Pulse therapy
as a cure for autoimmune diseases
Pasricha JS
Department of Dermatology and
Venereology, AIIMS, New Delhi - 110029Correspondence Address:
Skin Diseases Centre, 1-A, Masjid Moth, DDA Flats, Phase-1,
Outer Ring Road, Near Chirag Delhi Flyover, New Delhi - 110048
j
How to cite this article:
Pasricha JS. Pulse therapy as a cure for autoimmune
diseases. Indian J Dermatol Venereol Leprol
2003;69:323-8 |
Pulse therapy means the administration of large
(supra-pharmacologic) doses of drugs in an intermittent manner
to enhance the therapeutic effect and reduce the side effects.[1],[2],[3]
The first reported use of pulse administration of
corticosteroids is attributed to Kountz and Cohn[4]
who used it to successfully prevent renal graft rejection.
Subsequently, pulse doses of corticosteroids were used for
several other diseases such as lupus nephritis, rheumatoid
arthritis and pyoderma gangrenosum,[5],[6],[7]
but usually to deal with emergency situations only and not as a
preferred method of treatment. Methylprednisolone was the
commonest drug used, in a dose of 1 g per dose for a variable
number of days.
We first used pulse therapy in a patient having Reiter′s disease
and could save him from an almost certain death.[8]
Continued use of pulses at 1 month intervals led him to a
remarkable recovery and a fairly useful life for the next 10
years. For pemphigus, the pulse therapy was first used by us in
1982,[9] for systemic
sclerosis in 1989,[10]
for pyoderma gangrenosum in 1990,[11]
and other diseases in subsequent years.[1]
However, we used 100 mg dexamethasone on three consecutive days
at 4 week intervals and continued to use the pulses for a
specified period even after the patient had recovered from the
disease completely. This was done to ensure that the patient
would not develop a relapse in future. By now we have used pulse
therapy for more than 1000 patients having pemphigus, 100 cases
of systemic sclerosis, 25 patients having systemic lupus
erythematosus, 20 patients having dermatomyositis, 10 patients
having pyoderma gangrenosum and fewer cases of other diseases
including extensive lichen planus, prurigo nodularis,
generalized morphea, DLE, scleredema, recurrent alopecia
universalis, extensive vitiligo, allergic vasculitis,
disseminated porokeratosis, Darier′s disease, Hailey-Hailey
disease, multiple keloids, sarcoidosis, multicentric
histiocytosis, and Peyronie′s disease with similar success. With
this experience over the last nearly 20 years, it seems logical
to claim that it is now possible to cure almost all the
autoimmune and several other corticosteroid responsive
dermatoses and avoid the side effects commonly associated with
the conventional daily-dose regimens of corticosteroid
administration. To achieve optimum results it is important to
strictly follow the regimen recommended by us in all its
details. Any compromises have produced inferior results.
The pulse therapy regimen designed by us is called the DCP
regimen or the dexamethasone-cyclophosphamide pulse (DCP)
therapy regimen. In its present form,[1]
it consists of giving 100 mg dexamethasone dissolved in 500 ml
of 5% glucose as a slow intravenous drip over 2 hours repeated
on 3 consecutive days. On the second day, the patient is also
given 500 mg cyclophosphamide in the same drip. This constitutes
one DCP. Such DCPs are repeated at exactly 28 day intervals
counted from the first day of the pulse. In between the DCPs the
patient receives only 50 mg cyclophosphamide orally per day. The
DCP regimen is administered in four phases. During the first few
months (phase I) the patient may continue to develop recurrences
of clinical lesions in between the DCPs and can therefore be
given additional treatment (conventional daily doses of oral
corticosteroids or additional dexamethasone pulses) to achieve
quicker clinical recovery, and these are as a rule withdrawn
step-wise during the subsequent DCPs. After the skin and the
mucous membrane lesions have subsided completely and the
additional medication has been withdrawn, the patient is
considered to have entered phase II. During this phase, the
patient remains completely alright clinically but receives 9
more DCPs at exactly 28 day cycles along with 50 mg
cyclophosphamide orally per day. During the next phase (phase
III), the DCPs are stopped and the patient receives only 50 mg
cyclophosphamide orally per day for the next 9 months. After
this, the treatment for pemphigus is withdrawn completely and
the patient is followed up for the next 10 years to look for a
relapse if any (phase IV).
