Outcome Measures – Research Article
Dermatology
DOI: 10.1159/000508671
Short-Term Intravenous Infusion of
Cyclophosphamide in the Treatment of
Refractory Pemphigus Vulgaris:
A Retrospective Study
Wenjing Zhang a Shanshan Wei b Xuebiao Peng a Shuangde Xie a
Zhiwen Zhang a Kang Zeng a Kuan Lai a
a Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, China; b Department of
Dermatology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
Keywords
Pemphigus vulgaris · Cyclophosphamide · Glucocorticoid ·
Retrospective study
Abstract
Background: Pemphigus is an autoimmune disease of the
skin and mucous membranes. Glucocorticoids have been
the most effective drug for the treatment of pemphigus;
however, some patients are insensitive to glucocorticoid
therapy. Cyclophosphamide has been extensively used in
the treatment of pemphigus. Objectives: To observe and
evaluate the efficacy and safety of high-dose glucocorticoid
with weekly intravenous cyclophosphamide in the treat-
ment of refractory pemphigus vulgaris insensitive to gluco-
corticoids. Methods: Clinical data of 19 patients with refrac-
tory pemphigus vulgaris (insensitive to glucocorticoid) who
were treated with high-dose glucocorticoids(1.5 mg/kg/day
prednisone) and weekly intravenous infusion of cyclophos-
phamide, and 24 patients who were sensitive to glucocorti-
coid therapy received a medium dose of glucocorticoid
alone (1 mg/kg/day prednisone) were retrospectively ana-
lyzed. Results: By the time the disease was brought under
control, the average total dose of cyclophosphamide was
2.02 g. Comparison between the glucocorticoid-insensitive
and glucocorticoid-sensitive groups showed that the aver-
karger@karger.com © 2020 S. Karger AG, Basel
www.karger.com/drm
Received: December 18, 2019
Accepted: May 14, 2020
Published online: August 19, 2020
age time to disease control was 2.68 vs. 2 weeks, and the av-
erage daily dosage of steroid was 1.33 ± 0.53 vs. 0.90 ± 0.28
mg/kg. At the 12- and 18-month follow-ups, the recurrence
rate of the glucocorticoid-insensitive group was significantly
lower than that of the sensitive group (5.3 vs. 37.5%, 15.8 vs.
45.8%). No serious adverse reactions were observed. Conclu-
sion: High-dose glucocorticoid plus weekly intravenous in-
fusion of cyclophosphamide safely, effectively, and rapidly
controlled the conditions of the patients with refractory
pemphigus who were insensitive to glucocorticoids, short-
ened the duration of hospitalization, avoided the risk of
complications that could be caused by further increasing the
dose of glucocorticoids (>1.5 mg/kg/day), and lowered the
recurrence rate within 18 months. © 2020 S. Karger AG, Basel
Introduction
Pemphigus is a potentially lethal autoimmune disease
of the skin and mucous membranes caused by anti-des-
moglein (anti-Dsg) antibodies [1]. Glucocorticoids have
been the most effective drug for the treatment of pemphi-
gus. However, some patients are insensitive to or cannot
tolerate high-dose glucocorticoid therapy. Immunosup-
pressive agents have a good effect on controlling the dis-
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Auckland University of Technology
Kang Zeng or Kuan Lai
Department of Dermatology, Nanfang Hospital
Southern Medical University, No. 1838, North Guangzhou Avenue
Guangzhou, Guangdong 510515 (China)
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pfkzengk @ 163.com or lai_kuan @ 163.com
 File search in the clinical information system to identify
patients who were diagnosed with pemphigus vulgaris at the
Nanfang Hospital, Southern Medical University between
2004 and 2017

Inclusion criteria: Exclusion criteria:

