|Year : 2018 | Volume
| Issue : 2 | Page : 69-73
Outcome of pulse therapy in pemphigus: A 10-year study
Sirisha Varala1, Shashikant Malkud1, Geeta Kiran Arakkal1, Divya Siddavaram2
1 Department of Dermatology, Venereology and Leprosy, MNR Medical College and Hospital, Sangareddy, Telangana, India
2 Department of Dermatology, Venereology and Leprosy, Kamineni Institute of Medical Sciences, Hyderabad, Telangana, India
|Date of Web Publication||10-Jul-2018|
Department of Dermatology, Venereology and Leprosy, MNR Medical College and Hospital, Sangareddy - 502 294, Telangana
Source of Support: None, Conflict of Interest: None
Background: Pemphigus is a potentially fatal autoimmune blistering disease affecting the skin and mucosa. Pulse therapy has been tried in pemphigus in India and other countries with variable results. Aims: The aim of the study was to assess the outcome of pulse therapy in pemphigus patients treated over a period of 10 years. Materials and Methods: Patients with pemphigus treated with pulse therapy from 2006 to 2016 were taken into the study. Results: A total of 122 pemphigus patients were included in the study, of which pemphigus vulgaris was diagnosed in 112 patients, pemphigus foliaceus in 9 patients, and pemphigus vegetans in 1 patient. The mean age was 37.75 ± 8.60 years, with an age range of 19–58 years. Duration of the disease ranged from 7 days to 3 years, with a mean of 6.87 ± 8.81 months. Ninety-three patients were started on dexamethasone cyclophosphamide pulse therapy and 29 on dexamethasone azathioprine pulse therapy. Thirty-three patients discontinued treatment, pulse therapy was stopped in two patients due to complications, and four patients died while on treatment. Out of the remaining 83 patients, 22 patients were in Phase I, 13 in Phase II, 7 in Phase III, and 41 in Phase IV by the end of the study. Sixty-one patients completed Phase I and were maintaining remission. Seven patients relapsed (3 in Phase II and 2 each in Phase III and IV). Ten patients completed 5 years of Phase IV and were considered cured of the disease. Generalized weakness, myalgia, headache, diabetes, and amenorrhea were the most common side effects. Conclusion: Pulse therapy was found to be effective in inducing and maintaining remission in the treatment of pemphigus. Prevention of relapses requires continuation of the treatment during Phase II and III.
Keywords: Azathioprine, cyclophosphamide, dexamethasone, pemphigus, pulse
|How to cite this article:|
Varala S, Malkud S, Arakkal GK, Siddavaram D. Outcome of pulse therapy in pemphigus: A 10-year study. Clin Dermatol Rev 2018;2:69-73
| Introduction|| |
Pemphigus is a potentially life-threatening, autoimmune blistering disorder of skin and mucous membranes characterized by autoantibodies directed against desmogleins 1 and/or 3 in the epidermis. Incidence of pemphigus varies from 0.09% to 1.8% among dermatology outpatients. The disease which was almost considered fatal previously has seen a revolutionary change in the treatment modality with the introduction of dexamethasone-cyclophosphamide pulse (DCP) therapy by Pasricha et al., Here, we report the outcome of pulse therapy in 122 patients of pemphigus treated over a period of 10 years.
| Materials and Methods|| |
Our study was both prospective as well as a retrospective hospital-based study conducted from January 2006 to January 2016. Patients with pemphigus who were started on pulse therapy from 2012 to 2016 were prospectively analyzed, while retrospective analysis was done on patients treated from 2006 to 2011. Patients with confirmed pemphigus attending the dermatology outpatient department at a tertiary care center in South India were included in the study. Diagnosis of pemphigus was based on clinical features, Tzanck smear, histopathology, and direct immunofluorescence study of skin/mucous membrane biopsy. Patients with uncontrolled hypertension and diabetes mellitus, systemic infections, cardiac disease, renal disease, liver disease, and pregnant women were excluded from the study.
All patients were started on DCP therapy, except for unmarried patients and patients of reproductive age group who had not completed their family. These patients were considered for dexamethasone azathioprine pulse (DAP) therapy.
All the patients were admitted, and a thorough clinical and laboratory evaluation was done before starting pulse therapy. Routine investigations including complete blood count, random blood sugar level, complete urine examination, liver function tests, renal function tests, serum electrolytes, stool examination, electrocardiogram, and blood pressure recording were done at the first visit and then before every pulse thereafter. Chest X-ray and two-dimensional echo were done before the first pulse in all the patients.
The entire treatment was divided into four phases as per Pasricha and Poonam  schedule.
Phase I – Patients received monthly doses of 100 mg of dexamethasone dissolved in 500 ml of 5% dextrose by slow intravenous infusion over 2 h on 3 consecutive days along with 500 mg of cyclophosphamide in the infusion on day 2. In between the pulses, patients received 50 mg of oral cyclophosphamide daily. In known diabetic cases, 10 units of soluble insulin was added to each 500 ml of 5% dextrose.
Patient's blood pressure, pulse rate, heart, and lungs were monitored every 15 min during the period of infusion. Serum electrolytes and electrocardiography were repeated after completion of each pulse.
The cycles were repeated at 28-day interval starting from day 1 of the previous cycle and continued until patient achieves remission, i.e., development of no new lesions with healing of all existing lesions with the withdrawal of intermittent steroids.