During the earlier part of our project, we used to give 6 DCPs
during phase II and the duration of phase III was 12 months.
Since the pulse therapy regimen virtually cures every pemphigus
patient for the rest of his life and there are almost no side
effects, all pemphigus patients deserve to be treated with this
regimen irrespective of whether they are having severe or mild
disease. Even those patients who are in clinical remission but
have to
take maintenance doses of corticosteroids/immunosuppressive
drugs, can be made to give up the maintenance doses by
administering them a course of the DCP regimen.
There are almost no contraindications. DCP therapy can be given
to patients of all ages but the doses have to be reduced to half
for children below the age of 12 years. It can also be given to
patients having diabetes mellitus, hypertension, hyperacidity,
osteoporosis, tuberculosis, etc., but each patient must receive
additional appropriate treatment for the concomitant disease
whenever necessary. Diabetic patients need to be given 10 units
of soluble insulin for every 500 ml bottle of 5% glucose
dissolved in the same drip in addition to the routine treatment
for diabetes. Hypertensive patients must monitor the blood
pressure regularly and adjust the treatment for hypertension if
necessary. Patients having hyperacidity can continue to take
antacids or H2 blockers as required and even those having active
tuberculosis can continue the pulse therapy along with the
anti-tubercular treatment. Viral warts and molluscum contagiosum
can also be treated concomitantly along with the pulse therapy.
If a patient has severely infected lesions or there is a serious
infection elsewhere, the start of the pulse therapy can be
delayed for a week or two till the infection has been brought
under control. Similarly patients having herpes zoster, herpes
simplex or even chicken pox can be given concomitant treatment
with acyclovir and the pulse therapy can be continued except
under exceptional circumstances when the viral infection is very
severe.
The only contraindication for pulse therapy is pregnancy or if
the patient is a lactating mother and feeding her infant. This
is also not an absolute contra-indication; the pulse therapy is
only to be postponed till the patient has delivered her baby and
stopped feeding the child. Till that time, the patient is to be
maintained on a regular dose of corticosteroid just sufficient
to keep the disease under control or even given a shot or two of
dexamethasone alone in consultation with the obstetrician.
Patients who are unmarried or those who have not yet completed
their family and want to have more children, have to be given
only dexamethasone pulses (DPs) and not DCPs. Cyclophosphamide
in the pulses has to be avoided because it can lead to
amenorrhea or azoospermia in a significant proportion of
patients. The low dose daily cyclophosphamide can be continued.
During the first few years, pulse therapy was given to only a
few selected patients, especially those with severe disease.[9]
however, the dosage schedule was haphazard and arbitrary as we
were not sure of the total regimen. The patients were also
irregular in follow up; they reported for the pulses at their
own convenience and tended to stop the treatment by themselves.
After about 2 years, a review revealed that several of the
patients treated with the pulse therapy had not developed any
relapse for long periods without any maintenance treatment, and
thus we realized that pemphigus could possibly be cured.[12]
Subsequently, we formulated an arbitrary regimen divided into 4
phases which was used to treat almost all pemphigus patients.[13],[14],[15],[16],[17]
Several patients still did not complete the course and/or
received the pulses at irregular intervals.[1]
The relapse rates during follow up (recurrence of the disease
after having completely recovered from the disease) were 53.8%
in the patients who had received incomplete treatment and 18.2%
in the patients who had received their DCPs at irregular
intervals. Subsequently, we tried two modifications of the
regimen. In the first modification, we increased the number of
the mandatory DCPs during phase II from 6 in the original
regimen to 9, and correspondingly reduced the duration of phase
III from 12 months to 9 months. The relapse rate in the group
who received the pulses at irregular intervals was 18.7%
compared to 8% in the group who received their pulses at exactly
28 day cycles. In the second modification, we used only
cyclophosphamide for the pulses during phase II of the regimen.
