporine 5 mg/kg/d 1

2000, Greece
PRED 1 mg/kg/d vs PRED
1 mg/kg/d

49 (30-69) vs
51 (28-72)

Chrysomallis
et al,15 1994,
Greece

16 vs 17

52 (21-63) vs
54.5 (30-71)
(median)

57.6

NS

20,0

29,4

60

Incomplete
outcome data

Selective
reporting

High risk
Low risk; blinding Low risk
of bias
of biasz
of participants,
personnel, and
outcome
assessment
Low risk
Low risk; blinding Low risk
of biasx
of bias//
of participants,
personnel, and
outcome
assessment
Low risk Unclear risk High risk; open
Unclear risk Low risk
of bias
of bias
labeled
of bias
of bias

Low risk; blinding Unclear risk Low risk

of bias
of bias
of participants,
personnel, and
outcome
assessment
Unclear Unclear risk High risk; open
Low risk
Low risk
risk of
of bias
labeled
of bias
of bias
bias
Low risk Low risk
of bias
of bias

Low risk Unclear risk High risk; open

of bias
of bias
labeled

Mild- severe

Low risk Unclear risk Low risk; blinding Unclear risk Low risk
of bias
of bias
of bias
of bias
of participants,
personnel, and
outcome
assessment
Low risk Low risk
High risk; open
Low risk
Low risk
of bias
of bias
labeled
of bias
of bias

Mean severity
score ; 5/8

Low risk
of biasx

Low risk
of bias

Moderate-severe

AUGUST 2015

J AM ACAD DERMATOL

37.6 6
36.6
45.5
41.5

37.6 vs
6 14.7 vs
6 8.9 vs
6 15

Blinding

Low risk Low risk

Nonresponse to
of bias
of bias
oral PRED
[20 mg/d;
mean pemphigus
activity score 3.5
Mild- moderate
Low risk Low risk
of bias
of bias

27 vs 30 vs
24 vs 30

Chams-Davatchi Azathioprine (2.5 mg/kg/d

et al,11,21 2007,
for 2 mo and then 50 mg/d
Iran
for the rest of study) vs MMF
2 g/d vs pulse IV
cyclophosphamide (1000 mg
once/mo for 6 mo, and then
every 2 mo for another 6 mo)
(1PRED 2 mg/kg/d in all
groups) vs PRED 2 mg/kg/d
Chams-Davatchi Azathioprine 2.5 mg/kg/d 1
et al,12 2013,
PRED 2 mg/kg/d vs PRED
Iran
2 mg/kg/d 1 placebo

Allocation Allocation
generation concealment

268 Atzmony et al

Table I. Characteristics of included trials

J AM ACAD DERMATOL

Atzmony et al 269

FU, Follow-up; IV, intravenous; IVIG, intravenous immunoglobulin; MMF, mycophenolate mofetil; PF, pemphigus foliaceus; NS, not stated; PRED, prednisolone/prednisone; PV, pemphigus vulgaris.
*All trials used a randomized parallel-group design; Guillaume et al19 included cross-over for nonresponders.
y
Oral glucocorticoid dose in the table is the initial dose.
z
Remission rate is not reported.
x
Low risk for dichotomous variables, unknown risk for cumulative glucocorticoid dose.
//
Relapse rate was reported in the middle of FU time, when there was a statistically significant difference, but calculation of relapse rate at the end of FU, when it was not statistically lower for MMF
group was feasible.

Mild-moderate
60,0
71.7

24

36,11

Ioannides et al,13 MMF 3 g/d 1 PRED 1 mg/kg/d

24 vs 23
2012, Greece
1 vs PRED 1 mg/kg/d
Sharma et al,16
Pulse cyclophosphamide (15 mg/ 34 vs 26
2013, India
kg/mo) 1 PRED 1 mg/kg/d vs
PRED 1 mg/kg/d for 1 y

53.7 6 12.5 vs
53.2 6 12.8
48 6 17

61.7

12

Mild-moderate

Low risk Unclear risk High risk; open

of bias
of bias
labeled
Low risk High risk
High risk;
of bias
of bias
open labeled

Low risk
Low risk
of bias
of bias
Unclear risk Unclear
of bias
risk of bias

VOLUME 73, NUMBER 2

(n = 15), or infliximab (n = 5) compared with 108

patients treated with oral GCs alone. The results
showed a nonsignificantly lower mean cumulative
GC dose when adjuvants were added (mean difference 837 mg prednisone equivalent, 95% CI 1936
to 262) with some heterogeneity (P = .33, I2 = 13%).
Pooling the data for each adjuvant separately demonstrated a steroid-sparing effect for azathioprine and
cyclophosphamide (azathioprine: mean difference
2480.63 mg, 95% CI 4860.03 to 101.23; cyclophosphamide: mean difference -3355 mg, 95% CI
6144.28 to 565.72). This effect was not observed
with the other adjuvants (data not shown).
Withdrawal because of adverse events rate was
reported in all trials but one18 including 297 patients
treated with adjuvants and 195 patients treated with
oral GCs alone. No benefit was observed when
adjuvants were added (RR 1.23, 95% CI 0.6-2.51,
P = .66, I2 = 0%).
All-cause deaths were reported in all trials.11-20
The incidence of death was comparable in the
adjuvant and oral GC-only groups (1.77% vs 0.93%;
RR 1.2, 95% CI 0.3-4.77, P = .47, I2 = 0%).

