Randomized open comparative trial of dexamethasone-cyclophosphamide pulse and daily oral cyclophosphamide versus cyclophosphamide pulse and daily oral prednisolone in pemphigus vulgaris

Indian Journal of Dermatology, Venereology and Leprology, Sep/Oct 2009 by Sethy, Pradeep, Khandpur, Sujay, Sharma, Vinod

Introduction

Pemphigus vulgaris (PV) is a relatively common autoimmune vesicobullous disorder in India with a mortality of> 90% if untreated. [1] The prognosis has dramatically improved with the use of systemic corticosteroids and various anti-inflammatory and immunosuppressive agents. However, prolonged daily therapy required to achieve a good control of PV is associated with several distressing side-effects. Pulse therapy (administration of a suprapharmacological dose of a drug over a short period at a fixed interval), initiated with the aim of completely suppressing the cyclical proliferation of immunocompetent cells, gave a new vision to the treatment of pemphigus. [2] Since the advent of the fixed dose, fixed duration regimen of dexamethasone-cyclophosphamide pulse (DCP) with daily oral cyclophosphamide (DCP C regimen) for PV in India in 1983 and its subsequent modification (addition of daily oral steroid in the initial stage in very active cases), long-term remissions have been reported in large case series of patients. [3] However, this therapy carries the disadvantage of prolonged (3 days each month) hospital stay, with high-dose dexamethasone being associated with certain distressing side-effects like flushing, hiccups, generalized weakness lasting 1-2 weeks after each pulse and secondary infections.

Another pulse regimen comprising of intravenous cyclophosphamide pulse (CP) with daily oral prednisolone (CP P regimen) has also shown encouraging results in PV in an open trial. [4] This regimen circumvents the disadvantage of DCP in being a 1 day a month therapy, thus significantly reducing the number of workdays lost due to therapy, resulting in better treatment compliance. The degree of immunosuppression is also reduced. Several studies have shown encouraging results with intravenous cyclophosphamide pulse in other autoimmune diseases with fewer side effects than daily oral cyclophosphamide, especially with regard to urinary bladder malignancies and gonadal toxicity.[5],[6] Intermittent high-dose therapy with CP probably impairs immune surveillance for relatively short periods compared with daily therapy and therefore the malignant potential of CP would be lower.

We undertook this study to compare the efficacy and side-effects of these two regimens in PV.

Methods

We conducted a randomized prospective open clinical trial. Twenty-eight cases of PV of either sex, aged 25-70 years, were inducted. Enzyme-linked immunosorbent assay (ELISA) test for anti-desmoglein 1 and 3 antibodies was performed. Unmarried patients or those who had not completed their family, patients on immunosuppressive therapy within 8 weeks or anti-inflammatory agents within 4 weeks of randomization, severe renal or hepatic disease, active peptic ulcer, inherited or acquired immune deficiency, cases with chronic or frequent drug-resistant infections or bone marrow insufficiency were excluded.

Baseline hematological and biochemical investigations, weight and blood pressure measurements were carried out and repeated during each follow-up visit. Electrocardiogram (ECG) and chest X-ray were undertaken before starting treatment and repeated at 6 months and 1 year. ECG was also carried out if a patient reported of cardiac symptoms. Urine cytology for detection of bladder malignancy and bone densitometry (DEXA scan) for steroid-induced osteoporosis was not performed.

Informed written consent was obtained from all study patients. Approval for conducting the study was obtained from our ethics committee.

Patients were randomized into the following two groups, the randomization numbers being computer generated from the website www.http://randomizer.org :

Group A (DCP C): Dexamethasone-cycloposphamide pulse (DCP) with daily oral cyclophosphamide

Hundred milligrams of dexamethasone dissolved in 500 ml of 5% dextrose given as slow IV infusion over 2 h and repeated on three consecutive days combined with 500 mg cyclophosphamide in the same infusion on any one of the three days, preferably on the second day. Such DCP were repeated at 4 weeks. They also received cyclophosphamide 50 mg orally per day. Additional oral prednisolone (0.5-0.75 mg/kg/day) was added after 2 weeks of initiation of therapy (first follow-up visit) if initial disease activity was not controlled with DCP C (patient developing ≥5 new lesions/day).

Group B (CP P): Cyclophosphamide pulse (CP) with daily oral prednisolone

Iv 0 cyclophosphamide (15 mg/kg/day) on one day every 4 weeks along with daily oral prednisolone (starting dose of 1.5 mg/kg/day, tapered to 1 mg/kg/day after 2 weeks and then by 10 mg every 4 weeks after disease remission, until maintenance dose of 10 mg/day was reached, which was maintained until the end of therapy). Patients were advised to increase their daily water intake to at least 3 L/day for 3 days, starting a day before pulse. Cyclophosphamide pulse was followed by hydration with 500 ml of 5% dextrose or normal saline. They were advised not to hold urine and to void on urge. All patients were given sodium 2-mercaptoethanesulphonate (MESNA) at a dose of 60% of cyclophosphamide in the same infusion. Oral ondansetron (8 mg) was administered if the patient complained of severe nausea and vomiting. All patients on daily steroids were given calcium carbonate vitamin D (500 mg) twice a day and pantoprazole 40 mg once a day.