The relapse rate in this group was 23.5%.[1]
All patients who developed a relapse were given the second
course of the DCP regimen ensuring better compliance of the
regimen. There were only a few patients who were persistent
defaulters and needed more than 2 courses. The relapses in all
cases were mild and responded easily to the next course.
Between 1982 and 1998, 500 pemphigus patients (pemphigus
vulgaris 444, pemphigus foliaceus 33, pemphigus erythematosus
18, and pemphigus vegetans 5), with an almost equal sex ratio
(251 males, 249 females) were enrolled for the DCP regimen.
There were 44 patients younger than 20 years, 246 patients aged
20-40 years, 190 patients aged 40-60 years and 20 patients older
than 60 years. Of these, 97 patients could not complete the
treatment, and 19 patients died due to a variety of causes which
were mostly unrelated to the disease or its treatment, or causes
that were preventable with better patient management. The
remaining 384 patients recovered from the disease and are living
without any disease and without any maintenance treatment. Most
of them have already crossed the 5 year post-treatment follow up
period.[1]
This experience led us to conclude that pemphigus can be
controlled in almost every patient and if the patient strictly
follows the DCP regimen, he can be cured for the rest of his
life. The treatment administered during phase II and III is
necessary for ultimate cure; during phase II the most effective
treatment consists of 9 DCPs taken at exactly 28 day intervals,
with a daily oral dose of cyclophosphamide, followed by 9 months
of daily cyclophosphamide during phase III. Compromises of any
kind lead to inferior results and increase the chances of a
relapse.
It is also important to remember that although the DCP regimen
cures pemphigus, this does not mean that the patient has been
protected from developing other diseases. The patient is as
prone to develop other cutaneous or mucosal diseases as any
other normal individual. Therefore subsequent lesions such as
dermatophytosis, scabies, pyoderma or even lichen planus or
aphthous ulcers in the mouth should not cause apprehension in
the patient or the dermatologist that pemphigus has recurred.
Several patients continue to develop aphthous ulcers in the
mouth even during pulse therapy and this has often led some
dermatologists to consider the DCP regimen as a failure in a
small percentage of the patients. One should be able to
distinguish aphthous ulcers from pemphigus ulcers because
aphthous ulcers are far more painful, have a necrotic circular
centre and an inflamed red periphery, and most ulcers heal
within a few days, whereas pemphigus ulcers are far more
persistent.
During the earlier experience at AIIMS, although almost every
pemphigus patient recovered from the disease, in some patients
the duration of phase I was very long as oral ulcers would
persist for several months-years. After my retirement from AIIMS
therefore, the DCP regimen was modified as follows:
Treatment in all patients with active disease was started with
betamethasone 2-3 mg/day orally, ketoconazole 200 mg/day orally
and 500 mg ciprofloxacin or cefadroxil twice daily, in addition
to the DCPs and the daily dose of 50 mg cyclophosphamide. The
patients were also encouraged to clean the oral cavity with
regular brushing of the teeth, and ignore the pain, the bleeding
or the risk of peeling the oral mucosa. They were also advised
to massage a topical corticosteroid gel on the oral ulcers 3-4
times a day especially after every meal.
This change in the regimen generally led to healing of all the
skin lesions within 1-2 months and the oral lesions within 2-3
months. The antibiotic was withdrawn after all the skin lesions
had healed and ketoconazole was withdrawn after the oral ulcers
had healed, while the dose of betamethasone was reduced
step-wise by 1 mg at the time of each subsequent DCP.
