ARTICLE
Pemphigus foliaceus (PF) is an autoimmune blistering disease which usually
presents with cutaneous lesions [1, 2]. These lesions predominantly affect
the scalp, face, neck, chest, back, and abdomen [1, 2]. Mucous membranes
are usually not involved [1, 2]. The diagnosis of PF is confirmed by histology
and immunopathology [1, 2]. Histological studies of a PF lesion show subcorneal
vesicle formation with intraepidermal acantholysis [1, 2]. Acantholysis
results from in vivo deposition of autoantibodies to the desmoglein
1 (160 kDa protein) molecule in the upper layers of the stratum malphigii,
and subsequent loss of cell adhesion. Direct immunofluorescence studies
of perilesional skin demonstrate deposition of IgG on the keratinocyte cell
surface [2, 3]. The presence of antibodies to the keratinocyte cell surface
is typically observed on indirect immunofluorescence (IIF) using different
substrates including monkey esophagus [1-3]. On an immunoblot assay, using
human epidermis or other substrates as lysate, sera from patients with active
PF, characteristically bind only to a 160-kDa protein identified as desmoglein
1 [4-6]. Injection of sera from patients with active disease produces clinical
disease in neonatal balb/c mice, identical to that observed in humans. This
indicates that the autoantibody is directly responsible for manifestation
of the clinical disease [7].
Systemic corticosteroids and conventional immunosuppressive agents have
been the mainstay therapy [2, 8-17]. There are two major concerns related
to the use of these conventional agents. First, these drugs cause a significant
degree of immune suppression, and, as a result of their side effects,
lead to an increased incidence of morbidity and mortality [18-20]. Second,
certain patients do not have a satisfactory clinical response to therapeutic
dosages of these drugs [8, 9, 21-23]. In such cases, other therapies,
such as extracorporeal photochemotherapy, plasmapharesis, and intravenous
immunoglobulin (IVIg) administration, are used to control the disease
[22-28].
The purpose of this retrospective study was to present the use of IVIg
therapy in seven patients with severe PF. All seven patients had developed
multiple side effects. Further continuation of systemic corticosteroids
enhanced the risk of developing irreversible side effects or catastrophic
consequences. Immunosuppressive agents such as azathioprine, methotrexate,
cyclophosphamide, and others were contraindicated [18]. Hence, IVIg therapy
was used as an alternative treatment.
Materials and methods
This study presents seven patients with pemphigus foliaceus who were
steroid-dependent. In all seven patients, IVIg therapy was used as an
alternative treatment.
Inclusion criteria. The availability of the following information
was essential for inclusion in this study.
(1) Moderate to severe active clinical disease. Thirty percent or more
of cutaneous body surface area involvement. No mucosal involvement. (2)
Demonstration of intraepidermal subcorneal acantholysis in a subcorneal
vesicle on histology. (3) Deposition of IgG in the upper layers
of the epidermis on DIF studies of perilesional skin. (4) Presence of
antibodies to the keratinocyte cell surface in the sera of patients, demonstrated
by IIF using monkey esophagus as substrate (Table
I). (5) On an immunoblot assay using human epidermis lysate, the binding
of patients sera to a 160 kDa protein (desmoglein 1).
The following data was recorded on each of the seven patients included
in this study.
Demographics. Gender and age at onset of disease.
Prednisone Treatment. In all seven patients, the following information
was noted about prednisone treatment pre-IVIg therapy and after the initiation
of IVIg treatments.
(i) Highest dose of prednisone: the highest dose was defined as the
maximum dose of prednisone, in milligrams per day, that each patient had
received during the course of his disease. (ii) Total dose of prednisone.
(iii) Total duration of prednisone. (iv) Total number of relapses.
A patient was defined to have a relapse if adjustment in the dose of the
prednisone was necessary to control a recurrence of the disease. (v) Side
effects. All side effects which required medical treatment were documented.
These included hypertension, diabetes mellitus, glaucoma, gastrointestinal
distress, peptic ulcer disease, myopathy, systemic
infections, osteoporosis, bone fractures, and psychological reactions
such as depression and psychosis. In addition, all patients developed
more common constitutional side effects which are usually reversible upon
discontinuation of the systemic corticosteroids including moon facies,
buffalo hump, and weight gain.
IVIg treatment. We used a recently described IVIg treatment protocol
in these seven patients [28, 29]. The dose of IVIg was 1-2 g/kg/cycle,
and was administered in three equally divided doses, over 2-3 consecutive
days. Initially, each patient received IVIg treatment at an interval of
3 to 4 weeks. After the initiation of IVIg therapy, the dose of systemic
corticosteroids was slowly tapered and eventually discontinued. Isolated
lesions which failed to heal during the tapering were treated with local
sublesional triamcinolone injections and aggressive topical therapy. Patients
were recorded as being clinically controlled if they met the following
criteria: (i) complete healing of old lesions (ii) development of no new
lesions (iii) discontinuation of systemic corticosteroids. After achieving
clinical control, the intervals between IVIg infusion cycles were slowly
increased to 6, 8, 10, 12, 14, and 16 weeks. If patients had a relapse
while on IVIg as monotherapy, the frequency of cycles was increased until
patients regained clinical control. This was done without the reinstitution
of oral prednisone therapy. Patients were considered to have reached the
end point of therapy if they were clinically controlled at 16 weeks intervals
between the last two IVIg infusion cycles.
Total duration of observation. In each patient, this was defined
as the time interval between the initial biopsy diagnosis and the last
documented office visit.
