Am J Clin Dermatol (2014) 15:503–515

DOI 10.1007/s40257-014-0101-9

EVIDENCE-BASED REVIEW

Treatment of Pemphigus Vulgaris and Pemphigus Foliaceus:

A Systematic Review and Meta-Analysis
Lihi Atzmony • Emmilia Hodak • Michael Gdalevich •

Omer Rosenbaum • Daniel Mimouni

Published online: 18 November 2014

Ó Springer International Publishing Switzerland 2014

Abstract
Background No optimal therapeutic approach has been Key Points
established for pemphigus.
Objective Our objective was to evaluate the efficacy, Systemic glucocorticoids are the mainstay of
steroid-sparing effect, and safety of available treatment treatment of pemphigus. Due to their side effects,
modalities. multiple adjuvant treatment modalities have been
Methods PubMed, LILACS (up to July 2014), the studied, but only a few appear to be effective
Cochrane Central Register of Controlled Trials (CEN- according to current evidence-based data.
TRAL, issue 5 of 12, May 2014), and the ClinicalTri-
None of the combined therapies was found to be
als.gov registry and reference lists were searched for
more effective than glucocorticoids alone in terms of
randomized controlled trials of any treatment modality for
complete response rate. However, it is important to
pemphigus vulgaris and pemphigus foliaceus. Data were
emphasize that some adjuvant treatments have
extracted independently by two authors using predefined
shown a beneficial effect in terms of steroid-sparing
appraisal criteria and data fields.
effect (azathioprine and cyclophosphamide),
Results A total of 20 studies (826 participants) were
shortening time to achieve a sustained response and
included. Most were small and open-labeled; all but seven
delaying the time to relapse (mycophenolate
were not concealed for allocation. Owing to the variability
mofetil), initiating and maintaining disease control
(intravenous immunoglobulin), and hastening
Electronic supplementary material The online version of this
healing of lesions (topical epidermal growth factor).
article (doi:10.1007/s40257-014-0101-9) contains supplementary
material, which is available to authorized users.
Further well-designed randomized controlled studies
and case–control studies with similar outcome
L. Atzmony
E. Hodak
O. Rosenbaum
D. Mimouni (&) measures will allow us to combine more studies into
Department of Dermatology, Rabin Medical Center, Beilinson larger meta-analyses and to reach more definitive
Hospital, 39 Jabotinski St., 49100 Petach Tikva, Israel
conclusions regarding the treatment of this rare disease.
e-mail: mimouni@post.tau.ac.il

