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What is Pulse Therapy|
Pulse therapy means the administration of large doses of drugs
in an intermittent manner to enhance the therapeutic effect and
reduce the side effects.
The first reported use was 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, 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. 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,for systemic sclerosis in 1989, for pyoderma gangrenosum in 1990,and other diseases in subsequent years. 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, 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.
Indications and contraindications
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.
The AIIMS experience
During the first few years, pulse therapy was given to only a few selected patients, especially those with severe disease 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.
Subsequently, we formulated an arbitrary regimen divided into 4 phases which was used to treat almost all pemphigus patients. Several patients still did not complete the course and/or received the pulses at irregular intervals. 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%.
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.
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.
Methylprednisolone ,pemphigus ,aphthous,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