Pulse Therapy

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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 The antibiotic was withdrawn after all the skin lesions had healed and ketoconazole was withdrawn after the oral ulcers had healed, while the dose of betamethasone was reduced step-wise by 1 mg at the time of each subsequent DCP.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.

Side effects

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.

Immunofluorescence tests

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.

Other regimens and drugs

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.

What is Pulse Therapy