E. Hodak
D. Mimouni
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv,
Israel
in intervention arms, five meta-analyses were performed,
M. Gdalevich each pooling the data of two to three trials. Studies
Faculty of Health Sciences, Ben-Gurion University of the Negev, excluded from the meta-analyses were described quantita-
Beer Sheva, Israel tively. Azathioprine had a steroid-sparing effect but did not
increase remission rate. Mycophenolate mofetil induced
M. Gdalevich
South District Health Office, Ministry of Health, Beer Sheva, sustained remission more quickly than did placebo and
Israel delayed time to relapse but did not have a steroid-sparing
504
effect or favorable remission rate. Cyclophosphamide had a
steroid-sparing effect, though less than azathioprine, but
did not affect the remission rate or time-to-disease control.
Intravenous immunoglobulin had more favorable short-
term efficacy than did placebo. Topical epidermal growth
factor hastened lesion healing.
Conclusions Although some of the available therapeutic
modalities for pemphigus are beneficial in terms of steroid-
sparing, hastening response, or delaying relapse, none were
found to increase the complete response rate compared with
glucocorticoids alone, currently the mainstay of treatment.
Multicenter randomized controlled trials and case control
studies with uniform outcome measures are warranted.
1 Introduction
Pemphigus is an autoimmune bullous disease clinically
characterized by blistering and erosions of the skin and/or
mucous membranes. The most common forms are pem-
phigus vulgaris (PV) and pemphigus foliaceus (PF),
accounting for 70 and 20 % of cases, respectively. Annual
incidence rates range from 0.76 to 32 cases per million [1].
The goal of therapy in pemphigus is to induce and maintain
remission. This is achieved with immunosuppressive agents,
usually administered for a long duration. The best-estab-
lished modality is systemic glucocorticoids. Since their
introduction, the mortality rate of pemphigus has dropped
from about 75 % to less than 10 % [2]. Unfortunately, as the
therapy is prolonged, numerous steroid-induced side effects
can occur, many of which are serious. Therefore, researchers
continue to seek new modalities that could reduce the need
for systemic glucocorticoids and even increase their efficacy.
Over recent decades, several agents have been tested, with
varying efficacy and steroid-sparing effects, but the superi-
ority of any one over the others remains unclear [3].
A previous systematic review of pemphigus treatment
included 11 trials that were published until 2008 [4]. No
conclusions were reached regarding the most effective and
safest treatment, perhaps owing to the rarity of the disease
and its grave nature, which limited the number of high-
quality randomized controlled trials (RCTs) performed,
and the lack of consensus outcome measures [4]. Never-
theless, the authors were able to determine that azathio-
prine and cyclophosphamide have a steroid-sparing effect
and that topical epidermal growth factor (EGF) decreases
the healing time of cutaneous lesions [4].
Since then, additional evidenced-based trials have been
published that should allow for better assessment of the role
of each therapeutic regimen in pemphigus. Therefore, we
conducted a systematic review and meta-analysis of all RCTs
published until June 2014 in which the efficacy and/or safety
of a therapeutic modality for pemphigus was evaluated.
L. Atzmony et al.
2 Methods
We performed a comprehensive literature search accord-
ing to the recommendations of the Preferred Reporting
Items for Systematic Reviews and Meta-Analyses
(PRISMA) statement [5] for English-language publica-
tions. The following data sources were used: Cochrane
Central Register of Controlled Trials (CENTRAL, issue 5
of 12, May 2014) using the term ‘pemphigus’; PubMed
and LILACS (up to July 2014), using the terms ‘pem-
phigus’ OR ‘auto-immune bullous disease’ combined
with the Cochrane Highly Sensitive Search Strategy for
RCTs [6] and the ongoing trials registry of the US
National Institutes of Health (http://www.clinicaltrials.
gov). We also reviewed the reference lists of the retrieved
articles. Included in the review were all RCTs that tested
any intervention for PV and PF compared with another
intervention or placebo for a minimum follow-up time of
1 month. Participants were patients who were diagnosed
with PV or PF according to clinical features, histopa-
thology, and immunofluorescence.
Our predefined primary outcome measures were pro-
portion of patients achieving complete response (CR),
mean total cumulative glucocorticoid dose, and death. Our
predefined secondary outcomes were proportion of patients
achieving disease control, time to achievement of disease
control, time to achieve remission, proportion of patients
who had a relapse, and rate of withdrawal due to adverse
events.
CR was defined as an absence of cutaneous and oral
lesions or the presence of three or fewer transient lesions
that healed within 1 week while the patient was receiving
minimal therapy or was off therapy for at least 2 months,
according to the consensus statement [7], or at the end of
12 months’ follow-up. Minimal therapy was defined as a
daily dose of 10 mg or less of prednisolone (or equiva-
lent) and/or minimal adjuvant therapy [7]. Disease control
was defined as the cessation of new lesion formation and
onset of healing of established lesions, in accordance with
the consensus statement. In addition, we also considered
the absence of cutaneous and oral lesions with more than
10 mg prednisolone (or equivalent) or of unknown dura-
tion as disease control. The cumulative glucocorticoid
dose was used to compare the steroid-sparing effect
between treatment modalities. We assumed that a reduced
cumulative dose may be interpreted as a lower rate of
glucocorticoid-induced adverse events. Relapse was
defined as the appearance of new lesions or the extension
of established lesions following achievement of disease
control. When none of our predefined efficacy outcomes
were reported in a specific trial, we described the alter-
native outcomes that were used to evaluate disease
control.
Treatment of Pemphigus Vulgaris and Pemphigus Foliaceus
Studies that met the predefined selection criteria were
screened independently by two of the authors (LA and OR)
using predesigned data extraction forms. In case of dis-
agreement, a third author (DM) was consulted. Authors
were contacted for missing data and clarifications.
We calculated relative risks (RRs) for dichotomous
data and absolute mean differences with 95 % confidence
intervals (CIs) for continuous data. For time-to-event
outcomes, we calculated the hazard ratio (HR) when
possible or presented the published data if an appropriate
statistical method had been used. We applied intention-to-
treat (ITT) analysis when data were adequate and avail-
able case analysis when they were not. Quantitative
analyses were conducted using Review Manager 5.3. We
pooled interventions for meta-analysis if the same thera-
peutic agent was used, irrespective of dose and route of
administration.
Each study was evaluated for risk of bias by determining
the adequacy of randomization, concealment of allocation,
blinding, and extent of loss to follow-up against the criteria
suggested in the Cochrane Handbook for Systematic
Reviews of Interventions, v. 5.1.0 [6]. ITT analysis was
considered ‘adequate’ if the data permitted ITT analysis,
‘unclear’ if the numbers of randomized and evaluated
patients were not reported separately, and ‘inadequate’ if
only case analysis was performed.
Heterogeneity of the trial results was assessed by visu-
ally examining the forest plot to detect non-overlapping
CIs, using the chi-squared test of heterogeneity (with
p \ 0.1 indicating statistical significance) and the I2 sta-
tistic of inconsistency (with [50 % denoting moderate
levels of heterogeneity). All analyses are shown using the
fixed-effect model.
3 Results
3.1 Trials Included in the Review
From a total of 259 records identified, 39 full-text articles
were assessed for eligibility (Fig. 1). A total of 20 met the
inclusion criteria for this review, including 826 partici-
pants: 760 with PV and 66 with PF. The follow-up period
ranged from 1 to 60 months. The characteristics and main
efficacy results of the 20 trials are displayed in Table 1 [8–
27]. The majority of studies included patients with newly
diagnosed disease [8, 10–12, 14, 16, 18, 21] or a combi-
nation of newly diagnosed disease and recurrent disease [9,
13, 19, 20, 22, 25, 27]. Two studies included patients in the
maintenance phase [23, 24], one study included patients
who had relatively resistant disease (had symptoms under
treatment with prednisolone at C20 mg/day) [17]. Duration
of disease was not mentioned in two studies [15, 26].
505
Baseline disease severity, which was assessed by different
severity assessment tools, ranged from mild to severe; four
trials did not report it [14, 21, 22, 27] (Table 1).
The included studies varied markedly in design, inter-
ventions, and reported outcome measures (Electronic
Supplementary Material [ESM] 1). Therefore, we con-
ducted five meta-analyses, each pooling the results of two
to three trials. Studies that were not included in the meta-
analyses are described separately.
Overall, most of the trials had small samples. Adequate
randomization was reported in all 20 trials, and adequate
allocation concealment in seven. Six trials were double-
blinded, two single-blinded, and 12 open-labeled. Partici-
pant loss rates ranged between 0 and 39 %. ITT analysis
was feasible in 17 trials for dichotomous variables and in
six trials for continuous variables. Only seven trials used an
appropriate statistical technique for time-to-event data
(ESM 2).
3.2 Comparisons
3.2.1 High- vs. Low-Dose Glucocorticoid
Two trials compared different doses of glucocorticoids [8,
9].
The first compared 45–60 mg/day with 120–150 mg/day
oral prednisolone [8] and included 22 participants, 19 with
PV and three with PF, all with severe disease involving
more than 50 % body surface area. Disease control was
achieved in all cases. There was no between-group dif-
ference in relapse rate (RR 0.7, 95 % CI 0.43–1.14). There
were no cases of withdrawal due to adverse events and no
deaths.
The second trial tested the value of adjuvant dexa-
methasone pulse therapy against placebo in 20 participants
receiving conventional therapy with oral prednisolone and
azathioprine for PV [9]. None had refractory disease. There
was no significant difference between the groups in dis-
ease-control rate (RR 0.75, 95 % CI 0.5–1.1) or mean time
to achieve disease control (173.2 vs. 175.6 days; standard
deviations were not mentioned in the published paper).
There was also no difference in relapse rate (RR 1.91,
95 % CI 0.68–5.33) or rate of withdrawal due to adverse
events (RR 2.45, 95 % CI 0.31–19.74).
3.2.2 Oral Glucocorticoid Combined with an Adjuvant
Agent vs. Oral Glucocorticoid Alone
Nine trials [10–18] compared the efficacy of oral gluco-
corticoid alone or combined with an adjuvant agent.
Two trials compared prednisolone with or without
adjuvant azathioprine [10, 11]. They included a total of 116
participants, all with PV. There was no between-group
506 L. Atzmony et al.