● Clinical, histopathology or direct ● Simultaneous treatment with other immuno-
immunofluorescence assay, and serum anti- suppressants or immunoglobulin
desmoglein autoantibody examinations ● Voluntarily ceased the treatment for other
being consistent with the diagnosis of reasons
pemphigus vulgaris
● Presence of severe heart/lung/liver/kidney
● The disease in active phase disease, severe infection, or malignant
● Glucocorticoid or glucocorticoid plus tumors
weekly intravenous infusion of CTX as the ● Urinary tract infection
main treatment
● Lost to follow-up
● Complete follow-up records of nearly 18
months, including outpatient and telephone ● Incomplete data
follow-up

43 patients

Insensitive to glucocorticoid Sensitive to glucocorticoid

(n = 19) (n = 24)

● Glucocorticoids
● Weekly intravenous infusion Glucocorticoids
of CTX

Data collection:
● Patient demographics
● Disease severity
● Follow-up and outcome
● Therapy side effects

Statistical analysis

Fig. 1. Flowchart of Materials and Methods.

ease and help in reducing the dose of glucocorticoid need-
ed, resulting in good therapeutic effect. Such approaches
are often used in the treatment of pemphigus [2]. Cyclo-
phosphamide (CTX) has been extensively used in the
treatment of various immune diseases due to its strong
cytotoxicity and immunosuppressive effects. Neverthe-
less, there is no international consensus on using CTX for
the treatment of pemphigus [3], with usage varying from
place to place. This retrospective study analyzed the clin-
ical cases of refractory pemphigus vulgaris treated by
short-term, weekly intravenous infusion of CTX in our
hospital.
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2 Dermatology Zhang/Wei/Peng/Xie/Zhang/Zeng/Lai
DOI: 10.1159/000508671
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Table 1. Clinical data in the 2 groups Table 2. Follow-up

Glucocorticoid Glucocorticoid Evaluation Effect Treatment, n (%) p value

sensitive insensitive
glucocorticoid glucocorti-
Male/female, n 10/14 6/13 sensitive coid
Age, years 41.25±16.40 45.74±8.91 insensitive
Disease duration, months 18.90±31.19 26.32±42.57
First episode/relapse, n 16/8 10/9 6 months R-on-T 1 (4.2) 0 (0) 1.0
Anti-Dsg1, U/mL 97.15±69.76 127.72±49.62 Relapse 4 (16.7) 1 (5.3) 0.363
Anti-Dsg3, U/mL 58.45±56.74 100.7±58.71 12 months R-on-T 4 (16.7) 2 (10.5) 0.678
Severity, n Relapse 9 (37.5) 1 (5.3) 0.026*
Mild 1 2
Moderate 8 1 18 months R-on-T 8 (33.3) 4 (21.1) 0.373
Severe 15 16 Relapse 11 (45.8) 3 (15.8) 0.037*

None of the above indicators showed statistical significance. R-on-T, complete remission on therapy. * Significant.
Dsg, desmoglein.

