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A Systematic Review of Treatments for Bullous Pemphigoid
Nonhlanhla P. Khumalo, MD;
Dedeé F. Murrell, MD;
Fenella Wojnarowska, MD;
Gudula Kirtschig, MD
Arch Dermatol. 2002;138:385-389.
ABSTRACT
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Objective To assess the effectiveness of treatments for bullous pemphigoid.
Methods The Cochrane Library search strategy was used to identify randomized
controlled trials from MEDLINE and EMBASE, from their inception to September
30, 2001. All randomized controlled trials on interventions for bullous pemphigoid,
confirmed by immunofluorescence studies, were included.
Results We found 6 randomized controlled trials with a total of 293 patients.
Two trials, one comparing prednisolone, 0.75 mg/kg per day, with prednisolone,
1.25 mg/kg per day, and the other comparing methylprednisolone with prednisolone,
did not find any significant difference in effectiveness. The higher dose
of prednisolone, however, was associated with more severe adverse effects.
Combination treatments of prednisone with azathioprine in one trial and of
prednisolone with plasma exchange in another were useful in halving the corticosteroid
dose required (mean ± SD, 0.52 ± 0.28 mg/kg in the plasma exchange–treated
group vs 0.97 ± 0.33 mg/kg in the prednisolone only–treated group).
However, a fifth trial, including all 3 treatment groups (prednisolone alone,
prednisolone and azathioprine, and prednisolone and plasma exchange), failed
to confirm the benefit of combination treatment over prednisolone alone. A
trial of 20 patients, comparing prednisone with tetracycline and niacinamide,
found no statistically significant difference in response between the 2 groups,
but the prednisone-treated group had more serious adverse effects.
Conclusions There is inadequate evidence for a recommendation of a specific treatment
for bullous pemphigoid, and there is a need for larger randomized controlled
trials with adequate power. Starting doses of prednisolone greater than 0.75
mg/kg per day do not seem to give additional benefit, and it seems that lower
doses may be adequate for disease control. The effectiveness of the addition
of plasma exchange or azathioprine to corticosteroids has not been established.
Combination treatment with tetracycline and niacinamide seems useful, although
this needs further validation.
INTRODUCTION
BULLOUS PEMPHIGOID is the most common autoimmune blistering disease
in the West. It is usually a disease of elderly persons, but it can also affect
younger adults and children. The incidence is the same in both sexes.1 The characteristic clinical picture is the development
of tense blisters, which may arise on inflamed or normal-appearing skin. Immunofluorescence
(IF) is the most reliable investigation for making the diagnosis: direct IF
demonstrates deposits of the autoantibodies at the dermoepidermal junction,
and indirect IF demonstrates circulating autoantibodies directed against basement
membrane proteins that are localized to the epidermal side of the salt-split
skin.2 The natural history of treated and untreated
bullous pemphigoid shows a long-term course within which relapses and exacerbations
may occur. However, in most patients, the disease is in remission within 5
years.1, 3-4
Treatments include corticosteroids, antibiotics, and immunosuppressants.
Some of these interventions have the potential for severe adverse effects,
such as increased susceptibility to serious infections and organ damage, and
some are expensive to use. There is also variation in the long-term toxic
effect of systemic agents, ranging from mild (antibiotics) to severe (corticosteroids
or immunosuppressants). There is wide variation in practice among clinicians
as to which drugs or interventions are used and in what order or combinations.
This review aimed to establish the following: (1) the most effective drugs
or interventions with the least adverse effects; (2) whether combination therapy
(eg, azathioprine plus corticosteroids) offers any advantages over single
drugs (eg, oral corticosteroids alone); and (3) whether antimicrobials, such
as tetracyclines, erythromycin, dapsone, or sulfonamides, are useful.
MATERIALS AND METHODS
The Cochrane Library extended search strategy was used to identify randomized
controlled trials (RCTs) from MEDLINE and EMBASE, from their inception to
January 30, 2000, and again to September 30, 2001. The Cochrane Controlled
Trials Register and hand-searched trials awaiting incorporation into the Cochrane
Controlled Trials Register were also examined.
