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Indian Journal of Dermatology, Venereology and Leprology
Medknow Publications on behalf of The Indian Association of Dermatologists, Venereologists and Leprologists (IADVL)
ISSN: 0378-6323 EISSN: 0973-3922
Vol. 69, Num. 5, 2003, pp. 319-322
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Untitled Document
Indian Journal of
Dermatology, Venerelogy & Leprology,
Vol 69, No. 5
,Sept-Oct, 2003, pp.
319-322
Editorial
Dexamethasone pulse therapy in dermatology
M. Ramam
Department of Dermatology and Venereology,
All India Institute of Medical Sciences, New Delhi - 110029,
India. E-mail: mramam@hotmail.com
Code Number: dv03049
The first report of the use of dexamethasone pulse therapy for a dermatological
disease appeared in the pages of this journal two decades
ago.1 At that time, it represented a radical change in the approach
to skin diseases as pulse therapy had previously been used mainly to prevent
transplant rejection and in
the treatment of lupus nephritis.2,3 The therapy has since been used
to treat a very large number of patients
at several centers in India4-11 and
elsewhere.12-17 This issue of the journal
carries three articles describing the use of pulse therapy and its
variants.
Details of the treatment regimens have been published previously.4,18 Briefly,
dexamethasone pulse therapy consists of the intravenous administration of 100
mg dexamethasone dissolved in 500 ml of 5% dextrose on 3 consecutive days.
The pulses are repeated every 4 weeks. Cyclophosphamide 500 mg is given as
an intravenous bolus on one day as part of dexamethasone-cyclophosphamide pulses
(DCP) in pemphigus and other diseases; these patients also receive 50 mg cyclophosphamide
daily orally between the pulses. In some patients, to achieve a quicker remission,
daily oral corticosteroids and/or 2-weekly boluses of dexamethasone are used
in addition. In pemphigus, phase II of the regimen begins when complete clinical
remission has been achieved. During this phase, the patient receives 9 more
DCPs along with 50 mg cyclophosphamide orally per day. In phase III, the pulses
are discontinued and the patient receives only oral cyclophosphamide 50 mg
a day for another 9 months.
Several factors have contributed to the success and widespread
acceptance of dexamethasone pulse therapy. One important factor was the choice
of corticosteroid. Conventionally, methylprednisolone was the agent most commonly
used in corticosteroid pulse therapy. The choice of dexamethasone made the
treatment considerably more affordable and accessible
to patients. There was concern among some workers about the equivalence of 1000
mg of methylprednisolone and 100 mg of dexamethasone
and some groups have administered pulses of 136 mg
of dexamethasone.5 However, a dose of 1000 mg of methylprednisolone
is as arbitrary as a dose of 100 mg of dexamethasone, and in the absence of evidence
that 136 mg pulses of dexamethasone are more effective, nearly all centers continue
to use 100 mg boluses. There was initial alarm and anxiety about the large doses
of corticosteroids and cyclophosphamide involved, and in the early days some
centers would administer the therapy in the ICU under continuous cardiac monitoring.
It is now given as a routine infusion, often in a day care or OPD setting, with
the patient
going home a few hours after completion of the infusion.
Another factor responsible for the effectiveness of pulse
therapy is that the treatment has evolved in response to observations of the
results of treatment in patients who were receiving this form of therapy.19 Initially,
only dexamethasone pulses were used. Cyclophosphamide boluses were added because
relapses were frequent with dexamethasone alone. Earlier, patients received
only monthly pulses of corticosteroids but with the observation that many patients
developed some degree of recurrence of lesions between pulses in the early
stages of therapy, daily oral corticosteroids were added in the first few months.
Patients with extensive, active disease are also given interval pulses of dexamethasone
during this phase. The current recommendation of administering 9 pulses after
achieving clinical remission (phase II) and 9 months of oral cyclophosphamide
therapy after stopping the pulses (phase III) was also arrived at by observing
the relapse rate in patients who were treated with varying lengths of therapy.
Similarly, the insistence on a strict 28-day cycle for pulses is based on the
observation that relapses were commoner in those who took pulses irregularly.
