Alternate-Day Corticosteroid Therapy in Pemphigus Vulgaris and Bullous Pemphigoid
Lilla Mihályi1,
Zsuzsanna Bata-Csörg Å1, Lajos Kemény1,2, Krisztina Vas1
and Sándor Husz1
1Department of Dermatology and
Allergology, Albert Szent-Györgyi Medical Center, University of Szeged
2MTA-SZTE Dermaatological Research
Group, Szeged, Hungary Alternate-Day Corticosteroid Therapy in Pemphigus
Vulgaris and Bullous Pemphigoid
*Corresponding
author: Mihályi L, Albert
Szent-Györgyi Medical Center, University of Szeged, Korányi Fasor 6, H-Szeged,
Hungary, Tel: +36-62-545-260; Fax: +36 62545954; Email: mihalyililla@hotmail.com
Received Date: 02 November, 2016; Accepted Date: 21 November, 2016; Published
Date: 28 November, 2016
Citation: Mihályi L, Bata-CsörgÅ‘ Z, Kemény L, Vas K, Husz S (2016) Alternate-day corticosteroid therapy in pemphigus vulgaris and bullous pemphigoi. Clin Exp Dermatol Ther (2016) : G112. DOI: 10.29011/2575-8268/100012
Background: There are numerous therapeutic options for the treatment of
autoimmune bullous skin diseases, but systemic corticosteroid is still the gold
standard. The treatment of these diseases is based on empirical knowledge, and
the guidelines are not uniform. In many centers the patients are treated
according to local tradition. We use corticosteroid therapy as baseline therapy
at the start of the treatment and gradually decrease the dose on alternate
days. We use azathioprine as a steroid sparing agent. In our experience, a
symptom-free status can be reached in most cases.
Objectives: We set out to analyse the efficacy and the prevalence of
side-effects caused in our patients by this long term daily alternating
corticosteroid therapy.
Methods: The data on 148 patients (70 with pemphigus vulgaris, 78
with bullous pemphigoid) from 2004 to 2015 were processed.
Results: With intermittent
reduction of the corticosteroid dose and maintenance dose administration on
every second day, the symptom-free status was maintained, relatively few
side-effects were observed and the quality of life of the patients improved.
Conclusion: We recommend prednisolone as first-line treatment and for
maintenance therapy. The maintenance dose can be reduced to a very low level
but the permanent cessation of steroid is not suggested in most cases. A
lifelong low dose corticosteroid is usually required for these patients to
prevent recurrence of the disease.
Keywords: Systemic treatment; Autoimmune bullous diseases; Intermittent
corticosteroid therapy; Maintenance dose; Side-effects
1. Introduction
Autoimmune blistering
skin diseases are uncommon disorders characterized by the presence of
autoantibodies directed against desmosomal proteins (in the pemphigus group),
or against adhesion molecules of the dermal-epidermal junction (in pemphigoid
diseases) [1].
The most frequent
autoimmune bullous diseases are Pemphigus Vulgaris (PV) and Bullous Pemphigoid
(BP), the incidences of which differ in the various geographical regions
[2-10]. Pemphigus is less frequent, the incidence in central Europe ranging
from 0.6 to 6.8 new patients/million/year (3,7). The proportion of the
population with pemphigus is higher in South-east Europe, Iran, in the Romanian
Jewish population, and in the Mediterranean region [8-10]. BP has a reported
incidence of 13.4-42 new patients/million people/year [3-6] with 150-190 new
patients/million/year in the population aged 80 years and above [5,10].
The most frequent
subepidermal bullous disease is BP. The two major target antigens have been
identified in the hemidesmosomal proteins of the basal membrane, BP180 and
BP230. Autoantibodies against these proteins mainly belong in the IgG class. BP
is a much milder disease than PV, and lower doses of CSs are suggested for its
treatment.