Fig. 1 Study flow chart

Literature search:
Databases: PubMed, LILACS and the CENTRAL
ClinicalTrials.gov registry
Reference lists

Records screened on basis of tle and abstract Records Excluded (n=220):

(n=259) Duplicates (n=61)
Non-randomized controlled trials or
ineligible study populaon (n=159)

Full-text arcles excluded (n=19):

Full-text arcles assessed
for eligibility (n=39)
Studies included (n=20)
Non-randomized controlled trials (n=7)
Outcome of interest not reported (n=2)
Heterogeneous study populaon, pemphigus paents
cannot be isolated (n=3)
Full text not in English (n=3)
Small sample size (n=2)
Methods for diagnosis of eligible populaon not
defined (n=2)

Studies included in Studies included in

qualitave synthesis (n=12) quantave synthesis (n=8)

difference in CR rate (RR 1.11; 95 % CI 0.86–1.43) or rate
of withdrawal due to adverse events (RR 1.13, 95 % CI
0.48–2.62). The cumulative glucocorticoid dose was sig-
nificantly lower with azathioprine (mean difference
-2,275.29 mg, 95 % CI -3,886.55 to -664.02) with
moderate heterogeneity, which could have been attribut-
able to the different manner in which the cumulative
prednisolone dose was calculated for missing data (Fig. 2,
p = 0.16, I2 = 50 %). Azathioprine had no effect on time
to disease control (HR 0.90, 95 % CI 0.50–1.62) or relapse
rate (RR 0.67, 95 % CI 0.27–1.62), reported in one trial
[11]. There were no deaths in either trial [10, 11].
Three trials compared oral glucocorticoid with or
without mycophenolate mofetil (MMF) [10, 12, 13]. They
included a total of 201 participants, 190 with PV and 11
with PF. There was no between-group difference in CR rate
(Fig. 3, RR 1.02, 95 % CI 0.86–1.22). The cumulative
glucocorticoid dose, reported in two trials including 154
patients, did not differ between the groups (mean differ-
ence -731.57 mg, 95 % CI -2,049.92 to 586.78). Time to
CR on therapy, reported in one trial, was hastened by
adding MMF, but the difference from glucocorticoids alone
was not significant (p = 0.051). However, patients in the
MMF group achieved a sustained CR (i.e., CR on pred-
nisolone B10 mg/day that was maintained throughout the
study period) in significantly less time than the glucocor-
ticoid-only group (HR 1.85, 95 % CI 1.02–3.34) [13]. One
trial reported a nonsignificant between-group difference in
relapse rate (RR 1.44, 95 % CI 0.26–7.83) [12], but another
found a significantly longer time to relapse in the MMF
group after 24 weeks of therapy (HR 0.44, 95 % CI
0.2–0.97) [13]. One death occurred among the total 16
participants, in a patient treated with MMF. The cause was
documented as heart failure and was therefore not con-
sidered therapy related [12]. No difference was observed in
the rate of withdrawals due to adverse events between the
treatment groups in any of the studies (RR 1.48, 95 % CI
0.27–8.13).
Three trials compared glucocorticoids with or without
cyclophosphamide [10, 14, 15]. They included a total of
140 participants, all with PV. No significant between-group
difference was noted in CR rate (RR 1.23, 95 % CI
0.99–1.53). Significant heterogeneity was observed, but
after we excluded one trial in which the response rate was
affected by a high attrition rate [15], the comparison yiel-
ded the same results without heterogeneity (RR 0.99, 95 %
CI 0.85–1.15). Disease control was reported in all three
trials, with no significant between-group difference (RR
1.05, 95 % CI 0.92–1.21). One study evaluated the
reduction in the cumulative glucocorticoid dose and found
a significant difference when cyclophosphamide was added
(mean difference -3,355.00 mg, 95 % CI -6,140.51 to
-569.49) [10], and one study reported the time to achieve
disease control, which was not significantly different
Table 1 Characteristics and main efficacy results of included trials
References Intervention Trial Pts F (%) PV, PF FU Disease severity Efficacy Results Conclusion
location (m) definition
Interventions RR (95 % CI)
comparison