With this modification, the duration of phase I in almost all
the patients was reduced to around 3-6 months, with the result
that all the 20 patients enrolled during the year 1998 have
already completed the treatment and are now in phase IV.
Patients enrolled during the subsequent years are also following
the same pattern.
During the initial stages of the project, we had to evaluate the
side effects of the large doses of corticosteroids and
immunosuppressive drugs used. As a routine, we would admit every
patient enrolled for pulse therapy and undertake a complete
clinical and laboratory evaluation before starting the pulse and
again after completing the pulse to look for side effects.
Special care was taken to monitor the effects of the pulse on
the total leukocyte counts, electrolyte levels, blood sugar
levels (in normal individuals as well as in diabetic patients)
and blood pressure values (in normotensive as well as
hypertensive patients). The changes in all these parameters were
found to be infrequent, insignificant and random, and possibly
not related to the pulse administration. The admission period of
the patients was therefore reduced to 3 days from the initial 5
days and the laboratory monitoring of the patient was restricted
to the prepulse evaluation only.
Monitoring of the toxicity/safety on a long-term basis revealed
that pulse therapy is extremely safe, it does not lead to an
increase in the body weight unless the patient was receiving
daily corticosteroids, and if the patient had already developed
cushingoid obesity due to previous treatment the body weight and
appearance would actually return to normal during the pulse
therapy. There was also almost no risk of developing diabetes,
hypertension, peptic ulceration, osteoporosis, striae, acne,
hirsutism or other side effects commonly associated with
corticosteroids unless the patient was receiving or had received
conventional daily doses of corticosteroids. The risk of
increased pyogenic infections on the skin, and candidiasis in
the mouth persisted only as long as the patient had ulcers on
the skin and oral cavity, and therefore vigorous treatment with
systemic antibiotics and antifungal agents during this period
was very helpful. Subsequently there was almost no risk.
Similarly, viral or dermatophyte infections also needed to be
treated on their own merit without interrupting the pulse
therapy regimen. A few patients did develop reactivation of
tuberculosis for which anti-tubercular treatment was given
concomitantly without interrupting the schedule of the DCP
therapy.
Similarly, side effects associated with cyclophosphamide were
also generally very infrequent. Leukopenia, thrombocytopenia and
anemia were rarely seen. Generalized hyperpigmentation was
observed in 5 patients and hemorrhagic cystitis in another 5
patients, especially those who were irregular in their treatment
and needed too many DCPs for effectively controlling the
disease. Malignancy as a side effect of cyclophosphamide was not
seen in any patient. The major side effects of cyclophosphamide
in our patients were diffuse hair loss (which was reversible in
all cases) and amenorrhea (and possibly azoospermia) in a
significant proportion of patients. Subsequently therefore, for
the patients who had not yet completed their family and wanted
to have more children, we used only dexamethasone for the pulses
(DPs), though the low dose daily cyclophosphamide was continued.[1]
The other side effects of DCP therapy included a feeling of
weakness and tiredness due to corticosteroid withdrawal for 2-3
days after the pulse, bad taste in the mouth and loose motions
coinciding with the pulses (both of which would respond to a 7
day course of ciprofloxacin for 2-3 consecutive pulses),
recurrent hiccup after the pulse (observed in a few patients),
cataract (which was observed only in the elderly and could be
coincidental), and bone pains and aseptic necrosis of the bones
which were attributable more to the conventional daily dose
treatment received earlier rather than the pulse therapy.
It was thus obvious that the pulse mode of administration was
far safer than the daily dose regimens in spite of the high
doses used, and considering its curative effect on the disease
there is no justification for persisting with the conventional
daily dose mode of treatment.