Materials and Methods
For further details, see the online supplementary material (see
www.karger.com/doi/10.1159/000508671) [4, 5] (Fig. 1).
Results
In this study, among the 43 pemphigus vulgaris pa-
tients, 19 cases were included in the glucocorticoid-in-
sensitive group (6 males and 13 females; age ranging from
26 to 67 years, with a mean age of 45.74 ± 8.91 years; du-
ration of disease from 1 to 180 months, with an average
disease duration of 26.32 ± 42.57 months). These com-
prised 10 initial onset and 9 recurrent cases; there were 2
mild, 1 moderate, and 16 severe cases, with an average
anti-Dsg1 antibody level of 127.72 ± 49.62 U/mL and an
average anti-Dsg3 antibody level of 100.7 ± 58.71 U/mL.
The other 24 cases were included in the glucocorticoid
sensitive group (10 males and 14 females; age ranging
from 17 to 77 years, with a mean age of 41.25 ± 16.40
years; duration of disease from 0.6 to 120 months, with an
average disease duration of 18.90 ± 31.19 months). These
comprised 16 initial onset and 8 recurrent cases; there
were 1 mild, 8 moderate, and 15 severe cases, with an av-
erage anti-Dsg1 antibody level of 97.15 ± 69.76 U/mL and
an average anti-Dsg3 antibody level of 58.45 ± 56.74
U/mL. No statistically significant differences in age, dis-
ease duration, gender, initial onset or recurrence, disease
severity, and anti-Dsg1/3 antibody titers were found be-
tween the 2 treatment groups (p > 0.05; Table 1) and most
cases in the 2 groups were severe.
By the time the disease was brought under control, the
CTX treatment had been given 3.47 times on average, us-
ing an average total dose of 2.02 g. Comparison between
the glucocorticoid-insensitive and glucocorticoid-sensi-
tive groups showed that the average time to disease con-
trol was 2.68 vs. 2 weeks (p = 0.039), the total prednisone
dose was 1413.21 ± 960.02 vs. 562.29 ± 322.70 mg (p =
0.001), and the average daily dose was 1.33 ± 0.53 vs. 0.90
± 0.28 mg/kg (p = 0.001) at the time of disease control.
Statistically significant differences in the area of skin le-
sions before and after the treatment were found in both
treatment groups (p = 0.000), with the area of skin lesions
gradually decreasing over time during the follow-up
(Fig. 2). No statistically significant differences in the se-
verity of the disease were found between the 2 treatment
groups at the 6-, 12-, and 18-month follow-ups (p > 0.05).
Comparison between the glucocorticoid-insensitive and
glucocorticoid-sensitive groups showed a complete re-
mission on therapy (R-on-T) rate of 0 vs. 4.2% (p = 1.0)
and recurrence rate of 5.3 vs. 16.7% (p = 0.363) at the
6-month follow-up; an R-on-T rate of 10.5 vs. 16.7% (p =
0.678) and recurrence rate of 5.3 vs. 37.5% (p = 0.026) at
the 12-month follow-up; and an R-on-T rate of 21.1 vs.
33.3% (p = 0.373) and recurrence rate of 15.8 vs. 45.8%
(p = 0.037) at the 18-month follow-up (Table 2). Patients
who underwent recurrence regained control of the dis-
ease after an increased dose of steroids.
At the 6-month follow-up, the doses of prednisone
used in the glucocorticoid-insensitive and glucocorti-
coid-sensitive groups were reduced to 41.99 ± 16.17 and
51.54 ± 19.86%, respectively, of the dose used to bring the
disease under control (p = 0.097). They were reduced to
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Refractory Pemphigus Vulgaris Treated Dermatology 3

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 Color version available online
40 150
Severe Moderate

Percentages of the dose used to bring

Glucocorticoid-sensitive group #
Mild No lesions
Glucocorticoid-insensitive group*

the disease under control

30
100

#
Cases

20
#
#
50

10
*
* *
0
0 0 5 10 15 20
0 6 12 18
Months
a Months

50 Fig. 3. The mean doses of prednisone at different follow-up time

Severe Moderate
Mild No lesions points in the 2 treatment groups. #,* p < 0.05.
40

30 Fig. 4a). In the glucocorticoid-sensitive group, statistically

significant differences in the anti-Dsg1 and anti-Dsg3 an-
Cases

20
tibody levels were found between the 12-month follow-up
and the time of admission (p = 0.032 and 0.015, respec-
10
tively; Fig.  4b). Comparison of the anti-Dsg1 and anti-
Dsg3 antibody titers showed no significant difference be-
tween the 2 treatment groups. During the CTX treatment,
0
0 6 12 18 no hemorrhagic cystitis or decrease in blood cell counts
b Months was observed in the patients. Three patients had mild el-
evation of aminotransferases and 2 patients had oral can-
Fig. 2. Disease severity of the 2 treatment groups. a Disease sever- dida infection when they were taking CTX treatment, with
ity of the glucocorticoid-insensitive group. b Disease severity of the above disappearing after treatment.
the glucocorticoid-sensitive group.