Amagai et al. IVIG 400 mg/kg/day divided over Japan 61 55.7 40, 21 3 Pts who did not respond Number 19/21 for 1.84 IVIG superior
[17] 5 days vs. IVIG 200 mg/kg/day to oral prednisolone of pts 400 mg/kg (1.11–3.05) to PL
divided over 5 days vs. PL [20 mg/day. Mean who IVIG, 15/20
(?PRED C20 mg/day in all pemphigus activity stayed for 200 mg/
groups) score 3.5 on kg IVIG, 9/20
protocol for PL
Beissert et al. AZA 2 mg/kg/day vs. MMF 2 g/day Germany 40 60 33, 7 24 BSA involvement range Disease 13/19 for AZA, 0.72 MMF superior
[19] (?PRED 2 mg/kg/day in both 0 to [20 % control 20/21 for (0.52–0.99) to AZA
groups) MMF
Beissert et al. MMF 2 g/day vs. MMF 3 g/day vs. Int 94 59.6 94, 0 12 Mild-moderate CR 40/58 for 1.08 Not superior to
[13] PL (?PRED 1–2 mg/kg/day in all MMF, 23/36 (0.8–1.46) PLb
groups) for PL
Chams- AZA (2.5 mg/kg/day for 2 months, Iran 120 64 120, 0 12 Mild-severe CR 23/30 for NSb AZA, MMF,
Treatment of Pemphigus Vulgaris and Pemphigus Foliaceus

Davatchi then 50 mg/day for the rest of PRED, 24/30 CYP not
et al. [10] study) vs. MMF 2 g/day vs. pulse for AZA, superior to
IV. CYP (1,000 mg IV once a 21/30 for PRED alone
month for 6 months, and then every MMF, 22/30
2 months for another 6 months) for CYP
(?PRED 2 mg/kg/day in all
groups) vs. PRED 2 mg/kg/day
Chams- AZA 2.5 mg/kg/day ? PRED 2 mg/ Iran 56 58.9 56, 0 12 Mild-moderate CR 16/28 for AZA, 1.23 Not superior to
Davatchi kg/day vs. PRED 2 mg/kg/ 13/28 for (0.74–2.05) PRED alone
et al. [11] day ? PL 2.5 mg/kg/day PRED
Chrysomallis Oral CYP 100 mg/day vs. Greece 28 53.6 28, 0 60 Oral lesions only CR 10/10 for CYP, 1 (0.82–1.23) Comparable
et al. [14] cyclosporine 5 mg/kg/day (?PRED 8/8 for effect to
40 mg/day in both groups) vs. cyclosporine, CYP,
PRED 40 mg/day 10/10 for cyclosporine,
PRED and PRED
alone
Dastgheib TAC 0.05 mg/kg/day vs. AZA Iran 46 58.5 46, 0 6 Mild-moderate CR 20/23 for TAC, 0.95 TAC
et al. [20] 2.5 mg/kg/day (?PRED 1 mg/kg/ 21/23 for (0.78–1.17) comparable
day in both groups) AZA effect to AZA
Guillaume PRED 0.5 mg/kg/day with gradual France 40 60 33, 7 NS Moderate-severe DC 15/19 for 1.08 Comparable
et al. [18] tapering ? plasma exchange (10 plasma (0.73–1.38) effect to PL
sessions over 4 weeks) vs. PRED exchange,
0.5 mg/kg/day with gradual 11/15 for PL
tapering
Ioannides Cyclosporine 5 mg/kg/day ? PRED Greece 33 57.6 29, 4 60 Mean severity score DC 15/16 for 1.06 Not superior to
[16] 1 mg/kg/day vs. PRED 1 mg/kg/ *5/8 cyclosporine, (0.86–1.32) PRED alone
day 15/17 for
PRED
507
Table 1 continued
508

References Intervention Trial Pts F (%) PV, PF FU Disease severity Efficacy Results Conclusion
location (m) definition
Interventions RR (95 % CI)
comparison

Ioannides MMF 3 g/day ? PRED 1 mg/kg/ Greece 47 61.7 36, 11 12 Mild-moderate CR 20/24 for 1.06 Not superior to
et al. [12] day ? vs. PRED 1 mg/kg/day MMF, 18/23 (0.8–1.41) PRED alone
for PRED
Iraji et al. Acyclovir 1,200 mg/day ? PRED Iran 30 43.3 30, 0 1 Moderate DC 6/15 for 0.86 Not superior to
[26] 1 mg/kg/day ? AZA 2.5 mg/kg/ acyclovir, (0.38–1.95) conventional
day vs. PRED 1 mg/kg/ 7/15 for therapy
day ? AZA 2.5 mg/kg/day for control
2 weeks
Kanwar et al. RIT 1,000 mga 2 (2 doses at 15 days India 22 50 15, 7 12 Mild-severe CR 10/11 for high 0.91 Both doses
[25] interval) ? oral GCs vs. RIT dose, 11/11 (0.72–1.17) yield same
500 mg a2 (2 doses at 15 days for low dose response
interval) ? oral GCs ± AZA
Mentink et al. Pulse oral DEXA 300 mg/daya Int 20 35 20, 0 12 Mean no. of skin DC 8/11 for 0.75 (0.5–1.1) No benefit of
[9] 3 days per month ? AZA 3 mg/kg/ lesions 28 for DEXA DEXA, 9/9 oral DEXA
day vs. AZA 3 mg/kg/day ? PL group and 26 for PL. for PL pulse therapy
3 days per month (?PRED 80 mg/ No pt with refractory
day in both groups) disease
Parmar et al. Pulse IV DEXA (100 mg/day for 3 India 19 47.4 19, 0 9 Maintenance phase Relapse 1/9 for oral 1.11 Consolidation
[23] consecutive days) ? IV CYP CYP, 1/10 for (0.08–15.28) phase with
(500 mg once on day 2) every DCP DCP does not
4 weeks ? oral CYP 50 mg/day for decrease
9 months vs. oral CYP 50 mg/day relapse rate
for 9 months
Ratnam et al. PRED 120–150 mg/day vs. Singapore 22 72.7 19, 3 60 Severe DC 11/11 for low 1 (0.85–1.18) High dose
[8] 45–60 mg/day dose, 11/11 comparable to
for high dose low dose
Rose et al. Pulse IV DEXA (100 mg/day for Germany 22 72.7 16, 6 24 NS DC 5/11 for DCP, 0.56 DCP not
[21] 3 days) ? CYP (500 mg once) 9/11 for AZA (0.27–1.12) superior to
every 2–3 weeks with gradual AZA
elongation between
treatments ? oral CYP 50 mg/day
vs. AZA 2–2.5 mg/kg/
day ? PRED 2 mg/kg/day
Sethy et al. Pulse IV DEXA (100 mg/day for 3 India 28 82.1 28, 0 15 NS CR 9/15 for 1.3 Comparable
[22] consecutive days) ? IV. CYP DCP?CYP ± (0.63–2.67) response
(500 mg once on day 2) every PRED, 6/13
4 weeks ? CYP 50 mg/ for PRED ?
day ± PRED 0.5–0.75 mg/kg/day pulse CYP
vs. pulse IV CYP (15 mg/kg/
month) ? PRED 1.5 mg/kg/day
L. Atzmony et al.
Table 1 continued
References Intervention Trial Pts F (%) PV, PF FU Disease severity Efficacy Results Conclusion
location (m) definition
Interventions RR (95 % CI)
comparison

