DOI: 10.1111/j.1468-3083.2010.03753.

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ORIGINAL ARTICLE

High dose oral prednisone vs. prednisone plus

azathioprine for the treatment of oral pemphigus: a
retrospective, bi-centre, comparative study
G Chaidemenos,†,* Z Apalla,‡ T Koussidou,† I Papagarifallou,‡ D Ioannides‡
†
State Hospital for Dermatologic and Venereologic Diseases, Thessaloniki, and ‡A’ Department of Dermatology, Aristotle
University, Thessaloniki, Greece
*Correspondence: G Chaidemenos. E-mail: cgiorgos@otenet.gr

Abstract
Background Steroids are considered the cornerstone in the treatment of pemphigus vulgaris. However,
subsequent morbidity of their use has led to the development of combined therapeutic protocols, using steroid
sparing agents.
Objectives The aim of this study was to compare tolerability and efficacy of high dose oral prednisone daily, vs.
low dose oral prednisone on alternate days plus azathioprine every day (Lever’s mini treatment: LMT) in oral
pemphigus.
Patients and methods Data of 36 patients with oral pemphigus vulgaris, treated with either 1.5 mg ⁄ kg ⁄ day of
oral prednisone daily, or LMT were re-evaluated and statistically analysed. Primary endpoints were time required to
control disease activity, prednisone dose required until the end of consolidation phase, cumulative prednisone dose
and rates of remission. Secondary endpoints were time to complete (CR) or partial remission (PR) on ⁄ off therapy,
treatment-associated morbidity and days of hospitalization.
Results Both treatments resulted in high rates of clinical response. The mean prednisone dose required until the
end of consolidation phase, and until CR or PR, on ⁄ off minimal therapy, was significantly lower in LMT group.
However, the mean time required until the control of disease activity and CR or PR, for the same group, was
significantly higher. Adverse events were more frequent among patients under daily prednisone. Mean time of
hospitalization was also longer in the latter group.
Conclusions Both treatments seem efficacious. Rapidly progressive lesions necessitate high prednisone dose for
early and adequate control of the disease. Patients with impaired physical status, especially those with relatively
stable lesions, at baseline might safely and effectively be treated with LMT.
Received: 10 February 2010; Accepted: 3 May 2010

Keywords
azathioprine sodium, Lever’s mini treatment, oral pemphigus, pemphigus vulgaris, treatment

Conflict of interest
None declared.

Funding sources
None.

Introduction months to years before the development of extensive extraoral

Pemphigus vulgaris (PV) is a chronic debilitating autoimmune
disorder with a potentially life-threatening course. The mucosal-
dominant type, with mucosal lesions and sometimes minimal skin
involvement, is the most common form and it usually represents
an early and relatively stable phase of the disease.1 In most of the
cases, this type of PV remains limited at the oral mucosa for
lesions.2
Despite the significant progress in the field of etiopathogenetic
knowledge of pemphigus in recent years, there is a lack of stan-
dardized therapeutic protocols, especially for patients suffering
from specific forms of the disease, as the mucosal type of PV lim-
ited exclusively at the oral cavity.3 Previous clinical trials have