Abstracts of potentially relevant studies were screened, and full articles
were obtained if necessary. Articles that were possible RCTs were assessed
for eligibility using the inclusion criteria outlined in the protocol.5 Each study was individually and critically appraised
using a checklist to assess methodological quality (such as concealment allocation,
blinded outcome assessment, and inclusion of all randomized patients in the
analysis). The bibliographies from identified studies were also searched.
All RCTs of therapeutic interventions that included patients with bullous
pemphigoid confirmed by IF studies and all age groups were included.
Data were extracted from all included studies using a predefined data
extraction form for the following outcome measures: (1) rate of regression
or healing of the skin lesions when first treated and how soon new blisters
stopped appearing; (2) effect on the quality of life (ie, relief of soreness
or pruritus); (3) duration of remission after stopping treatment; (4) complications
of the primary disease (bullous pemphigoid) (eg, a localized skin infection);
(5) systemic infection, which may be a result of either the primary disease
or the treatment; (6) adverse effects of treatment (eg, organ failure or allergic
reactions); and (7) mortality as a result of the primary disease or treatment.
RESULTS
We identified 72 abstracts from MEDLINE, 27 from EMBASE, and 5 from
the Cochrane Controlled Trials Register (Table 1); of these, only 6 were RCTs, with a total of 293 patients.
These RCTs were all small trials; none used indirect IF on salt-split skin
to make the diagnosis or had a placebo group, and oral corticosteroids were
considered standard treatment. The first 2 outcome measures in our protocol
were only addressed by one trial each, and none of the trials addressed the
third (Table 2). The adverse effects
of medication were recorded in varying detail in the different trials (Table 3).
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Table 1. Retrieved Trials of Treatment of Bullous Pemphigoid by Database*
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Table 2. Characteristics of Included Trials for Treatments of Bullous
Pemphigoid
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Table 3. Adverse Effects in the Included Studies
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Two trials, one by Dreno and coworkers6
comparing 2 formulations (methylprednisolone with prednisolone) and a second
by Morel and Guillaume7 comparing different
doses of prednisolone (0.75 vs 1.25 mg/kg per day), did not find any statistical
difference in the groups compared for effectiveness. There were more adverse
effects associated with the higher dose of prednisolone (Table 2 and Table 3).
Burton et al,8 who compared prednisone
with prednisone and azathioprine, found a 45% reduction in the amount of prednisone
taken by the azathioprine-treated group during a 3-year period.8
The definition of disease control was not stated, and not much clinical data
were available. This trial excluded patients with contraindications to oral
corticosteroids or azathioprine and those "unlikely to attend follow-up."8(p1190) Another problem with this trial was that patients
were "started on oral prednisone 30-80 mg/day, to suppress new blisters" and
then only "did the consultant decide whether to include the patient in the
trial."8(p1190) Roujeau and coworkers9 compared prednisolone with prednisolone and plasma
exchange, and found that disease control was achieved with less than half
the total prednisolone dose in the plasma exchange–treated group. They
used low-dose prednisolone (0.3 mg/kg) initially, but control was achieved
with a mean ± SD daily prednisolone dose of 0.52 ± 0.28 mg/kg
in the plasma exchange–treated group vs 0.97 ± 0.33 mg/kg in
the prednisolone only–treated group. They found a similar adverse effect
profile in both groups, and the disease was controlled within weeks (mean
± SD, 41 ± 14 vs 32.5 ± 2.0 days for the prednisolone
only–treated group vs the plasma exchange–treated group). This
trial excluded patients older than 80 years and was not blinded.