In both diseases the
therapeutic management comprises mainly immunosuppression with CSs or
CS-sparing agents. Specific treatment options include the therapeutic blockage
of autoantibody production, cytokines or signaling pathways. A wide range of
medication is used in the treatment, such as azathioprine, methotrexate,
cyclophosphamide, mycophenolate mofetil, cyclosporine or dapsone. Intravenous
immunoglobulin (Ig), immunoadsorption, plasmapheresis and rituximab can also be
used [14-26].
Despite the numerous
therapeutic choices, the gold standard in the systemic treatment of PV and BP
is CS. A number of treatment guidelines have been put forward, but in many
centers the patients are treated according to the local tradition. We treat
autoimmune bullous skin diseases with CSs in an alternating daily dosage, which
differs from literature recommendations, and we report here a retrospective
analysis of the efficacy and the side-effects of this therapy.
2. Materials and
Methods
Between January 2004
and January 2015, 70 patients with PV (mean age at onset 54.37 years) and 78
with BP (mean age at onset 73.39 years) were treated at our clinic. There were
more female patients than male patients, in accordance with the literature
experience (Table 1) .
The diagnoses of the autoimmune bullous diseases were based on the clinical
features and routine histological and immunohistological examinations (Direct
Immunofluorescence (DIF), Indirect Immunofluorescence (IIF), and Salt Split
Skin Technique (SSS) as described previously [27-30]. In PV, DIF demonstrates
the binding of IgG and/or C3 to the Intercellular Cement Substance (ICS). IIF
with the use of epidermal substrate (monkey or rabbit esophagus) identifies the
presence of anti-ICS antibody with IgG and C3. The recombinant ectodomains of Dsg1
and Dsg3 have been utilized to develop highly sensitive and specific ELISA
assays. The different types of pemphigus (such as PV, pemphigus foliaceus and
paraneoplastic pemphigus) were also distinguished by the detection of
circulating autoantibodies by Western blotting.
In BP, linear basement
membrane zone deposits of IgG and C3 are seen in DIF. In IIF with SSS technique
the circulating IgG antibodies bind to the epidermal side of the SSS (lamina
lucida). We earlier used our “home-made” ELISA tests for the detection of
circulating autoantibodies in order to achieve a more accurate diagnosis
[28,29], here as in the last 6 years we have applied commercially available
ELISA tests to detect the main autoantibody entities (MESACUP BP180 and BP230
tests, Dsg1 and Dsg3 tests; MBL Medical and Biological Laboratories, Nagoya,
Japan) [28]. In some patients the presence of BP230 and BP180 autoantibodies
were also demonstrated by means of Western blotting, which helped to establish
the diagnosis of BP.
Before the treatment
of our patients was started, the blood glucose level, full blood count and
differential, electrolytes, liver and kidney function tests and blood pressure
were measured and urinalysis was performed. During the treatment osteoporosis
was controlled with DEXA scan in every second year.
3. Results
During the last 10
years, we have not lost any patients in the consolidation phase of either PV or
BP, and we have succeeded in stabilizing and achieving a symptom-free status in
almost 100% of the cases. The alternated-day CS therapy that we applied
differed from the treatment guidelines for autoimmune bullous skin diseases.
(Table 2).
Presents data on
patients followed up for at least 1 year and in whom the CS dose given every
second day reached a level which could be administered as long-term maintenance
therapy.
During the follow-up period, 12 PV patients and 29 BP patients died. The cause
of death was pulmonary embolism in 2 PV and 1 BP patients, different kinds of
tumors (breast cancer and lung cancer) in 2 PV patients and 2 BP patients, and
cardiac or respiratory failure in 3 PV patients and 6 BP patients. We could not
find information as to the exact cause of death of 4 PV patients and 20
The most common form
of pemphigus, PV; accounts for 70% of all pemphigus cases [1]. PV is often
life-threatening, without treatment its mortality is nearly 100% [12]. In the
1950s, before the use of oral corticosteroids (CSs), the mortality rate was 75%
[13] Antibodies are directed against antigens (desmoglein (Dsg) 1 and 3) in the
desmosomes linking keratinocytes.
BP patients in the
computer database at our department. The mean age at death in PV was 71.9
years, and in BP was 81.3 years.