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JEADV 2011, 25, 206–210 Journal of the European Academy of Dermatology and Venereology ª 2010 European Academy of Dermatology and Venereology
Daily prednisone vs. LMT in oral pemphigus
demonstrated efficacy and tolerance of the alternate-day 40 mg
oral prednisone plus 100 mg azathioprine daily (Lever’s mini
treatment) therapeutic scheme in oral pemphigus.4–8 The aim of
this study was to compare a well established therapeutic protocol,
using daily high dose prednisone as monotherapy, with the Lever’s
mini treatment (LMT) in patients with mucosal-dominant type of
PV.
Patients and methods
A retrospective, bi-centre comparative study was conducted in col-
laboration with two Dermatological Clinics – the First Department
of Dermatology of the Aristotle University of Thessaloniki, and
the Dermatologic Department of the State hospital of Dermato-
logic and Venereologic Diseases of Northern Greece. These two
centres that are located within the same hospital drain patients
from the same population basin and share similar hospital facili-
ties, while they differ in the therapeutic approach of PV; the first
being in favour of the high daily prednisone, and the second pre-
ferring the alternate-day prednisone scheme.
The study included 36 Caucasian patients that had been diag-
nosed with exclusively oral lesions of PV. The patients were con-
secutively admitted to the Dermatology Departments during the
last decade and were treated with either 1.5 mg ⁄ kg ⁄ day of oral
prednisone or 40 mg of oral prednisone on alternate days plus
100 mg of azathioprine sodium every day (Lever’s mini treat-
ment). Prerequisite for enrolment was a follow-up period lasting
at least 24 months after treatment initiation. Initial diagnosis of
pemphigus vulgaris was supported by the presence of oral lesions
suggestive of pemphigus, acantholysis on histological examination
and intercellular deposition of IgG within the epidermis on direct
immunofluorescence.
The first group consisted of 17 patients that had received oral
prednisone as monotherapy, while the second group consisted of
19 individuals that had received Lever’s mini treatment. Their
medical records were re-evaluated to collect data regarding time
required to achieve control of disease activity, prednisone dose
required until the end of consolidation phase (ECP), rates of com-
plete (CR) or partial remission (PR), on ⁄ off minimal therapy,
prednisone dose and time required to CR or PR, on ⁄ off therapy,
treatment-associated side-effects and days of hospitalization. The
definitions of the terms used in the text, including ‘ECP’, ‘CR and
PR on ⁄ off minimal therapy’ and ‘flares’, were based on the recent
consensus statement on definitions of disease end points, and
therapeutic response for pemphigus.9 Disease severity was defined
using the Pemphigus Area and Activity Score (PAAS) only for oral
involvement. It was calculated as an area score, using a 1 to 3
point-scale, corresponding to 1–3 sites of involvement, multiplied
by a 1 to 3 severity score, which refers to mild, moderate or severe
disease.10
Individuals of each group were further divided into those with
impaired and those with normal physical status at baseline.
Patients were arbitrarily characterized as having impaired physical
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207
status in case of elderly age (over 65), in case of comorbidities at
baseline (including diabetes mellitus and cardiovascular disorders)
and in case that they were under treatment with more than one
medication for any reason. Treatment related morbidity was
assessed taking into account treatment-associated adverse events.
An adverse event was characterized as serious when it resulted in
(i) death or (ii) prolonged hospital admission, (iii) persistent or
significant disability or incapacity, (iv) any important medical
event that put the patient’s life in danger.
Preventative treatment of osteoporosis and peptic ulcer
included the following medications: calcium tablets, vitamin D in
various forms and a proton-pump inhibitor capsule.
Statistics
Mean values and 95% confidence intervals (95% CI) for patients’
demographic and clinical characteristics at baseline (age, duration
of disease and PAAS for oral lesions alone at baseline) were esti-
mated for both monotherapy and LMT group.
The significance of difference of means for time to achieve con-
trol of disease activity, as well as the significance of difference of
means regarding time to reach CR on, CR off, PR on and PR off
minimal therapy, as estimated for individuals under prednisone
alone and under LMT, were evaluated using Mann–Whitney U
non-parametrical test. The significance of difference referred to
the mean prednisone dose required until the ECP, and the mean
prednisone dose required to reach CR on, CR off, PR on and PR
off therapy for both groups were evaluated using t-test for inde-
pendent samples. Kolmogorov-Smirnoff test (P value < 0.05) was
applied for the normality distribution of all variables and the
Levene’s Test for Equality of Variances.
All data were analysed with SPSS version 17.0 (Statistics Package
for the Social Sciences, SPSS Inc, Chicago, IL, USA).
Results
Monotherapy group consisted of 10 women (58.8%) and seven
men (41.2%), while LMT group consisted of 10 women (52.6%)
and nine men (47.4%). Mean age was 53.88 (± SD 12.786, range:
27–72.7) and 54.42 (± SD 12.607, range: 24–73.9) years respec-
tively. Disease duration in months, and PAAS score for oral lesions
at baseline, were 4.35 (± SD 2.523, CI 95%, range: 3.06–5.65) and
2.12 (± SD 0.697, CI 95%, range: 1.76–2.48) for the monotherapy
group and 4.16 (± SD 2.522, CI 95%, range: 2.94–5.37) and 2.21
(± SD 0.713, CI 95%, range: 1.87–2.55) for the patients under
LMT.
Disease activity in five patients, one (6%) treated with predni-
sone exclusively and four (21%) treated with LMT, could not be
controlled. These individuals required different therapeutic
schemes, including the combination of high dose (at least
1 mg ⁄ kg ⁄ day) oral prednisone plus cyclophosphamide or azathio-
prine, or steroid pulses, and they were recorded as treatment
failures; As discussed elsewhere, initial treatment with LMT had
no negative impact on the final outcome of patients who
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208 Chaidemenos et al.