Sharma and Pulse CYP (15 mg/kg/ India 60 71.7 60, 0 24 Mild-moderate DC 31/34 for pulse 1.13 Comparable
Khandpur month) ? PRED 1 mg/kg/day vs. CYP ? (0.91–1.4) response
[15] PRED 1 mg/kg/day for 1 year PRED, 21/26
for PRED
alone
Tabrizi et al. EGF 10 lg/g in sulfadiazine cream Iran 20 35 20, 0 9–15 NS Time to HR 2.35 (1.62–3.41)c EGF cream
[27] 0.1 % applied qd vs. sulfadiazine heal superior to
cream 0.1 % vehicle cream
Werth et al. Dapsone 150 (max 200) mg/day vs. USA 19 42.1 19, 0 12 Maintenance phase. Pts CR 5/9 for 1.85 Not superior to
[24] PL (?maintenance dosage of controlled with GC dapsone, 3/10 (0.61–5.63) PL
steroids ? AZA/MMF/gold in both and/or cytotoxics with for PL
groups) 2 unsuccessful
attempts to taper GCs
to \15 mg/day
Treatment of Pemphigus Vulgaris and Pemphigus Foliaceus

AZA azathioprine, BSA body surface area, CI confidence interval, CR complete response, CYP cyclophosphamide, DC disease control, DCP pulse dexamethasone-cyclophosphamide, DEXA
dexamethasone, EGF endothelial growth factor, F females, FU follow-up, GC glucocorticoid, HR hazard ratio, Int international, IV intravenous, IVIG intravenous immunoglobulin, MMF
mycophenolate mofetil, NS not stated, PF pemphigus foliaceus, PL placebo, PRED prednisolone/prednisone, pts patients, PV pemphigus vulgaris, qd once a day, RIT rituximab, RR relative risk,
TAC tacrolimus
a
Number of pts who stayed on protocol for 3 months without any additional treatment
b
Included in meta-analysis—details in text
c
See text
509
510
Fig. 2 Azathioprine vs. prednisolone: cumulative glucocorticoid dose. CI confidence interval, SD standard deviation
Fig. 3 Mycophenolate mofetil versus oral glucocorticoid: complete response rate. CI confidence interval, MMF mycophenolate mofetil, SD
standard deviation
between the groups (HR 1.11, 95 % CI 0.63–1.95) [15].
Two trials reported relapse rates, which were similar in the
two intervention groups (RR 0.7, 95 % CI 0.42–1.15) [14,
15]. One patient treated with cyclophosphamide died of
sepsis [15], but overall rates of adverse events leading to
discontinuation were similar in the two groups (RR 1.3,
95 % CI 0.21–8.09).
Two trials compared oral glucocorticoids with or with-
out cyclosporine [14, 16]. They included a total of 41
participants: 37 with PV and four with PF. No between-
group difference was observed in CR rate, reported in one
trial [14], and no difference was observed in disease control
rate (RR 1.04, 95 % CI 0.89–1.21) and relapse rates (RR
0.88, 95 % CI 0.22–3.41), reported in both trials. Cumu-
lative glucocorticoids, reported in one trial, had no
advantage over cyclosporine as a steroid-sparing agent
(mean difference -51 mg, 95 % CI -183.38 to 81.38)
[16]. None of the patients in either study discontinued the
trial because of adverse events. There were no deaths.
One trial investigated the effect of glucocorticoids
combined with single-cycle high-dose intravenous immu-
noglobulin (IVIG) 200 or 400 mg/kg/day administered on
5 successive days or placebo in 61 participants: 40 with PV
and 21 with PF [17]. All had active disease under treatment
with prednisolone at C20 mg/day. None of our pre-defined
efficacy outcomes were reported. Outcome measures were
number of participants who continued to receive the IVIG
protocol and time to escape from the protocol (i.e., duration
for which patients stayed on the IVIG protocol without
L. Atzmony et al.
additional treatment). At the end of 3 months’ follow-up,
the proportion of patients who did not need to escape from
the protocol was significantly higher in the composite IVIG
group (400 ? 200 mg) (RR 1.84, 95 % CI 1.11–3.05) and
in the 400 mg IVIG group (RR 2.01, 95 % CI 1.21–3.33)
than in the placebo group. Findings in the 200 mg IVIG
group compared with placebo did not reach statistical
significance (RR 1.67, 95 % CI 0.96–2.88). The time to
escape from the protocol was significantly longer relative
to the placebo group in the patients treated with 400 mg
IVIG (p \ 0.001) and nonsignificantly longer in the
patients treated with 200 mg IVIG (p = 0.052). The rate of
adverse events was similar in all treatment groups,
although one patient given 200 mg IVIG group died of
hepatic failure as a result of hepatitis C virus aggravation.
Rates of withdrawal due to adverse events could not be
calculated.
One trial compared oral glucocorticoids with or without
plasma exchange [18]. Rates of disease control were sim-
ilar in the two intervention groups (RR 1.08, 95 % CI
0.73–1.38). There was also no significant between-group
difference in cumulative glucocorticoid dose, calculated
only for responders (mean difference 991 mg, 95 % CI
-1,763.56 to 3,745.56). Four patients in the plasma-
exchange group died of severe infection compared with
none in the oral glucocorticoid-only group. Yet, the rate of
withdrawal due to adverse events was not significantly
higher in the plasma-exchange group (RR 7.2, 95 % CI
0.42–124.08).
Treatment of Pemphigus Vulgaris and Pemphigus Foliaceus
3.2.3 Oral Glucocorticoid Combined with an Adjuvant
Agent versus Oral Glucocorticoid Combined
with Other Adjuvant Agent
Two trials compared combination therapy of oral gluco-
corticoids with azathioprine or with MMF [10, 19]. They
included a total of 99 participants: 92 with PV and seven
with PF. One trial reported CR rate [10], with no significant
between-group difference (RR 1.14, 95 % CI 0.85–1.53).
The other trial reported disease control rate, which was
better in the MMF than in the azathioprine group on ITT
analysis (RR 0.72, 95 % CI 0.52–0.99) but not on case
analysis [19]. Patients treated with azathioprine required a
significantly lower cumulative glucocorticoid dose
than did patients treated with MMF (mean difference