3.1 The therapy of PV
and BP
Our first choice of
therapy was CS. The initial dose was selected with regard to the severity of
the disease, the general status of the patient, and incidental co-morbidities
(Diabetes Mellitus (DM), hypertension, anticoagulant treatment and cardiac diseases).
In PV we administered a higher dose of CS, generally 100 mg (1.2 mg±0.2 mg/kg
body weight/day), and in BP a lower dose, generally 50 mg (0.6±0.1 mg/kg body
weight/day). The CS was always given in a single daily dose, in the morning.
The CS was generally oral prednisolone, but methylprednisolone was administered
intravenously to patients with severe oral erosions or who experienced intense
pain on swallowing many tablets or who presented extensive clinical symptoms.
In the course of the dose reduction methylprednisolone was changed for
prednisolone as soon as possible; methylprednisolone treatment was given
throughout the follow-up period in 4 PV and 4 BP patients.
When progression ceased and no new blisters appeared, the initial dose was
begun to be gradually reduced. In PV this generally took 2 or 3 weeks, while in
BP 1 or 2 weeks was needed to reach the symptom-free state. The initial CS dose
was then decreased alternately, every second day. The treatment was
supplemented with azathioprine at 100−150 mg daily in 18 PV patients (25.7%),
especially who had oral mucosa involvement, due to its steroid-sparing feature.
In 13 cases of BP (16.6%), where the clinical lesions were wide spreader the
status of the patients did not improve sufficiently, the therapy was similarly
supplemented with azathioprine. Before the start of azathioprine therapy,
measurement of thiopurine methyl transferase activity is suggested in order to
examine the risk of drug-induced Bone Marrow Toxicity (BMT). Since there is no
technical possibility to use this test in Hungary, we closely monitored the
patients for BMT. The patients who received azathioprine treatment exhibited no
other risk factors or other suspected clinical or laboratory signs of
myelosuppression.
Besides the immunosuppresssant
therapy, gastroprotective medication (generally an H2 receptor inhibitor) and
potassium and calcium replacement were given with vitamin D3 to the prevent
osteoporosis.
An example of the alternating steroid therapy decrease in a representative BP case
is presented in (Table 3).
This demonstrates how the CS dosage was reduced in an alternating manner.
We start to reduce the dose on every other day by half. Then, in line with the
patient’s clinical symptoms, we continue the reduction of the corticosteroid
dose, usually at weekly intervals, maintaining the situation that the higher
dose is always alternated with a dose that is 50% lower. When the higher dose
has reached 30 mg/day, we reduce the lower dose in 5 mg steps to zero. The rate
of dose reduction and the final dose can depend on the patient’s status; the
severity and the extent of the disease slower in pemphigus, and faster in
pemphigoid during a period of some months or even years, until the definitive
maintenance dose is reached. Finally, the maintenance corticosteroid dose (in
PV 25-30 mg CS and in BP generally 15-20 mg,) is administered only every second
day. Thus the difference in the mode of reduction of the doses from the
literature recommendations is that we reduce the corticosteroid dose by
alternating between a lower and a higher corticosteroid dose, together with
progressive dose reductions. The achieved maintenance dose may be reduced very
cautiously during months or years, but its permanent omission is usually not
possible. The interval required for the reduction was longer in PV than in BP,
but the final dose was always defined by the actual status of the patient or
the emergence of new symptoms. In patients with DM, we strived to reduce the CS
dose and the azathioprine therapy as fast as possible.
In our practice, CS treatment combined with azathioprine was generally
sufficient.
3.2 Complications
The complications of
long-term systemic CSs are well known: DM, iatrogenic Cushing’s syndrome,
infections, osteoporosis, hypertension, gastrointestinal ulcers, and a loss of
calcium and potassium. The side-effects that occurred among our patients are
listed in (Table 4).
Infection was detected
in 16 patients with PV, and in 8 with BP. Herpes zoster, erysipelas and
pneumonia infections were most frequent.
