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Corticosteroid-Sparing Effect of Intravenous Immunoglobulin Therapy in Patients With Pemphigus Vulgaris
Naveed Sami, MD;
Ansa Qureshi, MD;
Eleonora Ruocco, MD;
A. Razzaque Ahmed, MD, DMSc
Arch Dermatol. 2002;138:1158-1162.
ABSTRACT
| |
Background Pemphigus vulgaris (PV) is a rare, potentially fatal autoimmune mucocutaneous
blistering disease. The prolonged use of systemic corticosteroids, though
clinically effective in high doses, can result in multiple debilitating adverse
effects. Immunosuppressive agents, used as adjuvants and as corticosteroid-sparing
agents, are not effective in all patients and are contraindicated in some.
Therefore, alternative treatment modalities are needed to provide effective
control of PV in such patients.
Objective To demonstrate the corticosteroid-sparing effect of intravenous immunoglobulin
(IVIg) therapy in patients with moderate to severe PV.
Design A retrospective analysis in a cohort of 15 patients with moderate to
severe PV who were treated with IVIg therapy. All 15 patients were corticosteroid
dependent, and the use of other systemic conventional immunosuppressive agents
was contraindicated. The patients were followed up over a mean period of 6.2
years.
Setting Ambulatory tertiary medical care facility of a university-affiliated
hospital.
Intervention All 15 patients received an IVIg dose of 1 to 2 mg/kg per cycle.
Main Outcome Measures The following information was documented in each of the 15 patients
before and after the initiation of IVIg therapy: total dosage and total duration
of prednisone therapy and number of relapses. Also, the highest dosage and
adverse effects of prednisone therapy, as well as the total duration of observation,
were recorded.
Results All 15 patients had a satisfactory clinical response to IVIg therapy.
The use of systemic prednisone was gradually discontinued over a mean period
of 4.3 months. A statistically significant difference was noted in the total
dose of prednisone (P = .004), total duration of
prednisone therapy (P = .003), and number of relapses
(P<.001) before and after the initiation of IVIg
therapy.
Conclusions Intravenous immunoglobulin therapy has a demonstrable corticosteroid-sparing
effect. It is a safe and effective alternative treatment modality in patients
with PV who are dependent on systemic corticosteroids or who develop significant
adverse effects as a result of their use.
INTRODUCTION
PEMPHIGUS VULGARIS (PV) is a rare, potentially fatal autoimmune blistering
disease. The lesions of PV can involve both cutaneous and mucosal tissues.1-3 The diagnosis is confirmed
by histological and immunopathological studies.1-5
An intraepidermal vesicle with acantholysis is usually seen on routine histological
examination of a biopsy specimen of the lesion.1-3
Deposition of IgG on the surface of the keratinocyte cell surface is typically
seen on direct immunofluorescence of perilesional tissue.1-5
Indirect immunofluorescence, using monkey esophagus as a substrate, demonstrates
the presence of antibodies to the keratinocyte cell surface antigen.1-5
On an immunoblot assay, using human epidermis as lysate, patients' serum binds
to a 130-kd protein identified as desmoglein 3.6-7
Systemic corticosteroids administered in high doses over prolonged periods
of time can provide effective control of active disease and are often used
for maintenance therapy.1, 8 As
a consequence of the cumulative doses of systemic corticosteroids, patients
often develop multiple serious adverse effects, sometimes resulting in a poor
quality of life.8-9 These adverse
effects are occasionally fatal.10-11
Several immunosuppressive agents, dapsone, and systemic antibiotics have been
used with the explicit purpose of reducing the dosage of systemic corticosteroid
therapy.12-29
In many treatment-resistant patients, alternative treatments such as plasmapheresis,
extracorporeal photopheresis, and intravenous immunoglobulin (IVIg) have been
recommended.30-33
We retrospectively studied the use of IVIg in 15 steroid-dependent patients
with PV. The prolonged use of high-dose systemic corticosteroid therapy had
resulted in multiple adverse effects. Continuation of such therapy was considered
inadvisable because of the heightened risk of further adverse effects and
possible mortality as a result of prolonged immunosuppression. In all 15 patients,
the use of IVIg resulted in clinical control of disease, and a gradual reduction
and an eventual discontinuation of the systemic corticosteroid therapy were
possible.
