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A Comparison of Oral and Topical Corticosteroids
in Patients with Bullous Pemphigoid
Pascal Joly, M.D., Ph.D., Jean-Claude
Roujeau, M.D., Jacques Benichou, M.D., Ph.D., Catherine Picard, M.D., Brigitte
Dreno, M.D., Ph.D., Emmanuel Delaporte, M.D., Ph.D., Loïc Vaillant, M.D.,
Ph.D., Michel D'Incan, M.D., Ph.D., Patrice Plantin, M.D., Christophe Bedane,
M.D., Ph.D., Paul Young, M.D., Philippe Bernard, M.D., Ph.D., for the Bullous
Diseases French Study GroupABSTRACT
Background Bullous
pemphigoid is the most common autoimmune blistering skin disease of
the elderly. Because elderly people have low tolerance for standard
regimens of oral corticosteroids, we studied whether highly potent
topical corticosteroids could decrease mortality while controlling
disease.
Methods A total of
341 patients with bullous pemphigoid were enrolled in a randomized,
multicenter trial and stratified according to the severity of their
disease (moderate or extensive). Patients were randomly assigned to
receive either topical clobetasol propionate cream (40 g per day) or
oral prednisone (0.5 mg per kilogram of body weight per day for
those with moderate disease and 1 mg per kilogram per day for those
with extensive disease). The primary end point was overall survival.
Results Among the
188 patients with extensive bullous pemphigoid, topical
corticosteroids were superior to oral prednisone (P=0.02). The
one-year survival rate was 76 percent in the topical-corticosteroid group
and 58 percent in the oral-prednisone group. Disease was controlled
at three weeks in 92 of the 93 patients in the topical-corticosteroid group
(99 percent) and 86 of the 95 patients in the oral-prednisone group
(91 percent, P=0.02). Severe complications occurred in 27 of the 93
patients in the topical-corticosteroid group (29 percent) and in 51
of the 95 patients in the oral-prednisone group (54 percent,
P=0.006). Among the 153 patients with moderate bullous pemphigoid,
there were no significant differences between the
topical-corticosteroid group and the oral-prednisone group in terms
of overall survival, the rate of control at three weeks, or the
incidence of severe complications.
Conclusions Topical
corticosteroid therapy is effective for both moderate and severe
bullous pemphigoid and is superior to oral corticosteroid therapy
for extensive disease.
Bullous pemphigoid is the most common
blistering autoimmune disease of the skin1,2; it
is manifested by cutaneous blisters without mucosal involvement.3
Histologic features include subepidermal blisters.4
Autoantibodies directed against two proteins of the basement-membrane
zone, bullous pemphigoid antigens 1 and 2, are detectable by both
direct and indirect immunofluorescence.5,6,7,8,9,10
Bullous pemphigoid is most common in elderly persons.11,12,13,14
Systemic corticosteroids are considered the standard treatment for
bullous pemphigoid.3,15 A
dose of prednisone of 1 mg per kilogram of body weight per day is
usually recommended for the treatment of patients with severe
disease; a lower dose may be used for patients with moderate
disease.15
Systemic corticosteroids are poorly tolerated by elderly patients,
however, and have been suspected of contributing to the high rates
of death observed in some series.11,12,16,17,18
Many efforts have been devoted to finding corticosteroid-sparing
agents for the treatment of bullous pemphigoid. Uncontrolled studies
have suggested the usefulness of immunosuppressive drugs.19,20,21,22,23,24,25,26
Unfortunately, the single controlled study published to date failed
to demonstrate a benefit from the addition of azathioprine to corticosteroid
therapy.27
Topical corticosteroids have been proposed as possible treatments
for mild forms of bullous pemphigoid.28,29,30
Because complications attributable to oral corticosteroids may contribute
to the poor prognosis of patients with bullous pemphigoid, we
conducted a randomized trial comparing topical corticosteroid treatment
with oral corticosteroid treatment in patients with bullous
pemphigoid. The aim of the present study was to assess whether
topical corticosteroids could substantially increase the rate of
survival among patients with bullous pemphigoid and whether they
could effectively control the disease.
Methods
Study Patients
Twenty dermatologic centers in France participated in this
prospective, randomized study. The study was approved by the ethics
committee of Seine Maritime, and written informed consent was
obtained from each patient.