-2,076.65 mg, 95 % CI -3,546.41 to -606.79) [10, 19].
The significant difference in cumulative glucocorticoid
dose did not correlate with the rate of withdrawal due to
adverse events, which did not differ between the two
intervention groups (RR 3.2, 95 % CI 0.53–19.2) [10, 19].
Relapse rate, reported in one study [19], did not differ
between the groups (p = 0.69), but we were unable to
calculate RR because of missing data. There were no
deaths in either study.
One trial compared prednisolone with adjuvant azathio-
prine or intravenous pulse cyclophosphamide 60 participants
were included, all with PV [10]. There was no significant
difference between the groups in CR rate (RR 0.92, 95 % CI
0.69–1.44) or in rate of withdrawal due to adverse events.
Cumulative glucocorticoid dose was significantly lower in
the azathioprine group (mean difference -564 mg, 95 % CI
-1,048.54 to -79.46). No deaths were recorded.
One trial compared prednisolone with adjuvant azathi-
oprine or tacrolimus [20]; 46 participants were included, all
with PV. There was no between-group difference in CR
rate (RR 0.95, 95 % CI 0.78–1.17) or cumulative gluco-
corticoid dose (mean difference -25 mg, 95 % CI
-109.64 to 59.64). Time to disease control was also almost
similar (p [ 0.05). One patient treated with azathioprine
discontinued therapy because of pancytopenia. Neverthe-
less, the difference in rate of withdrawal due to adverse
events was not significant (RR 0.33, 95 % CI 0.01–7.78).
No deaths were recorded.
One trial compared prednisolone with adjuvant intra-
venous cyclophosphamide pulse therapy or MMF [10].
There was no difference between the groups in CR rate
(RR 1.05, 95 % CI 0.76–1.44) or rate of withdrawal due to
adverse events (RR 0.33, 95 % CI 0.01–7.87). The cumu-
lative glucocorticoid dose was significantly lower in the
cyclophosphamide group (mean difference -1,522 mg,
95 % CI -2,980 to -63.35).
One trial compared prednisolone with adjuvant daily
oral cyclophosphamide or cyclosporine [14]. All
511
participants achieved CR. There was no significant
between-group difference in relapse rates (RR 2.5, 95 % CI
0.27–22.86). None of the patients withdrew from the trial,
and none died.
3.2.4 Other Comparisons
Three trials compared a regimen of intravenous dex-
amethasone-cyclophosphamide pulse therapy (DCP) and
oral cyclophosphamide between pulses with other inter-
ventions [21–23]. In the first study, comparison of this
regimen with combined azathioprine and oral methyl-
prednisolone [21] yielded no significant between-group
difference in disease control rate (RR 0.56, 95 % CI
0.27–1.12), relapse rate (RR 0.11, 95 % CI 0.01–1.85), or
rate of withdrawal due to adverse events (RR 0.25, 95 %
CI 0.27–1.12). No deaths were recorded. The second trial
compared the DCP regimen with intravenous cyclophos-
phamide pulse therapy and daily prednisolone in between
pulses [22].The two groups exhibited a similar CR rate (RR
1.3, 95 % CI 0.63–2.63) and relapse rate (RR 0.83, 95 %
CI 0.29–2.37). There were no withdrawals due to adverse
events and no deaths. The third trial evaluated 19 patients
who had already achieved CR to DCP (phase I), which
was followed either by additional DCP or by immediate
oral cyclophosphamide alone [23]. A similar relapse rate
was found in the two groups (RR 1.11, 95 % CI
0.08–15.28).
One trial compared dapsone and placebo in 19 patients
with chronic PV in whom the disease was controlled with
steroids and/or cytotoxic agents that could not be tapered
down [24]. There was no significant between-group dif-
ference in CR rate (RR 1.85, 95 % CI 0.61–5.63). None of
the patients withdrew because of adverse events.
One trial compared high-dose (1,000 mg biweekly) and
low-dose (500 mg biweekly) rituximab in 22 patients: 17
with PV and five with PF [25]. All patients were also
treated with oral glucocorticoids. Azathioprine was
administered to patients who did not achieve CR with
rituximab and oral glucocorticoids. Complete response
rates were similarly high (*95 %) in the two groups (RR
0.91, CI 95 % 0.72–1.17). All patients achieved disease
control, with no significant difference in relapse rates or
cumulative glucocorticoid dose (RR 0.57, 95 % CI
0.23–1.41; mean difference -573.77 mg, 95 % CI -
1,812.69 to 665.15). However, the total cumulative dose of
azathioprine was significantly higher for the low-dose
group (mean difference -15,150 mg, 95 % CI -20,284.33
to -10,015.67), but there was no significant between-
group difference in the number of patients who received
azathioprine (RR 0.4, 95 % CI 0.1–1.64). None of
the patients withdrew due to adverse events, and none
died.
512
One trial assessed the role of herpes simplex virus
infection in PV by comparing oral acyclovir, prednisolone,
and azathioprine with prednisolone and azathioprine alone
[26]. Disease control rates were similar in the two groups
(RR 0.86, 95 % CI 0.38–1.95).
One trial compared the effect of topical EGF in a sul-
fadiazine base cream to sulfadiazine cream alone on the
healing time of cutaneous lesions [27]. Time to healing was
significantly shorter when EGF was used (HR 2.35, 95 %
CI 1.62–3.41). Neither intervention was associated with
adverse events.
4 Discussion
In this systematic review, 20 RCTs assessing various inter-
ventions for PV and PF were analyzed. Ten of them were
added to the ten English-language trials already included in a
previous published systematic review [4]. We performed five
meta-analyses, including three comparing glucocorticoid use
alone to glucocorticoids with adjuvant azathioprine, MMF,
and cyclophosphamide, which pooled new data, strength-
ening the safety and efficacy evidence. However, the data for
other treatment modalities remain sparse. Therefore, we