Previously existing DM
worsened in 9 patients with PV, and in 3 with BP. New DM emerged in 3 patients
in each group. 5 PV and 4 BP patients with long-standing DM needed correction
of their antidiabetic therapy after the implementation of CS. In 3 DM PV patient’s
transient and in 1 permanent insulin therapy was needed after the CS therapy.
Iatrogenic Cushing’s syndrome developed in 5 patients with PV and in 1 with BP.
Osteoporosis (proved
by DEXA scan) developed in 9 PV patients. At the beginning of high-dose CS
therapy, blood pressure spikes were observed in 3 patients with PV, and in 2
with BP. Only 1 patient suffered a serious gastrointestinal complaint during CS
treatment (but no hemorrhagic ulcer).
During the treatment with azathioprine, the liver function levels increased in
5 PV and 3 BP patients, but in all 8 cases normalized after a decrease of the
dose of azathioprine or after a transient or permanent cessation of
azathioprine therapy.
4. Discussion
Since PV is an
autoimmune disease, the most common mode of treatment is CS and other
immunosuppressant agents. After CSs became available from the 1950s, the
mortality of PV fell from 73% to 29% and then to 5.9% following the
introduction of adjuvant therapy [31]. The cornerstone of therapy is still CS,
as both initial and maintenance therapy. The management guidelines of PV
published in 2015 by the European Dermatology Forum in cooperation with the
European Academy of Dermatology and Venereology recommend CS therapy at a daily
dose of 0.5-1.5 mg/kg daily dose for both PV and BP [32]. If the patient’s
clinical status does not improve within 2 weeks, a higher dose (up to 2
mg/kg/day) is suggested. Steroid pulse therapy is recommended in refractory
cases. After 2-3 weeks of prednisolone therapy, the blisters are usually
healing, and new lesions do not appear, and the CS dose may then be cautiously
decreased. The latest guidelines suggest the tapering of prednisolone in
bi-weekly 25% reduction steps. For adjuvant treatment, azathioprine,
cyclophosphamide, mycophenolate mofetil, gold, methotrexate, cyclosporine and
dapsone are available. The dose of azathioprine (most frequently used) is 1-3
mg/kg daily. In our 10-year study period there were 3 PV cases where CS
administration could be stopped, but these patients are currently receiving
azathioprine.
There have been no
large randomized controlled clinical trials to determine the most effective
treatment for PV. In severe or certain special cases, other forms of medication
or therapy may be suggested, e.g intravenous Ig or plasmapheresis. Rituximab,
an anti-CD20 monoclonal antibody, has recently proven to be highly effective in
severe and refractory patients [33].
The best-established
initial therapy for BP is systemic CS. In localized or mild BP, topical CSs alone
may be successful. The BP management guidelines, published in 2012 by the
British Association of Dermatologists, suggest 0.3, 0.5 and 0.75-1 mg/kg
prednisolone daily for the mild or localized, the moderate, and the severe
cases respectively [34].
In the treatment of PV
and BP, we use similar doses during the initial therapy as suggested in the
latest guidelines, but during the reduction of the prednisolone dosage we
prefer to reduce the CS dose on alternate days rather than daily, and for
maintenance therapy the patients receive CS only every other day. In the last
10 years we have treated and followed up 70 patients with PV and 78 patients
with BP by using this CS regimen, combined with azathioprine (100 to 150 mg
/day) if needed, and a symptom-free status could be attained in most cases. We
usually set the initial dose somewhat high, the reason being that when the
initial CS dose was not effective in preventing new symptoms within a few days,
it was more difficult to reach a symptom-free state and higher doses of CS with
additional immunosuppressant therapy were needed. We had only 2 cases where
intravenous Ig was required. We had no need for other therapies.
Table 4 reveals that
the alternate-day CS therapy that we used was accompanied by more side-effects
in PV than in BP. This can be explained by the higher dose and the slower CS
reduction in PV. The most frequent side-effects were infections, found in 16 PV
patients (20.1%) and 8 BP patients (9%). In a literature cohort of more than
1200 PV patients, infections were also the most frequent complications, in 19%
of the cases [35]. The infection rate seems similar for the alternate and the
daily usage of CS.