subsequently required other, more aggressive management.4 The
mean time until the control of disease activity in days was 19.20
and 58.53, for the monotherapy and the LMT group, accordingly.
Statistically significant difference between these values was
recorded (P = 0.000 < 0.05). With respect to the mean predni-
sone dose required until the ECP, statistically significant difference
was also observed. Analytically, the mean dose of prednisone was
1911.33 mg for the first, and 1170.67 mg for the second group
respectively. The flowchart illustrated in Fig. 1 signifies patients’
disposition in the study and highlights important time points.
Overall 30 patients, 15 under monotherapy (88.2%) and 15
under LMT (78.9%), achieved CR or PR, on or off minimal ther-
apy, and were considered as ‘responders’. The mean time to remis-
sion on or off minimal therapy was 119.67 days for the former
and 234.47 days for the latter group [t (16.380) = )8.064,
P = 0.000 < 0.05]. Reversely, the mean dose of prednisone
required to achieve remission on, or off minimal therapy was sig-
nificantly higher in monotherapy (4419.20) compared with LMT
(2616.33) group [t (28) = 8.883, P = 0.000 < 0.05]. Among the
‘responders’ of the first group, nine of 15 (60%) reached CR on,
and one of 15 (6.7%) reached CR off minimal therapy, while three
(20%) and two (13.3%) subjects achieved PR on, and PR off ther-
apy respectively. With respect to LMT, seven (46.7%), two
(13.3%), four (26.7%) and two (13.3%) of 15 individuals,
achieved CR on, CR off, PR on and PR off minimal therapy,
accordingly. Measurements regarding main studied parameters
and their statistics are summarized in Table 1. Clinical response of
pemphigus per group of patients 24 months after treatment initia-
tion, as well as treatment failure rate, is quoted in Table 2.
With respect to the days of hospitalization, the mean duration
among patients under daily prednisone was significantly longer,
comparatively to subjects under LMT (P = 0.000 < 0.05). Pro-
longed hospital admission among individuals under monotherapy
conforms to the development of higher rates of treatment-associ-
ated side-effects in the same group, as reported in Table 3.
According to our records, the number of adverse events among
individuals under daily prednisone with impaired physical status
was higher and more severe than in those of the LMT group
(Table 4).

Discussion
Steroid-associated side-effects during the course of PV remain a
major concern for physicians and patients. Different treatment
protocols in PV aim to succeed high rates of remission, minimiz-
ing adverse events.11,12
According to our results, both treatments resulted in high rates
of clinical response [monotherapy: 15 ⁄ 17 (88.2%) vs. LMT: 15 ⁄ 19
(78.9%)], while the mean time to induction of this remission was
shorter in the monotherapy group. However, the significantly
higher mean prednisone dose administrated to the latter group is
directly correlated with an increased rate of treatment-associated
adverse events. It is of particular interest that in patients under
prednisone, side-effects were more frequently recorded among
Figure 1 Patients’ disposition in the study and important time
points and outcomes.
older individuals with positive medical history for diabetes mell-
itus and ⁄ or cardiovascular disorders, while in patients under LMT

Table 1 Main studied parameters and statistical analysis (P-values)

Mean time to Mean dose Mean time to Mean dose Mean days of
control of DA to ECP remission† to remission† hospitalization
Monotherapy group 19.20 days 1911.33 mg 119.67 days 4419.20 mg 17.13
LMT group 58.53 days 1170.67 mg 234.47 days 2616.33 mg 3.00
P-values 0.000 < 0.05 0.000 < 0.05 0.000 < 0.05 0.000 < 0.05 0.000 < 0.05
†It refers to CR and PR, on or off minimal therapy.
DA, disease activity; ECP, end of consolidation phase; CR, complete remission; PR, partial remission; LMT, Lever’s mini treatment.