However, a fifth trial by Guillaume and coworkers10
included all 3 treatment groups (prednisolone alone, prednisolone and azathioprine,
and prednisolone and plasma exchange). It failed to confirm the benefit of
combination treatments over prednisolone alone. The adverse effects were not
given in detail for each group (except for those listed in Table 3), but the researchers stated that "most of the adverse events
could be attributed to corticosteroids."10(p51)
The sixth trial,11 comparing prednisone
with tetracycline and niacinamide, suggested that there was no statistically
significant difference in response to treatment between the 2 groups, but
that the prednisone-treated group had more serious adverse effects. Unfortunately,
this trial included few patients, two thirds of whom were in the tetracycline-treated
group (14 of the 20 patients). The randomization in this study was unclear,
and there was a high dropout rate (2 patients in the tetracycline-treated
group at 2 months, and 12 patients from both groups by the end of the study).
At 10 months, there were only 3 patients left in the corticosteroid-treated
group (2 of whom had multiple recurrences) and only 5 left in the tetracycline-treated
group (all of whom remained disease free during medication tapering). The
prednisone-treated group was associated with more severe adverse effects (including
a death due to sepsis) and disease recurrence.
Table 3 includes the adverse
effects in each trial. There are more adverse effects associated with corticosteroids,
and these seem to increase with higher doses. Only 2 trials had no deaths
reported. The first, by Dreno et al,6 is probably
irrelevant for this adverse effect because of a follow-up period of only 10
days. The second, the Roujeau et al9 trial,
had a follow-up comparable to that of other trials but used significantly
lower starting doses of prednisolone (0.3 mg/kg per day). Azathioprine was
mostly associated with a reduction in the white blood cell count (2 of 12
patients in the Burton et al8 trial and 4 of
36 patients in the Guillaume et al10 trial).
It was not possible to pool the data in a meta-analysis because the studies
were heterogeneous.
COMMENT
Four of the studies6-7,9-10
in this review are French, and 37, 9-10
are from a multicentric group in France. Morel was a coauthor in 2 studies7, 9; Guillaume in 37, 9-10;
and Crickx, Labeille, and Guillot in the same 2.9-10
Roujeau was the lead author in one study9 and
the senior author in another.10 The 2 studies
from the same group did not overlap in time (1980-19829
and 1984-198910) and used different dosing
regimens of prednisolone. It is unclear if the same patients participated
in both studies, as the later study only excluded those who had received oral
immunosuppressants in the previous month. The definition of disease control
changed, and higher doses of prednisolone were used in the later study10; plasma exchange was a comparison treatment in the
2 studies,9-10 with the addition
of azothiaprine in the later study.
The studies in this review used oral prednisolone or prednisone in the
control group (no comparison with placebo) and are all small trials. Prednisone
is converted to the biologically active form, prednisolone, in the liver by
the action of 11- -hydroxydehydrogenase enzyme. Thus, liver disease could
impair this conversion. In healthy patients, however, the time to peak levels
and half-lives of prednisone and prednisolone are similar, 1.3 and 2.6 to
3 hours for prednisone vs 1 and 2.6 to 3 hours for prednisolone, respectively.
The bioavailability of prednisone is 92% and that of prednisolone is 84%;
they both suppress the hypothalamic-adrenal axis for 24 to 36 hours after
a single dose.12-13 However, 2
French studies14-15 have contradicted
this view, suggesting a much higher bioavailability after taking prednisone
than prednisolone (P<.001). Several US studies
support the bioequivalence of prednisone and prednisolone12-13
or the higher availability of prednisolone when orally administered.14 The RCT by Ferry et al12
comparing the bioavailability of these drugs after a single 10-mg oral and
intravenous infusion concluded that prednisone and prednisolone tablets were
bioequivalent. The pharmacokinetics are further complicated by the reversible
metabolism of prednisone to prednisolone and vice versa.16
For this review, prednisone and prednisolone are regarded as bioequivalent.
It was impossible to compare outcomes of response of the patients to
dosing schedules of prednisone or prednisolone at 1 mg/kg per day because
2 studies8, 11 did not provide
individual doses for patients given a range of corticosteroid doses. The outcome
measures in these studies are different, as can be seen when looking at the
definition of disease control and the interventions used (Table 2).