separated the interventions included in the analysis into those
that appeared beneficial or promising and those that appeared
disappointing but warranted further investigation.
4.1 Beneficial or Promising Treatment Modalities
4.1.1 Azathioprine
Azathioprine was found to have a steroid-sparing effect
compared with oral prednisolone alone in a meta-analysis
that included 116 participants [10, 11], and compared to
adjuvant MMF in a meta-analysis that included 99 partic-
ipants [10, 19]. Azathioprine-associated CR rates, time to
disease control, rate of withdrawal due to adverse events,
and rate of death were similar to those for oral glucocor-
ticoid alone [10, 11] or oral glucocorticoids combined with
MMF [10, 19].
4.1.2 Mycophenolate Mofetil (MMF)
MMF did not have a steroid-sparing effect compared with
oral glucocorticoids alone in a meta-analysis that included
154 participants [10, 13], nor did it yield a better response
rate than oral glucocorticoid alone in a meta-analysis that
included 201 participants [10, 12, 13]. Nevertheless, in one
trial, the addition of MMF hastened the average time to a
sustained CR and delayed the time to relapse [13]; in
another, it was associated with a similar relapse rate to oral
glucocorticoids alone [12]. In one trial, MMF was
L. Atzmony et al.
significantly superior to azathioprine in terms of disease
control [19]. However, it is noteworthy that the latter result
was obtained after inclusion of one patient who dropped
out after allocation without receiving treatment. On per-
protocol analysis, the findings were inconclusive. In addi-
tion, as mentioned, the response rates for MMF were
similar to those for azathioprine in one trial [10]. Thus, the
data so far are insufficient to determine whether azathio-
prine or MMF is the more effective agent.
4.1.3 Cyclophosphamide
Cyclophosphamide was evaluated in six trials and found to
have a steroid-sparing effect compared with oral gluco-
corticoids alone and oral glucocorticoids with adjuvant
MMF [10, 14, 15, 21–23]. However, in one trial in 54
participants, it had a poorer steroid-sparing effect than
azathioprine [10]. The effect of cyclophosphamide on other
outcomes evaluated in this review was similar to that of
oral glucocorticoids alone or with adjuvant azathioprine or
MMF. Adding DCP to oral cyclophosphamide did not
decrease the relapse rate, and DCP did not have a greater
effect on response rate, relapse rate, or rate of withdrawal
due to adverse events than oral methylprednisolone with
adjuvant azathioprine or oral prednisolone with adjuvant
cyclophosphamide pulse therapy. Definitive conclusions
cannot be reached regarding DCP because all the trials
were insufficiently powered.
4.1.4 Intravenous Immunoglobulin (IVIG)
Single-cycle high-dose IVIG was evaluated in one trial of
61 participants [17]. Specifically, the 400 mg/kg/day dose
showed significant superiority over placebo in terms of two
short-term efficacy outcomes: number of participants who
remained on the protocol and time to escape from the
protocol. A dose-response relationship was demonstrated,
although 200 mg/kg/day was associated with a nonsignif-
icant increased and prolonged response. Efficacy was
proved for a single cycle in patients who were relatively
resistant to systemic glucocorticoids, whereas most previ-
ous uncontrolled studies used repeated cycles for patients
with refractory or severe disease [28]. Rates of adverse
events were similar in the IVIG and placebo groups.
4.1.5 Rituximab
Rituximab was introduced as a promising treatment for
pemphigus in 2002 [29]. Since then, several retrospective
studies have demonstrated high remission rates of up to
91 % on repeated cycles [30, 31]. Because we limited the
present review to RCTs, we analyzed only one study of
rituximab in which two doses were compared: 500 mg
Treatment of Pemphigus Vulgaris and Pemphigus Foliaceus
biweekly and 1,000 mg biweekly [25]. CR was achieved in
95.2 % of participants, with no between-group difference
in rates of CR, relapse, withdrawal due to adverse events,
or cumulative glucocorticoid dose. High rituximab dose did
decrease the need for adjuvant azathioprine therapy in
terms of total cumulative azathioprine dose. However, the
significance of this finding is questionable, as the total
number of patients treated with azathioprine in the low-
dose group was insignificantly higher. This, together with
the facts that the trial was insufficiently powered and an
inappropriate statistical method was used to analyze time-
to-event outcomes, did not allow us to conclude which dose
is preferable. At least one RCT trial is currently assessing
the efficacy of rituximab as adjuvant therapy to oral glu-
cocorticoids [32]. The results, together with the increasing
use of the consensus statement endpoints [7], will help us
to better assess rituximab efficacy and safety in the near
future.
4.1.6 Topical Epidermal Growth Factor (EGF)
Topical EGF appears to hasten lesion healing according to
one study in 20 patients [27]. However, it was not com-
pared with the more commonly used therapy—topical
corticosteroids—that may have yielded a similar response.
In addition, its long-term safety was not assessed.
4.2 Treatment Modalities that Require Further
Investigation
4.2.1 High-Dose Glucocorticoids
The best-established therapy for pemphigus is systemic
glucocorticoids. Nevertheless, we identified only two RCTs
that assessed different regimens of glucocorticoids, and
none that compared the efficacy of glucocorticoid versus
other immunosuppressive monotherapies [8, 9]. One trial,
which was inadequately powered, compared high- and low-
dose prednisolone and failed to show the superiority of one
over the other in terms of rates of disease control, relapse,