Consecutive patients with newly diagnosed bullous pemphigoid were
eligible for entry if the following criteria were met: clinical
features suggestive of bullous pemphigoid14;
subepidermal blister on skin biopsy; and linear deposits of IgG and
C3 along the basement-membrane zone. Exclusion criteria were
predominant or exclusive mucosal involvement and treatment with oral
or topical corticosteroids, dapsone, or immunosuppressive drugs
during the previous six months.
Study Design
This randomized, nonblinded study compared two parallel groups
of patients treated with topical or oral corticosteroids. Since overall
survival was the primary outcome, blinding was not deemed necessary.
Randomization was stratified according to the clinical center and
the severity of disease, which was determined on the basis of the
mean number of new bullae that had appeared daily during the three
previous days (moderate disease was defined by 10 new bullae daily and extensive disease by >10). Randomization
was performed centrally with the use of random numbers in permuted blocks
of four within each stratum. Patients were randomly assigned to
receive either topical applications of 0.05 percent clobetasol propionate
cream (Dermoval cream, Glaxo SmithKline, Philadelphia), or oral
prednisone (Cortancyl, Roussel, Paris). Prednisone was administered
once daily at a dose of 0.5 mg per kilogram of body weight per day
in patients with moderate disease and a dose of 1 mg per kilogram
per day in those with extensive disease. The initial dose was
maintained for 15 days after control of the disease had been
attained; thereafter, the dose was reduced by 15 percent every 3
weeks. Treatment was stopped after 12 months.
Irrespective of the severity of their disease, patients who were
assigned to receive topical corticosteroids received a daily dose of
40 g of clobetasol propionate that was applied twice daily on the
entire surface of the body until 15 days after control of the
disease had been attained. The doses were then gradually reduced —
to 20 g daily for one month, 10 g daily for two months, 10 g every
other day for four months, and finally 10 g twice a week for four
months. When possible, topical corticosteroids were applied by the
patients themselves or by members of their households. A nurse
performed this task for patients who were in poor condition
generally.
Relapse was defined as the occurrence of at least three new bullae
daily for three consecutive days during treatment. In patients who
had a relapse during the period when the dose was being reduced, the
dose was increased to the previous level that had permitted control
of the disease. Other therapy that might affect the activity of
bullous pemphigoid was avoided throughout the study period.
Investigators stopped treatment if a life-threatening side effect
occurred, irrespective of the patient's treatment group.
Base-Line and Follow-up Measurements
At base line, each patient underwent physical examination. The
Karnofsky score was assessed. The score is a measure of the patient's
general condition and degree of autonomy on a scale ranging from 0
to 100, with higher scores indicating better condition and greater
autonomy.31
The number of new bullae that appeared daily was noted by a nurse
who was not otherwise involved in the study. Because of the high
mortality reported in recent studies during the first year after the
diagnosis of bullous pemphigoid, we planned 12 months of follow-up.
At each follow-up visit (on days 7, 14, 21, 30, 90, 180, and 360),
the patients underwent physical examination, and the number of new
bullae that appeared daily was noted, as was the number of units of
clobetasol propionate cream that had been used. The date of any
relapse was recorded, as were the date and cause of death in any
patient who had died. Any side effects of treatment were assessed,
and their severity was graded 1 for mild effects, 2 for moderate
effects, 3 for severe effects, or 4 for life-threatening effects,
according to standard criteria of the World Health Organization.32
Statistical Analysis
The primary end point was overall survival during the first year
after the onset of bullous pemphigoid. Secondary end points were
control of the disease at day 21, defined as the absence of new
bullae for three consecutive days; occurrence of severe (grade 3 or
4) side effects (adverse events requiring hospitalization or
prolongation of hospitalization or life-threatening events) during
the first year; and cumulative hospital days (including the initial
hospitalization plus all rehospitalizations).
The study was designed to have 80 percent power to detect a 50
percent reduction in the one-year mortality rate for both moderate
and extensive bullous pemphigoid, from 40 to 20 percent, with the
two-sided log-rank test and a type I error of 5 percent. To achieve
this power, 75 patients were needed in each treatment group.
Separate intention-to-treat analyses were performed for patients
with moderate and severe bullous pemphigoid. No interim efficacy
analysis was either scheduled or performed.