Dexamethasone-cyclophosphamide pulse therapy is primarily used for pemphigus
(and most of the preceding comments refer to this indication). It was initially
described as a treatment that produced quick control of the disease and reduced
hospital stay
in pemphigus.20 Later, it was noted to lead to long lasting remissions
even after stopping therapy,
virtually amounting to "cure".21-26 Pulse therapy has also
been used for other conditions, chiefly autoimmune diseases, and found to be
an effective therapy. Several papers have reported its effectiveness in systemic
sclerosis.8-10,28 By extension, other conditions associated with increased
dermal sclerosis and fibroblastic activity such as generalized morphea, keloids,
post-burn contractures and scleredema have also been treated. The treatment is
also effective in other autoimmune conditions like bullous lupus
erythematosus,30 dermatomyositis and pyoderma
gangrenosum.11,31,32 The enthusiasm for a new and effective treatment
has led to its use in a small number of patients with a wide variety of difficult-to-treat
conditions including multicentric
reticulohistiocytosis,32 prurigo
nodularis,33 disseminated
porokeratosis,34 urticarial
vasculitis,13 toxic epidermal
necrolysis,17 Stevens-Johnson
syndrome,15 generalized lichen planus, extensive alopecia areata,
extensive, rapidly spreading vitiligo, sarcoidosis, Peyronie's disease, Darier's
disease
and Hailey-Hailey disease.27 Larger studies are required to establish
the role of dexamethasone pulse therapy
in these disorders.
The adverse effects of pulse therapy are those of its constituent
drugs, corticosteroids (infections, diabetes mellitus, hypertension, hyperacidity,
and osteonecrosis) and cyclophosphamide (leukopenia, hematuria, gonadal failure,
pigmentation, and hair loss).19 These side effects are infrequent
compared to daily corticosteroid therapy. Side effects peculiar to pulse therapy
include hiccups,35 facial flushing,36 diarrhea, weakness,
generalized swelling and weight gain, joint and muscle pains.12 These
side effects are usually observed with each pulse and last for a few days afterwards.19 Most
patients are able to tolerate these symptoms and continue treatment. On testing,
pituitary-adrenal function was found to be suppressed in about half the patients
1 month after the last pulse of phase II. However, all these patients were
asymptomatic and remained well during
subsequent follow up and thus the clinical
significance of the abnormal test results is
unclear.37
Where do we go from here? We need to have reports from other
centers that use pulse therapy to confirm that the guidelines formulated for
DCP therapy are effective in producing remissions and preventing relapses.
We need to identify problem situations that require modifications of pulse
therapy and to rigorously examine that the modifications actually work. One
such problem pointed out by the Hyderabad group is the patient in whom the
disease smolders for many months. They comprise a small minority of patients
who are seen in nearly all the large centers where pemphigus is treated. In
spite of regular treatment, including daily corticosteroids and interval pulses,
these patients do not have a remission of their clinical lesions for many months.
These patients may benefit by a change in the adjuvant as was seen in two patients
reported by the Hyderabad group who responded after they were switched to dexamethasone-methotrexate
pulse. Another option may be the addition of another immunosuppressive agent
to DCP therapy. This will require close and careful monitoring of the patient
but may lead to a shorter duration of treatment and fewer side effects.
At the other extreme, we also need a way to identify those
patients who respond to treatment and have long lasting remissions even though
they have taken DCP therapy for a very short time. Attempts should be made
to identify such patients early in the course of treatment so that they may
be given a briefer or abbreviated course of therapy. This will reduce the burden
of repeated visits to the hospital and prolonged therapy.
Another change in the DCP therapy that may be considered is
the omission of daily doses of cyclophosphamide when pulse doses are being
administered. Daily cyclophosphamide is not usually required when monthly boluses
are administered, as in the treatment of lupus nephritis. It would be worthwhile
to evaluate if the results of DCP therapy can be achieved without daily cyclophosphamide
therapy while pulses are being given (i.e. during phase I and II). It may be
given only in phase III. Other variations that have been practiced include
oral pulses
with dexamethasone or betamethasone, administration of boluses
of cyclophosphamide without boluses of dexamethasone, and the use of azathioprine
or methotrexate with monthly pulses of dexamethasone.
All these variations need to be compared with the original
DCP schedule both for the rapidity of control of disease and for the
length of remission achieved after stopping the treatment. Every evaluation
of
pulse therapy, its variants or indeed any treatment for pemphigus should
report three clinical outcomes: the time to clinical remission, the duration
of remission while on treatment and the duration of remission after withdrawing
treatment. This will enable valid comparisons to be made between different
treatments.
Finally, though we know that DCP therapy works very well
in practice, there is little information about the basic science aspects
of this treatment regimen. Pharmacokinetic studies and studies of the
effects of the therapy on the immune system may help us to understand the mechanism
of action and refine this path breaking therapy further.
Acknowledgments
Dr. V. K. Sharma and Dr Binod Khaitan read the manuscript
and provided useful suggestions.
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Copyright 2003 - Indian Journal of Dermatology, Venereology & Leprology.
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