36.04 ± 18.86 and 38.17 ± 17.37%, respectively, at the
12-month follow-up (p = 0.703), and to 30.76 ± 19.12 and
32.67 ± 16.86%, respectively, at the 18-month follow-up
(p = 0.730), with no statistically significant differences be-
tween the 2 treatment groups. However, statistically sig-
nificant differences were found in the dose of prednisone
at different times during follow-up (6, 12, and 18 months)
compared with the dose used to bring the disease under
control within each treatment group (Fig. 3).
At the 12-month follow-up, 11 and 9 patients, respec-
tively, in the 2 treatment groups had the anti-Dsg antibod-
ies re-examined. In the glucocorticoid-insensitive group,
no statistically significant difference was observed in the
anti-Dsg1 antibody level between the 12-month follow-up
and the time of admission (p = 0.089), while differences
were found in the anti-Dsg3 antibody level between the
12-month follow-up and the time of admission (p = 0.020;
Discussion
The mortality rate of pemphigus has increased slightly in
the past 2 decades, mainly because of the complications
brought on by treatment. Therefore, rational and scientific
application of immunosuppressive agents and glucocorti-
coids is of great significance for the treatment of pemphigus
nowadays and the reduction of its mortality rate [6]. Cur-
rently, no unified treatment scheme for pemphigus is avail-
able. Therapeutic regimens have varied depending on the
experience of the physicians. Therefore, it is important to
find effective, highly efficient therapeutic regimens with few
adverse reactions. CTX has been used clinically since the
1950s [7] in the treatment of a variety of autoimmune dis-
eases [3]. CTX is usually administered in combination with
glucocorticoids, either orally or intravenously. However, a
previous study has shown that oral CTX increased the inci-
dence of malignant tumors (e.g., a 31- to 33-fold increase in
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4 Dermatology Zhang/Wei/Peng/Xie/Zhang/Zeng/Lai
DOI: 10.1159/000508671
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 weeks to control the disease (average disease control dura-

Color version available online

200 Anti-Dsg1
Anti-Dsg3 tion of 5.7 weeks), and 76.5% of the patients achieved com-
* plete remission after a year of treatment. All cases enrolled
in the study were mild to moderate pemphigus. In the pres-
150
ent study, high-dose glucocorticoids (1.5 mg/kg/day pred-
nisone) and CTX were used to treat the glucocorticoid-in-
Level, U/mL

sensitive refractory pemphigus cases, with the average dis-

100
ease control duration of 2.68 weeks, which was significantly
shorter than that of the monthly CTX pulse therapy, and a
10.5% remission rate at the 1-year follow-up. A previous
50
study by Gokhale et al. [11] used intravenous infusion of
CTX (500 mg/time) and high-dose glucocorticoid (80 mg/
day prednisone) orally to treat pemphigus. The patients
0
0 12
were given an intravenous infusion of CTX once a month in
a Months the first year, followed by once every 2 months in the second
year. The CTX treatment was terminated in the third year,
200 and the patients were followed up for a year. The results
Anti-Dsg1
Anti-Dsg3 showed that this therapeutic regimen took 8–20 weeks (av-
* erage 12 weeks) to show the efficacy. Additionally, 11.1% of
150 the cases relapsed within a year after the termination of CTX
treatment. However, in the current study, the recurrence
* rate in the glucocorticoid-insensitive group was only 5.3%.
Level, U/mL