After having gained experience with the administration of pulse
therapy, it also became clear that there was no need to
hospitalize the patient (and no need to have continuous cardiac
monitoring during the pulse, as practiced in the West). Slow
administration of the dose over approximately 2 hours given in
the same manner as any glucose drip in a day-care unit (at the
AIIMS) or in a private clinic (post-retirement) is all that is
necessary. The patients are, as a rule, sent back home after
receiving the pulse. Patients having renal, hepatic or cardiac
disease (especially arrhythmias) would certainly require
clearance and appropriate treatment from the respective
specialists.
Two types of immunofluorescence tests were undertaken in our
patients: direct immunofluorescence (DIF) on the
perilesional/normal-looking skin (to look for autoantibodies
deposited at the intercellular areas), and indirect
immunofluorescence (IIF) on the blood (to look for circulating
intercellular autoantibodies). These tests were positive in
almost all patients and helped confirm the diagnosis and monitor
the response to the treatment, but occasionally they were
negative even when the clinical diagnosis was undisputed and the
titer of the autoantibodies was higher after treatment even when
the patient had clinically recovered completely. We have
encountered patients who continued to show positive DIF and/or
IIF even 5 years after treatment without their disease
relapsing. Thus, in our opinion the amount of treatment to be
given should depend upon the clinical state and not the DIF/IIF
results.
The selection of drugs and their dosages was completely
arbitrary and based upon intuition and convenience. Whereas
people in the West had used methylprednisolone, we preferred to
use dexamethasone which was nearly 200 times cheaper. The dose
of dexamethasone was fixed at 100 mg because it was easily
available commercially. Three doses per pulse were considered to
be adequate and convenient and found to be effective. The dose
of cyclophosphamide for the pulse was also fixed at 500 mg for
the sake of convenience and effectiveness without producing any
serious side effects. It was however given only on one day of
the pulse and not repeated earlier than 4 weeks. More frequent
administration or using higher doses per pulse can lead to more
frequent side effects. The oral dose of 50 mg cyclophosphamide
per day had also been found to be safe because it does not lead
to leukopenia and does not need any monitoring. The interval
between the two pulses was fixed at 4 weeks for the sake of
convenience, but later on it was realized that patients who did
not follow the 28 day cycle had an increased risk of developing
a relapse during the follow up, and it is necessary to
administer the next pulse before the cells responsible for
autoimmunity start proliferating again.
The most important decision made by us to achieve ultimate cure
in pemphigus was to administer a standard dose of the treatment
after clinical remission (the treatment given during phase II
and phase III). If the treatment is stopped after completing
phase I, almost every patient is expected to develop a relapse.
On learning about the success of our regimen, several
dermatologists in other towns/institutions and even other
countries have used the pulse therapy approach for treating
pemphigus and other autoimmune diseases and many workers have
introduced their own modifications. Some people have used
methylprednisolone instead of dexamethasone, others have used
larger or smaller doses of the corticosteroid, some have not
bothered about the 28 day cycle for repeating the pulses and
some have used the oral route for administering the
corticosteroid. Similarly, some workers have used only
cyclophosphamide for the pulses while others have used
azathioprine instead of cyclophosphamide. Basically, we believe
that any combination of a corticosteroid and an
immunosuppressive drug in comparable doses should produce
similar results. Comparative studies may be undertaken but they
are really not necessary. The combination of dexamethasone and
cyclophosphamide is the cheapest and the safest. Methotrexate,
azathioprine and cyclosporine are potentially more hazardous
than cyclophosphamide. Similarly, placebo-controlled trials are
also not necessary because each patient has acted as his own
control whenever he has received treatment from other sources
before starting the pulse therapy regimen, and the differences
in the results are too obvious. Most patients treated with
conventional regimens have died, while almost all the patients
treated with the DCP regimen are alive (or have died due to
unrelated causes).
Recently some workers have also used mycophenolate mofetil or
intravenous immunoglobulin (IVIg) for pemphigus. These
drugs/regimens have no doubt been successful in inducing
remissions in pemphigus, but there is a tremendous difference
between a remission and a cure/prolonged remission without
maintainence treatment.
|
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