Osteoporosis was
demonstrated by the DEXA scan in 13% of the PV patients, but its close
association with the CS treatment could not be proved in every case as it can
otherwise occur in elderly patients. CS-induced DM is also well known to
develop during long-term daily CS therapy via the development of insulin
resistance. The use of CS increases the risk of new DM 2−4- fold [36]. A
Brazilian study found that the incidence of DM and glucose intolerance among PV
patients treated daily with CS was 22.5% among females and 26.67% among males
[37]. With alternating CS treatment, we observed a lower incidence: 13 cases
with DM-related side-effects, i.e 15.5% of the PV patients. Iatrogenic
Cushing’s syndrome occurred in 7.1% of the PV and 1.3% of the BP cases.
Hydrocortisone at a dosage of 20 mg/day was earlier reported to decrease the
function of the hypothalamic-pituitary system. Prednisolone at 5 mg/day can
promote the formation of Cushing’s syndrome. However, if CS is given every
second day, this side-effect occurs only if the dose of prednisolone reaches 40
mg [38,39]. In a view of these results and our own experience, the relatively
rare occurrence of Cushing’s syndrome can be explained by the use of
prednisolone instead of methylprednisolone and alternate-day steroid therapy.
Although we have
reported here only our experience with alternating CS therapy during the last
10 years, we have been using this therapeutic approach for 40 years. During
this period, we have gained considerable experience with the treatment and the
follow-up of patients with autoimmune bullous diseases: 463 patients with BP
and 282 with PV have been diagnosed and treated at our clinic since the 1970s.
Some of our early patients gave up the maintenance CS treatment arbitrarily,
because they felt fully recovered. Moreover, the therapy was sometimes also
stopped at the suggestion of the general practitioner because of the
development of other medical problems. In these cases, the disease generally
recurred within several months, or at most 1 or 2 years. Hence, as the
recurring disease is less responsive to treatment, we consider that a very low
sustaining dose of CS is necessary virtually lifelong for most patients. Most
of our patients have in fact continued with the maintenance therapy. We do not
have exact data as to how many patients stopped the CS therapy arbitrarily
during the treatment, but we are aware of 2 PV and 3 BP patients who have been
without therapy for 1.5 and 3 years and in whom the disease has not recurred
yet. This draws attention to the recommendation of the latest guidelines
advising that, without clinical symptoms, discontinuation of the treatment
should be considered if the Dsg ELISA results and/or IIF findings are negative.
In the 1970’s and 80’s some reports were published about the beneficial effect
of alternate-day CS therapy, but its use in the daily routine has not spread.
Fauci et al found that prednisone given in a single dose on alternate days in
the morning did not interfere with the normal ACTH-cortisol cycle, nor would it
expose the tissue to sustained levels of hormone throughout the day, which
would have been the situation if the CS was given daily [40]. Gallant reported
normal neutrophilic accumulation in patients receiving alternate-day therapy
but decreased numbers of it in patients getting daily-dosage regimen. Monocyte
accumulation was normal on the alternate day and a little bit reduced on the
prednisolone day. This accumulation in patients receiving daily prednisone was
persistently suppressed [41].
Only a few reports are
available concerning the benefits of alternating versus daily CS treatment in
autoimmune diseases. Uchino et al. reported the same efficacy of alternating
and daily-dose prednisolone therapy in patients with myositis, the incidence of
side-effects proving lower in the former. The incidence of diabetes was found
to be significantly higher in the daily therapy group. They additionally found
a difference in the 20-year survival rate, which was significantly higher (68%)
in the alternating group than in the daily group (37%) [42]. In a retrospective
cohort study carried out in Germany on 369 patients diagnosed with BP and given
CSs daily, 209 patients (57%) died during the 10-year follow-up (from 1987
until 1997) [43]. The 10-year survival rate in the BP group among our patients
was 37% [29 -78]. Although the German and Hungarian patient groups are not
directly comparable, it is possible that our better survival rate may be
related to the alternating CS dosage that we used.