100 Since 2000, refractory pemphigus patients who were in-

50
0 once the disease was under control while glucocorticoid
0 12
b Months
Fig. 4. Anti-Dsg (desmoglein) levels in the 2 treatment groups.
a The glucocorticoid-insensitive group. b The glucocorticoid-sen-
sitive group. * p < 0.05.
the incidence of bladder cancer) [6]. In 1974, Medved and
Maxwell [8] first used intravenous CTX pulse therapy to
successfully treat refractory pemphigus and bullous pem-
phigoid. This method has been shown to have low toxicity,
lowering the incidences of bladder cancer and gonadal tox-
icity. This intravenous CTX pulse therapy is an alternative
to oral CTX [9]. However, traditional CTX pulse therapy
requires high doses of CTX (1 g or 15 mg/kg) and long in-
tervals between doses (once per month) [6, 10], taking a long
time to show therapeutic efficacy. A study by Sharma and
Khandpur [6] showed that oral glucocorticoids (1–1.5 mg/
kg/day) and intravenous CTX pulse therapy (15 mg/kg)
once a month for a full year of treatment required 2–28
sensitive to glucocorticoids were given high-dose glucocor-
ticoid (1.5 mg/kg/day prednisone) and 600 mg CTX week-
ly, intermittent intravenous infusion in our hospital, to ef-
ficiently control the disease. The same dose of glucocorticoid
was used between CTX infusions. CTX was discontinued
continued (with gradual reduction of the dose). This meth-
od has achieved good therapeutic outcomes. Here, compar-
ing them to the glucocorticoid-sensitive cases showed that,
although the time to disease control in the glucocorticoid
plus CTX group was slightly longer and the daily dose of
steroid used at the time of disease control was higher, this
therapeutic regimen was able to shorten the duration of
hospitalization and avoid the risk of complications that
could be caused by further increasing the dose of glucocor-
ticoid (>1.5 mg/kg/day) in the refractory cases, such as sec-
ondary infection, electrolyte confusion, hypertension, and
hyperglycemia. No significant difference in the complete
remission rate was observed between the glucocorticoid-
insensitive and glucocorticoid-sensitive groups at the 12-
and 18-month follow-ups; however, the recurrence rate of
the glucocorticoid-insensitive group was significantly low-
er than that of the glucocorticoid-sensitive group (5.3 vs.
37.5%, 15.8 vs. 45.8%). These results suggested that short-
term intravenous infusion of CTX had a long-term effect on
the course of pemphigus and reduced the long-term recur-
rence rate of the disease.
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Refractory Pemphigus Vulgaris Treated Dermatology 5

with Cyclophosphamide DOI: 10.1159/000508671
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 The most common adverse effects of CTX are nausea, Acknowledgments
vomiting, leukopenia, cystorrhagia, and secondary infec-
We thank LetPub (www.letpub.com) for providing linguistic
tion. Because a small dose of CTX was given each time assistance during the preparation of this manuscript.
(weekly) in this study, no obvious nausea, vomiting, leu-
kopenia, cystorrhagia, or severe infection was observed in
this work. Only a few patients developed elevation of ami- Statement of Ethics
notransferases or oral candida infection. These data sug-
gested that the high dose of glucocorticoid and intermit- An ethics statement is not required because this is a retrospec-
tent, weekly intravenous infusion of CTX in this study tive study.
had rare adverse reactions.
In summary, high-dose glucocorticoid plus weekly in-
travenous infusion of CTX safely, effectively, and rapidly Conflict of Interest Statement
controlled the conditions of the patients with refractory
The authors have no conflicts of interest to declare with regard
pemphigus who were insensitive to glucocorticoids. It was to this study.
also an effective method of using CTX to lower the rate of
recurrence within 18 months. However, a large-sample
prospective randomized controlled trial is necessary to Funding Sources
validate our conclusion. Given that the 1-year remission
rate of this weekly short-term application of CTX was sig- This study was supported financially by the Natural Science
nificantly lower than that of the monthly intravenous Foundation of Guangdong Province (No. 2018A030313949) and
the National Natural Science Foundation of China (No. 81803119).
CTX pulse therapy [6], we envisaged that these 2 methods
could be combined by first using weekly therapy to rap-
idly control the disease, followed by monthly maintenance
Author Contributions
of CTX pulse therapy to achieve long-term relief. Further
clinical research is needed to verify this hypothesis. W.Z. conceived and designed the experiments, performed the
experiments, analyzed the data, contributed reagents/materials/
analysis tools, prepared figures and/or tables, authored or re-
Key Message viewed drafts of the paper, and approved the final draft. S.W., X.P.,
K.L., and K.Z. conceived and designed the experiments and ap-
High-dose glucocorticoid plus weekly intravenous infusion of proved the final draft. S.X. and Z.Z. contributed reagents/materi-
cyclophosphamide safely, effectively, and rapidly controlled the als/analysis tools and approved the final draft.
conditions of the patients with refractory pemphigus who were
insensitive to glucocorticoids.

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