PATIENTS AND METHODS
A total of 15 patients with moderate to severe mucocutaneous PV were
enrolled in the study. The following criteria had to be present before IVIg
therapy was initiated: (1) moderate to severe mucocutaneous disease, defined
as involvement of 30% or more of body surface and at least 2 mucosal surfaces;
(2) an intraepidermal vesicle with acantholysis observed on routine hematoxylin-eosin
staining; (3) deposits of IgG on the keratinocyte cell surface antigen of
the epidermis demonstrated on direct immunofluorescence; (4) antibodies to
the keratinocyte cell surface antigen at a titer of 1:160 or greater demonstrated
by indirect immunofluorescence of serum samples using using monkey esophagus
as a substrate; and (5) antibodies to a 130-kd protein on immunoblot analysis
using human epidermis as a lysate.
PREDNISONE TREATMENT
In addition to sex and age at onset of disease, the following information
was recorded for each patient before and during IVIg therapy (the dosage of
systemic corticosteroid therapy was converted to an oral daily dose of prednisone):
- The highest dose of prednisone, which was defined
as the maximum dose per day a patient received to control PV during the course
of the study and which was considered to be one of the indices to determine
disease severity.
- The total dose of prednisone.
- The total duration of prednisone therapy.
- The total number of relapses. Relapse was defined
as a recurrence of lesions at previous and new sites. If patients had a relapse
while taking only systemic corticosteroids, the dosage of prednisone therapy
was increased to achieve clinical control.
- Adverse effects. The adverse effects noted were
a direct consequence of the prolonged use of high-dose corticosteroids. Those
that required further medical intervention included hypertension, diabetes
mellitus, gastrointestinal distress, peptic ulcer disease, psychological reactions
(eg, depression, mood swings, and psychosis), myopathy, multiple infections
(eg, urinary tract infection, pneumonia, and cellulitis), osteoporosis, and
bone fractures. However, all patients developed other adverse effects, such
as moon facies, buffalo hump, and redistribution of body adipose tissue, which
are excluded from the discussion because they required no specific medical
treatment.
INDICATIONS FOR IVIg TREATMENT
There were 3 indications for the use of IVIg therapy in the 15 patients
with PV:
- Dependence on high doses of systemic corticosteroids.8 Patients required 30 mg/d or more of prednisone to
keep diseases under control. Attempts to lower the dosage of prednisone therapy
resulted in recurrence of lesions.
- Multiple significant adverse effects from prolonged
use of high-dose systemic corticosteroid therapy.9
- Contraindications for the use of immunosuppressive
agents,34 including a strong family history
of cancer, complex medical problems that required repeated adjustment of the
dosage of other medications, and increased risk of infertility and teratogenicity
in young patients.
All 15 patients refused other alternative treatment modalities, including
plasmapheresis, photochemotherapy, and intravenous pulse doses of methylprednisone
with cyclophosphamide.
IVIg TREATMENT
A recently described IVIg treatment protocol was used in every patient.35-36 The dosage was 1 to 2 g/kg per cycle.
The total dose for the cycle was divided into 3 equal doses, given on 3 consecutive
days, as a slow 4- to 5-hour infusion. Initially, IVIg therapy was adminstered
at a frequency of every 3 to 4 weeks, until an effective clinical response
was achieved. Effective clinical response was defined as the complete healing
of previous lesions and the absence of new lesions. Thereafter, the intervals
between infusion cycles were slowly increased to 6, 8, 10, 12, 14, and 16
weeks. This gradual tapering of IVIg therapy was defined as the "maintenance
therapy" period. The end point of therapy was defined as that point at which
patients continued to remain free of lesions after 2 consecutive cycles of
IVIg therapy at a 16-week interval.
In all 15 patients, relapses and adverse effects were closely monitored.37 Also, all 15 patients were orally premedicated with
650 mg of acetaminophen and 50 mg of diphenhydramine hydrochloride to prevent
headaches and hypersensitivity reactions, respectively.35-36
When IVIg therapy was instituted and control of disease was established,
the dosage of oral prednisone was gradually reduced, and eventually the prednisone
therapy was discontinued. Existing and new lesions were treated with sublesional
triamcinolone injections and intensive topical therapy. When relapses occurred
during IVIg therapy, the frequency of the infusions was temporarily increased
until the disease was controlled. Systemic corticosteroids were not used during
such relapses.
DURATION OF TOTAL OBSERVATION
The duration of total observation was defined as the interval between
the initial diagnosis and the last documented visit of the patient.
STATISTICAL ANALYSIS
Wilcoxon signed rank tests were used to analyze pre- and post-IVIg data.
The variables used in this analysis were total dose of prednisone treatment,
total duration of prednisone treatment, and number of relapses.