The short follow-up periods in some of the studies (eg, 10 days in one6) make judgment of the significance of the results
difficult, especially in view of the long-term nature of this disease.6 The aim of the Morel and Guillaume7
study was to compare the starting dose of prednisolone, so perhaps the follow-up
of only 51 days may be more reasonable. The study8
with the longest follow-up (3 years) had little clinical data.
Probably the most interesting feature of the Roujeau et al9
study was the lower dose of prednisolone used in both treatment groups. Strict
measures of disease control were used (complete disappearance of blisters,
pruritus, and erythema), and in both groups, the disease was controlled within
weeks (mean ± SD, 41 ± 14 vs 32.5 ± 2.0 days for the
prednisolone only–treated group vs the plasma exchange–treated
group); however, higher doses were needed to achieve disease control. There
were no deaths during the study, but this may be partly because of the exclusion
of patients older than 80 years. This study found that the plasma exchange–treated
group required much less prednisolone than the prednisolone only–treated
group. This benefit was, however, not confirmed by the Guillaume et al10 study. This latter study also failed to confirm the
benefit of the addition of azathioprine to prednisolone.
The Fivenson et al11 study had a flawed
method of randomization, a high dropout rate, and small numbers, but does
suggest merit in the use of tetracycline and niacinamide. However, further
study is needed to confirm these findings.
Because it is unlikely that future studies on interventions for bullous
pemphigoid including a placebo group would ever obtain ethics committee approval,
a comparison of low-dose prednisolone with tetracyclines and niacinamide (or
potent topical corticosteroids, for mild and/or localized disease) may prove
a worthy alternative. Uncontrolled studies15-19
have suggested the successful use of topical corticosteroids as a first-line
treatment for localized and mild disease, and a recent abstract of an RCT20 seems to confirm this view. The use of potent topical
corticosteroids is favored because they have minimal adverse effects and a
limited number of contraindications.
The results of this review show a need for larger RCTs (with adequate
power) of treatments for bullous pemphigoid. The numbers needed can probably
only be achieved in multicenter trials. The available evidence is inadequate
for a confident recommendation of optimal treatment. However, it seems that
a less aggressive approach with lower doses of corticosteroids might be adequate
and associated with less morbidity and mortality. The value of the addition
of azathioprine and plasma exchange to oral corticosteroids remains doubtful.
AUTHOR INFORMATION
Accepted for publication October 23, 2001.
This study was supported by the Nuffield Trust Fellowship Scheme.
Corresponding author and reprints: Nonhlanhla P. Khumalo, MD, Department
of Dermatology, Groote Schuur Hospital, Observatory, 7925 Capetown, South
Africa (e-mail: n_khumalo{at}hotmail.com).
A cooperative effort of the Clinical Epidemiology Unit of the Istituto
Dermopatico dell'Immacolata–Istituto di Ricovero e Cura a Carattere
Scientifico (IDI-IRCCS) and the Archives of Dermatology
From the Departments of Dermatology, The Churchill Hospital, Oxford,
England (Drs Khumalo, Wojnarowska, and Kirtschig); Groote Schuur Hospital,
Capetown, South Africa (Dr Khumalo); St George Hospital, The University of
New South Wales, Sydney, Australia (Dr Murrell); and Vrije Universiteit Medical
Centre, Amsterdam, the Netherlands (Dr Kirtschig).
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Section Editors:
Damiano Abeni, MD, MPH,
Istituto Dermopatico dell'Immacolata, Rome, Italy
Michael Bigby, MD, Beth Israel Deaconess Medical Center, Harvard Medical
School, Boston, Mass
Paolo Pasquini, MD, MPH,
Istituto Dermopatico dell'Immacolata, Rome, Italy
Moyses Szklo, MD, MPH, DrPH, The Johns Hopkins University, Baltimore,
Md
Hywel Williams, MD, Queens Medical Centre,
Nottingham, England
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