Distributions of overall survival according to treatment group
were estimated by the Kaplan–Meier method and compared with
the use of the log-rank test. A Cox model was used to adjust the
comparisons between treatment groups for base-line characteristics that
were suspected a priori to have prognostic significance — namely,
older age (80 years vs. <80 years)
and poor general condition as measured by the Karnofsky score (40 vs. >40).11
Fisher's exact test was used to compare the treatment groups in
terms of the proportions of patients with controlled bullous
pemphigoid at day 21, as well as the frequency of severe side
effects. Exact binomial probabilities were used to estimate 95
percent confidence intervals for the rates of control of disease.
Student's t-test was used to compare the mean durations of
hospitalization. For all tests, two-sided P values of less than 0.05
were considered to indicate statistical significance. Continuous
variables are expressed as means ±SD.
Results
Patients
Between January 1996 and December 1998, 364 patients were assessed
for eligibility. Eight declined to provide informed consent. Previous
use of medication effective against bullous pemphigoid (in eight
patients), diagnosis of another autoimmune blistering-skin disease
(in four patients), spontaneous healing of skin lesions (in two
patients), and immediate withdrawal of consent (in one patient) were
other reasons for exclusion. Of the 341 remaining patients, 153 had
10 or fewer new bullae daily (moderate disease) and 188 had more
than 10 new bullae daily (extensive disease). A total of 77 patients
with moderate disease were randomly assigned to receive clobetasol
propionate cream and 76 to receive oral prednisone at a dose of 0.5
mg per kilogram per day. A total of 93 patients with extensive
disease were randomly assigned to receive clobetasol propionate
cream and 95 to receive oral prednisone at a dose of 1 mg per
kilogram per day. The base-line characteristics of the patients are
shown in Table 1.
Among both patients with moderate bullous pemphigoid and patients
with extensive bullous pemphigoid, the treatment groups were well
balanced in terms of the base-line characteristics. The mean
duration of follow-up among surviving patients with severe bullous
pemphigoid was 360 days in the oral-prednisone group and 359 days in
the topical-corticosteroid group. The corresponding figures among
surviving patients with moderate bullous pemphigoid were 361 and 360
days, respectively. One patient with moderate bullous pemphigoid who
was randomly assigned to the topical-corticosteroid group decided to
stop treatment during the third month of the study.
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Overall Survival
A total of 107 patients died during the one-year follow-up; 46
of these had moderate bullous pemphigoid, and 61 had extensive bullous
pemphigoid. The causes of death were determined in 71 cases; the
main causes were sepsis (in 27 patients, including 20 with
pneumonia), cardiovascular disease (in 13 patients), and stroke (in
9 patients).
Among the patients with moderate bullous pemphigoid, 23 patients
in the topical-corticosteroid group died (30 percent), and 23 in
the oral-prednisone group died (30 percent). The log-rank test did
not indicate any difference in overall survival between the two
treatment groups (P=0.95). The one-year Kaplan–Meier survival rate
was 69 percent in both groups (Figure 1A).
Similarly, no difference was evident in the Cox regression model
that included age and Karnofsky score (P=0.69).
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Among the patients with extensive bullous pemphigoid, 22 patients in
the topical-corticosteroid group died (24 percent), and 39 patients
in the oral-prednisone group died (41 percent). Overall survival was
significantly longer with topical corticosteroids than with oral
prednisone (P=0.02). One-year Kaplan–Meier survival rates were 76
percent and 58 percent, respectively (Figure 1B). With
the use of the Cox regression model, this beneficial effect of
clobetasol propionate was confirmed after adjustment for age and
Karnofsky score (P=0.009).
Disease Control and Relapse
In all 77 patients with moderate bullous pemphigoid who were assigned
to the topical-corticosteroid group (100 percent; 95 percent
confidence interval, 95 to 100 percent) and 72 of the 76 patients
with moderate bullous pemphigoid who were assigned to the
oral-prednisone group (95 percent; 95 percent confidence interval,
87 to 99 percent), control of bullous pemphigoid was achieved by day
21 (P=0.06). Control was achieved by day 21 in 92 of the 93 patients
with extensive bullous pemphigoid in the topical-corticosteroid
group (99 percent; 95 percent confidence interval, 94 to 100
percent) and in 86 of the 95 patients with extensive bullous
pemphigoid in the oral-prednisone group (91 percent; 95 percent
confidence interval, 83 to 96 percent; P=0.02).