DISCUSSION
The aim of this review was to determine whether
the common practice of adding adjuvant therapy to
oral GCs is justified. Our results showed that adjuvant
therapy did not increase the number of patients who
achieved remission. However, it had significant
added value for other important outcomes. The
addition of adjuvant therapy was associated with a
decrease in relapses, such that 12 patients needed to
be treated with adjuvant therapy to prevent 1 relapse
with oral GCs alone. Specifically MMF, azathioprine,
and cyclophosphamide were shown to decrease
relapses. We also found that adding IVIG increased
the number of patients achieving disease control, but
this effect was not duplicated with other adjuvants. A
positive steroid-sparing effect was observed for
azathioprine and cyclophosphamide. However, no
difference was found between combined therapy
and oral GC monotherapy for withdrawal because of
adverse events and deaths.
Our analysis has several limitations. First, some
heterogeneity was observed. Our preemptive decision to pool data from studies with differing adjuvant
modalities, routes of administration, and doses
because of the lack of sufficient data for each
adjuvant separately created some heterogeneity in
the minority of the comparisons, which was resolved
by performing additional analyses of each adjuvant
separately relative to oral GCs alone. Accordingly,
our results support the concept of adjuvant therapy
for pemphigus but did not lead to an optimal

270 Atzmony et al

J AM ACAD DERMATOL

AUGUST 2015

Fig 2. Adjuvants versus oral glucocorticoids alone: remission rate. CI, Confidence interval;
df, degrees of freedom; GC, glucocorticoid; M-H, Mantel-Haenszel.11-15,17

Fig 3. Adjuvants versus oral glucocorticoids alone: disease control rate. CI, Confidence
interval; df, degrees of freedom; GC, glucocorticoid; M-H, Mantel-Haenszel.12,13,15-20

Fig 4. Adjuvants versus oral glucocorticoids alone: relapse rate. CI, Confidence interval;
df, degrees of freedom; GC, glucocorticoid; M-H, Mantel-Haenszel.12-17,21

treatment strategy. Patient population, disease

severity and outcome definitions were not the
same across studies. Moreover, the protocol for
escalation and tapering of oral GC dose varied
between studies, which could have impacted all of
the study outcomes. This clinical heterogeneity was
partially addressed by a sensitivity analysis for
outcome definitions. There was some methodological heterogeneity between studies, but as all trials

were subjected to a risk of bias, sensitivity analysis

was limited. Nonetheless, we included only RCTs,
enhancing uniformity in study design and improving
homogeneity. It should be noted that the negative
results of most of the trials argue against serious
publication biases. Second, by limiting the review to
RCTs, promising treatment modalities for which
RCTs have not yet been published were not
included,22 nor were long-term cohort studies.23,24

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Atzmony et al 271

VOLUME 73, NUMBER 2

Third, as direct data on adverse events were sparse,

we elected to use an indirect outcome measure,
namely cumulative GC dose, for GC-induced
adverse events. The use of an indirect outcome
measure and the exclusion of long-term cohort
studies powered to assess for adverse effects calls
for caution when interpreting this outcome.
In summary, according to the currently available
evidence, adjuvant therapy does not increase remission rate of pemphigus, but it has some benefit in
decreasing relapse rate. Further studies are needed to
confirm the clinical relevance of the steroid-sparing
effect demonstrated here for specific adjuvants. Welldesigned RCTs are needed to evaluate adjuvant
modalities that were not included in this review and
could potentially increase the remission rate. This
review provides proof of concept for the advantage of
combined oral GCs and adjuvant therapy over oral
GCs alone for the treatment of pemphigus.
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APPENDIX 1
Search strategy in PubMed
((((((((((randomized controlled trial [Publication
Type]) OR controlled clinical trial [Publication
Type]) OR randomized [Title/Abstract]) OR
placebo [Title/Abstract]) OR randomly [Title/
Abstract]) OR trial [Title]) OR clinical trials as topic
[MeSH Terms])) NOT ((animals [MeSH Terms])
NOT humans [MeSH Terms]))) AND pemphigus
[all fields].