withdrawal due to adverse events, and death [8]. Another
small trial assessed the additive effect of pulse dexameth-
asone and found that it had no beneficial effect on CR or
rates of relapse, withdrawal due to adverse events, and
death [9]. However, as the study included only newly
diagnosed patients and patients with flare-up, results cannot
be extended to patients with refractory disease. These
results, although insufficiently powered, were supported by
two nonrandomized controlled studies [33, 34]. The first
used a retrospective case-controlled design and included 71
patients assigned to receive an initial dose of 1 or 2 mg/kg/
day according to disease severity. No difference in clinical
513
response was found between the groups. The higher dose
was associated with a significantly higher rate of adverse
events [33]. Another non-randomized controlled trial that
compared pulsed intravenous betamethasone with oral
glucocorticoids in 20 patients found no difference in time
to resolution of disease [34].
4.2.2 Cyclosporine
According to two trials that were also included in the
previous review [4], the effect of cyclosporine on rates of
remission, disease control, relapse, withdrawal due to
adverse events, and death was not superior to that of oral
glucocorticoids and cyclophosphamide [10, 14]. However,
the sample size was small, and results were inconclusive.
4.2.3 Plasma Exchange
In the only trial of plasma exchange, the effect on disease
control, relapse, and withdrawal due to adverse events did not
exceed that of placebo [18]. However, again, the sample was
small and the analysis was insufficiently powered to be con-
clusive. The mortality rate was higher in the plasma exchange
group. Although the difference was not significant, the finding
might have been attributable to the treatment itself.
4.2.4 Tacrolimus
In the sole trial comparing tacrolimus and azathioprine, no
benefit was noted in CR rate, cumulative glucocorticoid
dose, time to achieve disease control, rate of withdrawal
due to adverse events, or rate of death [20].
4.2.5 Dapsone
In one trial, the effect of dapsone on CR rate and rate of
withdrawal due to adverse events was similar to that with
placebo [24], but the trial was underpowered.
4.3 Limitations
This review has several limitations. First, the studies
included were highly variable in terms of outcome mea-
sures and intervention arms, which restricted our ability to
pool several trials into one comparison. Second, consider-
ing the grave course of pemphigus, it is unethical to
compare any one treatment with placebo alone and, given
the rarity of the disease, it is difficult to prove the efficacy
of one intervention over another as that requires a very
large group of patients. Third, one of our primary outcomes
was cumulative glucocorticoid dose, which we considered
a surrogate for adverse events resulting from
514
glucocorticoid use. However, this correlation is not well
established. Fourth, the response rates were not higher for
azathioprine, MMF, or cyclophosphamide than for oral
glucocorticoid alone. However, this does not answer the
question of whether any of these therapies help to achieve
an earlier response. Only seven trials addressed this issue
appropriately, but used four different outcome measures,
precluding a direct comparison of the results. Fifth, most
patients included in the major comparisons that included
larger samples (100 or more) were diagnosed with mild to
moderate disease. Moreover, only five trials included
patients with severe disease (Table 1); all were insuffi-
ciently powered and not included in the meta-analysis.
However, different disease severity assessment tools were
used in the included trials; in four trials, disease severity
was not mentioned. In light of this, there are currently
insufficient data to guide treatment according to disease
severity. Last, although most of the trials were adequately
randomized, only six were double-blinded and only seven
had adequate allocation concealment, making outcome
assessment in the other trials that did not meet these criteria
open to bias.
5 Conclusions
Systemic glucocorticoids are the mainstay of treatment of
pemphigus. The optimal dose is still not known. Multiple
adjuvant treatment modalities have been studied, but only a
few appear to be effective according to the limited current
evidence-based data. None of the combined therapies was
found to be more effective than glucocorticoids alone in
terms of CR rate. Adjuvant azathioprine and cyclophos-
phamide appear to have a steroid-sparing effect, although no
direct clinical efficacy was observed. MMF apparently
shortens the time to achieve a sustained response and delays
the time to relapse, but it has no proven steroid-sparing
effect. High-dose IVIG is effective in initiating and main-
taining disease control, and topical EGF appears to hasten
lesion healing. Rituximab holds promise for improving the
response rate, but the optimal dose is unknown, and its
efficacy and safety need to be evaluated against oral gluco-
corticoids. Due to the limitations of this review, many
questions remain open. The formulation of further well-
designed RCTs and case-control studies with similar out-
come measures will allow us to combine more studies into
larger meta-analyses and to reach more definitive conclu-
sions regarding the treatment of this rare disease.
Acknowledgments No sources of funding were used to conduct this
study or prepare this manuscript. Lihi Atzmony, Emmilia Hodak,
Michael Gdalevich, Omer Rosenbaum, and Daniel Mimouni have no
conflicts of interest that are directly relevant to the content of this
study.
L. Atzmony et al.
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