Statistical Analysis. The following data pre-IVIg treatment and
after the initiation of IVIg therapy were compared using Wilcoxon
test for paired samples with 2 sided p-values: total dose of prednisone,
total duration of prednisone, and relapses.
Results
Details regarding clinical profiles, systemic corticosteroid therapy
and resultant side effects, contraindications to the use of immunosuppressive
agents, and IVIg therapy and treatment outcomes are presented in Table
I.
Demographics. Four patients were male and three were female.
The mean age of onset was 48 years.
Pre-IVIg treatment. The highest dose of prednisone ranged from
60 to 90 mg/day (mean 73). The total dose of prednisone ranged from 4,500
to 20,500 mg (mean 12,380) (Fig.
1). The total duration of prednisone ranged from three to 24 months
(mean 10.6) (Fig. 2).
Six of seven patients had at least one episode of relapse while on prednisone
treatment after initially establishing clinical control. The total number
of relapses while patients were on prednisone ranged from two to six episodes
(mean 4.1). The total number of side effects in each patient ranged from
three to seven. All seven patients developed psychological side effects
which required treatment with anti-depressants and anti-psychotic medications.
Other side effects which required medical treatment included gastrointestinal
distress, myopathy, and diabetes mellitus each in three patients. Two
patients developed glaucoma, hypertension, weakness, multiple infections,
and osteoporosis with multiple fractures. Urinary tract infections (UTIs),
pneumonias, and cellulites were the most common infections observed in
these patients.
After initiation of IVIg treatment. The total dose of prednisone
after IVIg was initiated, ranged from 735 to 1,570 mg (mean 930) (Fig.
1). The total duration of prednisone, while patients were receiving
IVIg treatment ranged between 2 and 4 months (mean 2.8 months) (Fig.
2). All seven patients achieved an effective clinical response and
prednisone was eventually discontinued. The number of relapses ranged
between 0 and 2 episodes (mean 0.7). Only two of seven patients developed
short-term side effects during the IVIg infusions. These included headaches
and nausea.
Total duration of observation. In each patient, this was defined
as the time interval between the initial biopsy diagnosis and the last
documented office visit.
Statistical Analysis. The following data pre-IVIg treatment and after
the initiation of IVIg therapy were compared using Wilcoxon test for paired
samples with 2 sided p-values: total dose of prednisone, total duration
of prednisone, and relapses.
Statistical Analysis. The Wilcoxon test for paired samples showed
highly significant results pre- and post-IVIg with respect to the total
doses (p = 0.005) and duration (p = 0.02) of systemic corticosteroid treatment
(Fig. 1, 2). A statistically
significant result was also observed when the number of relapses pre-
and post-IVIg treatment (p = 0.002) was compared.
Discussion
This study presents a group of seven patients with PF, who were treated
with IVIg therapy. Prior to IVIg administration, these patients had received
high doses of systemic corticosteroids. They had become steroid-dependent
and developed multiple serious side effects. Attempts to reduce the doses
of prednisone frequently resulted in relapses. The use of other conventional
systemic immunosuppressive agents was contraindicated in these patients.
They refused other treatment modalities, such as extracorporeal photochemotherapy
and plasmapharesis. Hence, IVIg therapy was used as an alternative treatment.
Once IVIg therapy was initiated, a gradual tapering and eventual discontinuation
of prednisone therapy was achieved, over a mean period of 2.8 months.
Thereafter, IVIg was used as monotherapy.
Systemic corticosteroids are the most common treatment for PF [2-3,
8-9]. Systemic immunosuppressive drugs have been used as steroid-sparing
agents [2, 10-16]. However, in some patients, these drugs are contraindicated
[18]. Such patients are treated with alternative modalities including
extracorporeal photochemotherapy and plasmapharesis [22-25]. While these
treatments have proven to be beneficial in some patients, long-term follow-up
is not available. Moreover, such treatments often require the simultaneous
use of immunosuppressive agents [22-25].
There are three studies in the English literature which have reported
the use of IVIg in 11 patients with PF [26-28]. All eleven patients had
failed to respond to multiple systemic agents. IVIg therapy has also been
used to treat other autoimmune blistering diseases and chronic inflammatory
disorders, both as an adjuvant and as a steroid-sparing agent [29-31].
In addition to providing effective clinical
control of the disease, use of IVIg in our PF patients was associated
with safely discontinuing systemic prednisone without any acute exacerbation.
This had not been possible prior to IVIg therapy. In addition, there was
a statistically significant reduction in the number of relapses. The relapses
occurred during a sudden interruption in IVIg treatment due to the shortage
of the drug in the United States. Control of the disease was achieved
again after IVIg was reinstituted, without the use of systemic corticosteroids
or adjuvants. These relapses demonstrated that IVIg therapy must be gradually
discontinued when used as monotherapy [28].
In five of seven patients, IVIg therapy was eventually discontinued,
and thus these patients were considered to be in clinical remission. At
the time of writing this report, only two patients continue to receive
IVIg cycles as maintenance therapy at an interval of 10 and 12 weeks.
While the molecular mechanism of IVIg in PF is not known, idiotypic and
anti-idiotypic interactions may provide an explanation for reduction of
autoantibody titers [32].
CONCLUSION
In conclusion, we describe seven patients with PF who were steroid-dependent.
In these patients, who had contraindications to the use of immunosuppressive
agents, IVIg was used. IVIg therapy allowed the reduction of prednisone
doses, and eventually its discontinuation. Hence, IVIg was steroid sparing
in these patients. We recommend a multi-center trial to determine the
use of IVIg, as an effective alternative, in the treatment of severe PF.
Article accepted on 4/12/01
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