A total of 30 of the 76 patients with moderate disease in the
oral-prednisone group (39 percent; 95 percent confidence interval, 28
to 50 percent) and 27 of the 77 patients in the topical-corticosteroid group
(35 percent; 95 percent confidence interval, 24 to 46 percent) had
relapses during follow-up after a mean interval of 149±109 days and
178±118 days, respectively. The corresponding figures among the
patients with extensive disease were 44 of the 95 patients in the
oral-prednisone group (46 percent; 95 percent confidence interval,
36 to 56 percent) after a mean interval of 210±133 days and 34 of
the 93 patients in the topical-corticosteroid group (37 percent; 95
percent confidence interval, 27 to 46 percent) after a mean interval
of 187±118 days.
Compliance with Treatment and Adverse
Effects
In accordance with the study protocol, the investigators switched
three patients with moderate bullous pemphigoid and four with extensive
bullous pemphigoid from the oral-prednisone group to the
topical-corticosteroid group because of side effects of treatment. The
life-threatening side effects in these patients were septicemia (in
two patients), severe pneumonia with respiratory distress (in two
patients), postoperative sepsis after hip fracture (in one patient),
necrotizing cellulitis of the leg (in one patient), and myocardial
infarction with acute cardiac failure (in one patient). Two of these
seven patients died during the study period. There were no
life-threatening side effects in patients assigned to the
topical-corticosteroid group. One patient with severe bullous
pemphigoid who was initially assigned to the topical-corticosteroid
group was later treated with oral prednisone, at a dose of 1 mg per
kilogram per day, by a physician who was not aware of the protocol;
this patient died of pneumonia 15 days after the treatment was
changed.
Overall, 172 severe (grade 3) or life-threatening (grade 4) side
effects were reported in 132 patients (Table 2). Severe
side effects were reported in 29 of the 76 patients with moderate disease
in the oral-prednisone group (38 percent), as compared with 25 of
the 77 patients with moderate disease in the topical-corticosteroid group
(32 percent, P=0.46). Severe side effects were observed in 51 of the
95 patients with extensive disease in the oral-prednisone group (54
percent), as compared with 27 of the 93 patients with extensive
disease in the topical corticosteroid group (29 percent, P=0.006).
Among the 10 patients with extensive bullous pemphigoid in whom
disease was not controlled by day 21, severe adverse events occurred
in 5 of the 9 patients in the oral-prednisone group, and 3 of the 9
patients in that group died, whereas neither a severe adverse event
nor death occurred in the 1 patient in the topical-corticosteroid
group.
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Duration of Hospitalization
Most patients were initially hospitalized during the acute phase
of their disease. Some patients were rehospitalized during the follow-up
period because of relapse or side effects. The length of hospital
stay according to treatment group is shown in Table 3. The
mean cumulative duration of hospitalization was shorter in the
topical-corticosteroid group than in the oral-prednisone group:
11±11 days and 17±14 days, respectively, among patients with
moderate bullous pemphigoid (P=0.02) and 17±14 days and 25±20 days,
respectively, among those with extensive bullous pemphigoid
(P=0.002).
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Discussion
Systemic corticosteroids have been considered the mainstay of
treatment for bullous pemphigoid for 40 years.3
However, this treatment is responsible for numerous side effects in
elderly people and has been suspected of being associated with a
mortality rate of up to 40 percent per year among elderly persons
with bullous pemphigoid.11,12,16,17,18,33,34
The present study confirms the poor prognosis of patients with
bullous pemphigoid who are treated with 1 mg of prednisone per
kilogram per day, among whom the one-year mortality rate was 41
percent. Among the patients who received topical treatment, there
was no difference in overall survival between patients with moderate
bullous pemphigoid and those with extensive bullous pemphigoid,
suggesting that survival of patients with bullous pemphigoid is more
likely to be related to the type of treatment than to the severity
of disease.11,27
The present study was designed to test the hypothesis that topical
corticosteroids could be an effective alternative treatment for
patients with bullous pemphigoid and would result in a decrease in
the incidence of severe adverse events. Our results clearly demonstrate
the efficacy of clobetasol propionate cream. In all patients with
moderate bullous pemphigoid and 99 percent of those with extensive
bullous pemphigoid, the disease was controlled by day 21 — an
improvement over oral-corticosteroid treatment that was significant
among those with extensive disease. Moreover, the rates of control
of disease in both subgroups of the oral-prednisone group were
higher than those usually reported with oral corticosteroids.27,35
This finding may be related to the high bioavailability of
prednisone and seems consistent with the greater effectiveness
reported for prednisone than for prednisolone in controlling bullous
pemphigoid.35
The main finding of this study is the significant and substantial
improvement in outcome among patients with extensive bullous pemphigoid
who were treated with clobetasol propionate cream, as compared with
those treated with 1 mg per kilogram per day of oral prednisone.