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Daily prednisone vs. LMT in oral pemphigus 209

Table 2 Clinical response of pemphigus per group of patients concept, the lack of randomization and the open label follow-up,
24 months after treatment initiation as well as possible bias as a result of the selection process and the
Clinical variable Monotherapy LMT group participation of different examiners.
group (n = 17) (%
%) (n = 19) (%
%) Even though there is a lack of therapeutic clinical trials dealing
Patients failing treatment (TF) 1 (6) 4 (21) with exclusively oral cases of PV, our observations are in agree-
Patients with severe side-effects 3 (18) 1 (5) ment with those of previous studies evaluating safety and efficacy
Flares 2 (12) 6 (32) of LMT. Indeed, Benoit Corven et al. reported complete clinical
12 months response in 18 of 22 (82%) patients, with a mean delay of
PR on 3 (18) 4 (21) 4.3 months, until complete healing of oral lesions. Furthermore,
PR off 2 (12) 2 (11)
treatment failure was recorded in four patients, which is in accor-
CR on 9 (53) 7 (37)
dance with the failure rate observed in our patients under LMT.
CR off 1 (6) 2 (11)
In addition, more severe adverse events occurred in low-weight
CR, complete remission; PR, partial remission; LMT, Lever’s mini patients, in whom the regimen dose related to weight was rated as
treatment.
among the highest. Previous experience with a 13-year prospective
study evaluating LMT in early-stage PV, also suggests that LMT is
Table 3 Side-effects per group of patients of significant benefit, resulting in disease control in 57 of 74
(77%) individuals. Besides the favourable clinical outcome, this
Monotherapy Combination
group (n = 17) (%
%) group (n = 19) (%
%) treatment modality required no hospital admissions and mini-
Weight gain 13 (76) 6 (32) mized adverse events, while offering patients a high quality of life.4
Psychological effects, 5 (29) 2 (11) Our current data suggest that patients’ physical profile, includ-
including sleep ing concomitant diseases and medication, as well as certain demo-
disturbance
graphic characteristics (especially age and bodyweight) at baseline,
Redistribution of body fat 10 (59) 5 (26)
should be taken into consideration before deciding about the final
Muscle weakness 4 (24) 4 (21)
therapeutic scheme. In terms of early disease control and rapid dis-
Deregulation of 12 (71) 7 (37)
Glu serum levels ease regression, monotherapy turned out to be superior to LMT.
Liver enzymes’ elevation 2 (12) 7 (37) Thus, in cases of rapidly progressive lesions, in the absence of
Haematologic toxicity 1 (6) 5 (26) severe concomitant diseases, high dose prednisone treatment seems
GI disturbance 4 (24) 3 (16) a reasonable choice. On the other hand, in patients with impaired
Hypertension 7 (41) 3 (16) physical status and non-extensive and ⁄ or relatively stable lesions at
Hair loss 0 (0) 2 (11) baseline, LMT could represent a rather safe and effective therapeu-
Eye disease 6 (35) 2 (11) tic option. Furthermore, given that the management of the disease
Arrhythmias 4 (24) 0 (0) must take into account its impact on various aspects of patients’
Internal infection 2 (12) 1 (5) life, including physical, emotional and functional involvement,
Death 1 (6) 0 (0) patient’s will and expectation should be considered before deciding
about the optimal therapeutic protocol. In view of these clinical
Table 4 Number of adverse events in patients with impaired considerations, individualization of treatment would be advisable.
and normal physical status per treatment group