Alternating CS therapy
is used in other autoimmune diseases (lupus nephritis, myeloma multiplex,
Crohn’s disease, myasthenia gravis, IgA nephropathy and membranoproliferative
glomerulonephritis). Berenson et al. observed that alternate-day CS (50
mg/every second day) as maintenance therapy improved the survival of myeloma
multiplex patients [44]. A retrospective analysis of Crohn’s disease patients
concluded that alternate-day prednisone may even reduce the symptomatic flares
[45]. Greek experts successfully used the combination of azathioprine and the
alternate-day 40 mg prednisone in patients with oral involvement of PV to achieve
effective control of the illness. [46].
Our results and the
literature references lead us to recommend alternate-day CS treatment in the
therapy of autoimmune bullous skin diseases.
5. Conclusions
Our 10-year
statistical data and our experience of more than 40 years with the treatment of
autoimmune bullous disease patients indicate that alternated-day CS treatment
is adequately effective without causing side-effects. In both PV and BP it is
probable better to “overshoot” than down-dose the CS at the beginning, but
bearing in mind that the subsequently given increased dose is not always
effective, especially in PV.
Alternating CS therapy
causes relatively few side-effects, the patients can reach and maintain a
symptom-free condition, and the maintenance CS dose can be decreased to a very
low level.
We have experienced
that a very low dose of CS dose should generally be prescribed almost lifelong
for these patients. A very low dose of CS given virtually lifelong may result
in fewer side-effects than when an elevated re-dosage is required because of
recrudescence of the disease after the total cessation of CS. Very rarely, we
have encountered patients with autoimmune bullous diseases in long-term
equilibrium without CS therapy. In certain cases, following the ELISA
measurement of anti Dsg1 and/or Dsg3 IgG and with negative direct IF results,
the CS therapy might possibly be discontinued. Further investigations are
called for to clarify this question.
2004-2014 |
PV |
BP |
No. of Patients |
70 |
78 |
Male |
32 |
34 |
Female |
38 |
44 |
Age on Onset |
27-82 years |
49-99 years |
Mean age at Onset |
54.37 years |
73.39 years |
Table 1: Age and Gender Charateristics of patients followed up during the last 10 years.
2004-2014 |
PV |
BP |
No. of Patients |
70 |
78 |
Follow-up time |
1.5-10 years |
1.5-10 years |
Mean Follow-up time (years) |
6.93 years |
3.45 years |
Steroid Maintenance Dose |
5-40mg/every second day |
5-30mg/every second day |
Mean Steroid Maintenance Dose |
16.64 mg/ecery second day |
15.67 mg/ecery second day |
Table 2: Steriod Therapy in Patients.
Treatment Time |
Prednisolone Dosage |
0 weeks |
60mg everyday |
2 weeks |
60mg-30mg alternated |
4 weeks |
30mg-15mg alternated |
6 weeks |
30mg-10mg alternated |
8 weeks |
30mg-5mg alternated |
10 weeks |
30mg every second day |
14 weeks |
25mg every second day |
26 weeks |
20mg every second day |
50 weeks |
15mg every second day |
Table 3: Reduction of prednisolone dosage in BP.
Side-effects |
|
PV (n=70) |
BP (n=78) |
Infection |
Herpes Zoster |
4 |
2 |
Erysipelas |
2 |
2 |
|
Pneumonia |
8 |
4 |
|
and other inf. |
|
|
|
Total |
14 |
8 |
|
|
|
20% |
10.20% |
DM |
Worsening of existing DM |
9 |
4 |
|
|
12.80% |
5.13% |
Iatrogenic Cushing's sy. |
|
5 |
1 |
|
|
7.10% |
1.30% |
Osteoporosis |
|
9 |
1 |
Blood Pressure spike |
|
3 |
2 |
Steroid acne |
|
2 |
0 |
Gastric complaint |
|
1 |
0 |
Table 4: Side-effects of corticosteroid treatment.