RESULTS
The study included 8 male patients and 7 female patients (mean age at
onset, 58 years; age range, 30-82 years). Before IVIg therapy was initiated,
the dosage of prednisone therapy ranged from 80 to 160 mg/d (mean, 100 mg/d),
the total dose ranged from 5200 to 90 000 mg (mean, 21 280 mg),
and the duration ranged from 4 to 60 months (mean, 19.9 months). During IVIg
therapy, the total dose of prednisone ranged from 300 to 9500 mg (mean, 1964
mg) (Figure 1), and the duration
of prednisone therapy ranged from 2 to 18 months (mean, 4.3 months) (Figure 2).
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Figure 1. Comparison of the mean total dose
of prednisone before and during intravenous immunoglobulin (IVIg) therapy.
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Figure 2. Comparison of the mean total duration
of systemic prednisone therapy before and during intravenous immunoglobulin
(IVIg) therapy. Note the significant decline in the total duration of prednisone
therapy after the initiation of IVIg therapy.
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Thirteen of the 15 patients had relapses after initial clinical response
was achieved. The total number of relapses before IVIg treatment ranged from
3 to 7 (mean, 4.9 relapses). Only 5 patients had a relapse during IVIg therapy,
and the number of relapses ranged from 0 to 3 (mean, 0.7 relapse). The total
time of observation ranged from 2 to 17.25 years (mean, 6.2 years).
ADVERSE EFFECTS
During prednisone therapy, all 15 patients had psychological adverse
effects that required medical treatment, including psychosis, depression,
and mood swings. There were also several other systemic adverse effects, including
multiple infections (10 patients [67%]), corticosteroid-induced myopathy (7
patients [46%]), hypertension (5 patients [33%]), osteoporosis (5 patients
[33%]), cataracts (4 patients [27%]), diabetes mellitus (3 patients [20%]),
and gastrointestinal distress and/or peptic ulcer disease (3 patients [20%]).
Two patients also had vertebral fractures (13%), and 1 patient had a fracture
of the neck of the femur (7%).
The most common adverse effects observed during IVIg therapy were headaches
(5 patients) and nausea (2 patients), which were controlled with oral analgesics
and antiemetics.35-37
RESPONSE TO IVIg THERAPY
All 15 patients responded to IVIg therapy. Effective clinical response
was achieved in 3.2 to 5.4 months (mean, 4.6 months). Thereafter, the interval
between the infusion cycles was increased. This maintenance period of IVIg
therapy lasted 15 to 27 months (mean, 18.7 months). All patients achieved
the end point of therapy.
STATISTICAL ANALYSIS
The Wilcoxon signed rank test showed highly statistically significant
results before and during IVIg therapy between the total doses of prednisone
(P = .004), the duration of prednisone therapy (P = .003), and the number of relapses (P<.001).
COMMENT
Our study included 15 patients with PV who were treated with IVIg therapy.
Before IVIg therapy was initiated, all 15 patients had received high daily
doses and high total doses of oral prednisone. The majority of these patients
had multiple relapses requiring frequent dose adjustment. All 15 patients
had developed "corticosteroid dependency," in that it was not possible to
reduce their daily oral prednisone dose without recurrence of disease and
repeated increases in the dose were necessary. Consequently, these patients
developed multiple debilitating adverse effects. Immunosuppressive agents,
which are often used as corticosteroid-sparing agents in the treatment of
PV, were contraindicated in all 15 patients, and the patients had refused
other treatments such as plasmapheresis, photochemotherapy, and intravenous
pulse corticosteroids with or without intravenous cyclophosphamide. Therefore,
IVIg therapy was instituted. After the initiation of IVIg therapy, the oral
corticosteroid therapy was gradually reduced in dosage and eventually discontinued.
The patients were eventually treated with IVIg as monotherapy, with success.
All 15 patients had a clinical remission and the IVIg therapy was discontinued.
The mortality of patients with PV has been significantly reduced since
the advent of the use of systemic corticosteroids. Although most patients
with PV do respond to prednisone therapy, such therapy can result in multiple
adverse effects, requiring medical intervention, and can sometimes be fatal.
There are many other systemic agents that have been reported to have proven
clinical benefit in the treatment of PV and have been used as corticosteroid-sparing
agents. However, in some patients, these agents are contraindicated because
of their long-term, and often irreversible, adverse effects. Other alternative
therapies, such as extracoporeal photopheresis and plasmapheresis, have been
used as corticosteroid-sparing treatment modalities, but have required the
simultaneous use of other systemic agents.