> 4 AE (%) 2–3 AE (%) < 2 AE (%) Acknowledgements

Monotherapy: 17 7 ⁄ 17 (41) 8 ⁄ 17 (47) 2 ⁄ 17 (12) We thank Agorasti Toka, Dipl. Mechanical Engineer, Phd
IPS 10 ⁄ 17 (59%) 6 ⁄ 7 (86) 4 ⁄ 8 (50) 0 ⁄ 2 (0) Candidate to the Industrial Management Division of the
NPS 7 ⁄ 17 (41%) 1 ⁄ 7 (14) 4 ⁄ 8 (50) 2 ⁄ 2 (100) Aristotle University of Thessaloniki, who contributed to the
LMT: 19 4 ⁄ 19 (21) 6 ⁄ 19 (32) 9 ⁄ 19 (47) study design and provided excellent assistance on the field of
IPS 12 ⁄ 19 (63%) 3 ⁄ 4 (75) 4 ⁄ 6 (67) 5 ⁄ 9 (56) statistics.
NPS 7 ⁄ 19 (37%) 1 ⁄ 4 (25) 2 ⁄ 6 (33) 4 ⁄ 9 (44)
IPS, number of patients with impaired physical status at baseline; References
NPS, number of patients with normal physical status at baseline; AE, 1 Chrysomallis F, Ioannides D, Teknetzis A et al. Treatment of oral
adverse events; LMT, Lever’s mini treatment. pemphigus vulgaris. Int J Dermatol 1994; 33: 803–807.
2 Scully C, Paes de Almeida O, Porter SR, Gilkes JJH. Pemphigus vulga-
ris: the manifestations and long-term management of 55 patients with
side-effects were more frequent among individuals with low body- oral lesions. Br J Dermatol 1999; 140: 84–89.
weight. 3 Leshem Y, Pavlovsky L, Mimouni F, David M, Mimouni D. Trends in
pemphigus research over 15 years. J Eur Acad Dermatol Venereol 2010;
However, there are some limitations concerning the study
24: 173–177.
design that should be stated. These include the retrospective

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210
4 Chaidemenos GC, Mourellou O, Koussidou T, Tsatsou F. An alternate-
day corticosteroid regimen for pemphigus vulgaris. A 13-year prospec-
tive study. J Eur Acad Dermatol Venereol 2007; 21: 1386–1391.
5 Benoit Corven C, Carvalho P, Prost C et al. [Treatment of pemphigus
vulgaris by azathioprine and low doses of prednisone (Lever scheme)].
Ann Dermatol Venereol 2003; 130: 13–15.
6 Lever WF, Schaumburg-Lever G. Immunosuppressants and prednisone
in pemphigus vulgaris: therapeutic results obtained in 63 patients
between 1961 and 1975. Arch Dermatol 1977; 113: 1236–1241.
7 Lever WF, Schaumburg-Lever G. Treatment of pemphigus vulgaris.
Results obtained in 84 patients between 1961 and 1982. Arch Dermatol
1984; 120: 44–47.
JEADV 2011, 25, 206–210 Journal of the European Academy of Dermatology and Venereology ª 2010 European Academy of Dermatology and Venereology
Chaidemenos et al.
8 Mourellou O, Chaidemenos GC, Koussidou TH, Kapetis E. The treat-
ment of pemphigus vulgaris. Experience with 48 patients seen over an
11-year period. Br J Dermatol 1995; 133: 83–87.
9 Murrell DF, Dick S, Ahmed AR et al. Consensus statement on defini-
tions of disease, end points, and therapeutic response for pemphigus.
J Am Acad Dermatol 2008; 58: 1043–1046.
10 Agarwal M, Walia R, Kochhar AM, Chander R. Pemphigus area and
activity score (PAAS) – a novel clinical scoring method for monitoring
of pemphigus vulgaris patients. Int J Dermatol 1998; 37: 158–160.
11 Ioannides D, Lazaridou E, Rigopoulos D. Pemphigus. J Eur Acad
Dermatol Venereol 2008; 22: 1478–1496.
12 Bystryn JC, Rudolph JL. Pemphigus. Lancet 2005; 366: 61–73.
ª 2010 The Authors