This difference was observed consistently for all the outcomes we
studied: overall survival, control of disease, occurrence of severe
side effects, and duration of hospitalization.
It is important to consider whether the nonblinded nature of the
study may have biased our results. We think such bias is unlikely,
for several reasons. First, it is unlikely that overall survival,
our primary end point, could be subject to such bias. Moreover, bias
concerning secondary end points is unlikely as well, because most
were graded semiquantitatively and were not directly dependent on
subjective judgment. Indeed, assessment of the control of disease
was based on the determination of the number of new bullae that
appeared daily by nurses who were not directly involved in the
study, and most grade 3 and grade 4 side effects represented
well-known side effects of corticosteroids that were characterized
biologically (diabetes mellitus), radiologically (stroke, pneumonia,
and bone fracture), or bacteriologically (septicemia, arthritis, and
peritonitis). Differences in the cumulative duration of
hospitalization were due, at least in part, to rehospitalizations
initiated by the patients' general practitioners — not by study
investigators — because of side effects of the treatments.
Our study demonstrates the superiority of an alternative treatment
regimen over oral corticosteroids in the treatment of extensive bullous
pemphigoid, in terms of both the control of disease and survival. In
patients with extensive bullous pemphigoid, topical corticosteroids
led to a 43 percent reduction (95 percent confidence interval, 19 to
69 percent) in the one-year mortality rate. This benefit is further
supported by the demonstration of a 50 percent reduction in the
mortality rate (95 percent confidence interval, 15 to 71 percent)
after adjustment by Cox regression for age and Karnofsky score — two
factors strongly suspected to be related to the prognosis in
patients with bullous pemphigoid.11
The chief explanation for the present results is the fact that
topical treatment has lower toxicity than 1 mg of prednisone per
kilogram per day, as demonstrated by the fact that fewer patients in
the topical-corticosteroid group had severe side effects of
treatment. This difference was particularly marked in the case of
side effects, such as sepsis and diabetes mellitus requiring
insulin, that are classically reported with high-dose systemic
corticosteroids. Our results suggest that topical corticosteroids
should be considered the standard treatment for patients with
extensive bullous pemphigoid.
Supported by
research grants from Rouen University Hospital and the French
Society of Dermatology.
We are indebted to the patients who participated in the study;
to Veronique Chambaretaud for technical assistance during the study;
and to Annick Horville and Richard Medeiros for their assistance in
the preparation of the manuscript.
* Other participants in the Bullous
Diseases French Study Group are listed in the Appendix.
Source Information
From the Departments of Dermatology and Biostatistics, INSERM
Unite 519, University of Rouen, Rouen (P.J., J.B., P.Y.); and the Departments
of Dermatology at the University of Paris XII, Creteil (J.-C.R.); Bichat
University, Paris (C.P.); the University of Nantes, Nantes (B.D.); the
University of Lille, Lille (E.D.); the University of Tours, Tours (L.V.); the
University of Clermont-Ferrand, Clermont-Ferrand (M.D.); the General Hospital
of Quimper, Quimper (P.P.); the University of Limoges, Limoges (C.B.); and the
University of Reims, Reims (P.B.) — all in France.
Address reprint requests to Dr. Joly at the Clinique
Dermatologique, Hôpital Charles Nicolle, 1, rue de Germont, 76031 Rouen CEDEX,
France, or at [log in to unmask].
References
Appendix
The following persons also participated in the Bullous Diseases
French Study. Investigators:
P. Saiag, M.D., Ph.D., Boulogne Billancourt; E. Tancrede-Bohin,
M.D., Paris; B. Sassolas, M.D., Brest; C. Lok, M.D., Ph.D., Amiens;
B. Labeille, M.D., Valence; J.C. Guillaume, M.D., Colmar; F. Loche,
M.D., Toulouse; M.S. Doutre, M.D., Ph.D., Bordeaux; I. Gorin, M.D.,
Paris; O. Chosidow, M.D., Ph.D., Paris; C. Pauwels, M.D., Saint
Germain en Laye. Contributors:
C. Neveu, M.D., Lillebonne; M.F. Hellot, M.Sc., Rouen; I. Noblesse,
M.D., Rouen.
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