Intravenous immunoglobulin therapy has been used successfully to treat
autoimmune blistering diseases, including PV, pemphigus foliaceus, cicatricial
pemphigoid, bullous pemphigoid, linear IgA bullous disease, and epidermolysis
bullosa acquisita, as well as many other chronic autoimmune inflammatory disorders,
both as an adjuvant and a corticosteroid-sparing agent.33, 35-49
It has also been used as an adjuvant along with other therapies in patients
who have failed to respond to treatment with multiple systemic agents.
In our group of 15 patients, IVIg therapy was a reasonable a choice,
since there was a relative contraindication to the use of systemic immunosuppressive
agents owing to their possible or potential serious adverse effects.34 The incidence of long-term adverse effects requiring
medical treatment has been reported to be relatively low with IVIg therapy
compared with other alternative treatments.37, 43
The most common adverse effects of IVIg therapy, including headache, nausea,
and hypersensitivity reactions, are usually short term.35, 43
Such adverse effects can be prevented by premedication with oral diphenhydramine
and acetaminophen.35-36 There
are a few reports of patients developing acute renal failure and aseptic meningitis
during IVIg therapy.37, 43
Institution of IVIg therapy allowed the dosage of prednisone therapy
to be slowly reduced over a mean period of 4.3 months, without any acute exacerbations.
The differences in the total doses (P = .004) and
duration(P = .003) of prednisone therapy before and
during IVIg therapy were highly statistically significant, demonstrating that
IVIg is an effective corticosteroid-sparing agent.
The number of patients who were having relapses declined while the patients
were receiving IVIg therapy. The difference in the number of relapses that
occurred between prednisone treatment and IVIg therapy was also statistically
significant (P<.001). Only 5 patients had a relapse
during IVIg therapy. The relapses occurred when patients did not receive their
treatments at appropriate time intervals, owing to a shortage of the drug
in the United States. Clinical control of disease was achieved when IVIg therapy
was reinstituted, without additional systemic therapy. These relapses resulting
from the abrupt involuntary interruption of IVIg therapy indicate that a slow
withdrawal of IVIg therapy is necessary to maintain a sustained clinical remission.
Most patients with PV and other chronic autoimmune diseases who are being
treated with IVIg therapy have required multiple treatments over an extensive
period and a gradual discontinuation of the therapy to maintain adequate control
of their disease.44-49
During the course of therapy, antibody titers to the keratinocyte cell
surface antigen were monitored and correlated with clinical disease. In all
15 patients, a decrease in antibody titers to the keratinocyte cell surface
antigen was observed, corresponding directly to effective clinical control
of their disease (data not shown). When patients achieved the end point of
therapy and their disease was in clinical remission, antibody titers to the
keratinocyte cell surface antigen were nondetectable (N.S. and A.R.A, unpublished
data, 2002).
We recognize that the cost of IVIg is prohibitive. However, in these
15 patients, other alternatives were not available. The cost of treating present
and future adverse effects of long-term therapy with high-dose systemic corticosteroids
and immunosuppressive agents would also be high, and probably comparable.
There are 7 postulated mechanisms of action of IVIg therapy,35, 43 which is thought to work through
anti-idiotypic interactions in such chronic inflammatory autoimmune diseases
as dermatomyositis.35, 43 A similar
mechanism of immune modulation may be operative in PV.
This study demonstrates that IVIg therapy is an effective alternative
for patients with PV whose disease cannot be controlled with long-term high-dose
systemic corticosteroid therapy, which may also cause serious adverse effects.
It is especially useful for patients in whom the use of immunosuppressive
agents is contraindicated. Other benefits of IVIg therapy are that (1) it
also has a corticosteroid-sparing effect; (2) it can be used as monotherapy;
(3) it is relatively safe compared with systemic corticosteroid therapy; and
(4) in addition to controlling PV, it can induce a sustained clinical remission.
Further multicenter trials, with a larger group of patients, are needed to
determine whether IVIg is an effective choice for the treatment of PV.
AUTHOR INFORMATION
Accepted for publication December 10, 2001.
Corresponding author: A. Razzaque Ahmed, MD, DMSc, Department of
Oral Medicine, Harvard School of Dental Medicine, 188 Longwood Ave, Boston,
MA 02115 (e-mail: Razzaque-Ahmed{at}HMS.Harvard.edu).
From the Department of Oral Medicine, Harvard School of Dental Medicine
(Drs Sami, Qureshi, Ruocco, and Ahmed), the Department of Dermatology, Harvard
Medical School (Dr Ahmed), and the Center for Blistering Diseases, Department
of Medicine, New England Baptist Hospital (Dr Ahmed), Boston, Mass.
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