Phase II – Patients who achieved remission were shifted to Phase II wherein they received monthly pulses and daily oral cyclophosphamide for a fixed period of 9 months.
Phase III – Only daily oral cyclophosphamide 50 mg was given for an additional 9 months.
Phase IV – All treatment withdrawn and patients were followed up for relapse, if any.
In DAP pulse therapy, cyclophosphamide bolus dose on day 2 was omitted, and a daily dose of 50 mg of azathioprine was given throughout the pulses.
In patients with severe disease at presentation, high-dose oral steroids in divided doses were started initially for rapid control of disease and gradually tapered while starting pulse therapy. Intermittent oral steroids were given in patients with recalcitrant oral and skin lesions. Systemic antibiotics were given in cases with secondary infection.
| Results|| |
A total of 122 patients were included in the study, of which 80 were females and 42 were males, with a male-to-female ratio of 0.5:1. The mean age was 37.75 ± 8.60 years, with an age range of 19–58 years. Majority of the patients were in the age group of 30–40 years. One hundred and twelve patients were diagnosed as pemphigus vulgaris, 9 patients as pemphigus foliaceus, and 1 patient as pemphigus vegetans. Out of 112 pemphigus vulgaris patients, both skin and mucosal lesions were present in 107 patients, only skin lesions in 3 patients, and only mucosal lesions in 2 patients. Duration of the disease ranged from 7 days to 3 years, with a mean of 6.87 ± 8.81 months. Sixty-six patients presented with 1st episode, whereas 56 patients had a history of recurrent episodes. One hundred and twelve patients gave a history of receiving treatment other than pulse therapy before presenting to us, of which 44 patients received oral and/or topical steroids.
Course of pulse therapy received by the patients (phase wise)
Phase I: At the end of the study, 22 patients were still receiving Phase I of pulse therapy. Eighteen patients had discontinued and three patients died during Phase I. Two patients developed avascular necrosis of femur during Phase I of DCP therapy and hence treatment was stopped. Thirty-two patients (51.6%) who were on DCP therapy achieved remission after 6–9 pulses, whereas 9 patients (42.8%) on DAP achieved remission after 9–12 pulses. Phase I duration ranged from 4 to 24 months, with a mean of 10.6 ± 4.40 months.
Phase II: 13 patients were still receiving Phase II at the completion of the study. Nine patients discontinued and one patient died during Phase II.
Phase III: Seven patients were still in Phase III and were maintaining remission.
Phase IV: Forty-one patients reached Phase IV, of which ten patients had completed 5 years and were considered cured of the disease.
Seven patients (5 on DCP and 2 on DAP) developed new lesions after attaining remission (3 in Phase II and 2 each in Phase III and IV). Patients who developed new lesions in Phase II were shifted back to Phase I, whereas those in Phase III and Phase IV were restarted with pulse therapy except in one patient where the relapse was mild in severity and was controlled with a short course of oral and topical steroids.
Fifty-seven patients required daily steroids in between pulses. One patient who showed poor response to DAP was shifted to DCP following which remission was attained. One patient with severe pemphigus vulgaris refractory to DCP therapy was started on infusions of rituximab 375 mg/m 2 body surface area weekly  but eventually succumbed to septicemia and death after two doses. Four patients (3 on DCP and 1 on DAP) died while on treatment with pulse therapy. The causes of death were septicemia in three patients and acute respiratory distress syndrome in one patient [Table 1]. Side effects observed during the therapy were divided into immediate and delayed [Table 2] and [Table 3].
|Table 1: Outcome of dexamethasone-cyclophosphamide pulse and dexamethasone azathioprine pulse therapies|
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|Table 2: Immediate side effects observed in the present study in comparison to Kandan et al. study|
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|Table 3: Delayed side effects observed in the present study in comparison to Kandan et al. study|
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| Discussion|| |
Pemphigus was considered as a fatal disease before the advent of glucocorticoids. The prognosis of the disease has improved with the use of systemic steroids and other immunosuppressives which are considered as the mainstay of treatment. Introduction of pulse therapy for the treatment of pemphigus by Pasricha has revolutionized the therapy from mere control to probable cure. Further, it has been observed that complete remission is possible with the introduction of definitive and potent immunosuppressive therapy at the initial stages of the disease.
Although pemphigus is a disease of middle age, the patients are younger at presentation in India. Our study also found that the majority of the patients were in the age group of 30–40 years, with a mean age of 37.75 ± 8.60 years. This finding was similar to a study conducted by Rao et al. wherein the patients were of the age group of 30–40 years. However, Kandan et al. reported a higher age group with a majority of the patients between 40 and 59 years with a mean age of 44.65 ± 11.85 years. As pemphigus affects the young and the middle-aged population, it has a significant impact on the socioeconomic condition of the family.
In the present study, mean duration of disease before initiation of pulse therapy was 6.87 ± 8.81 months. This finding was almost similar to Kandan et al. study where the mean duration was 6.2 ± 9.47 months.
Administration of monthly high doses of steroids in a pulse has been shown to induce early remission with lesser side effects. In our study, remission was achieved and maintained in 47 cases (70.1%) on DCP and 14 cases (63.6%) on DAP. In a study by Rao et al, remission was achieved in 29 out of 30 pemphigus patients (96.6%) treated with DCP therapy. Pasricha et al. treated 103 pemphigus patients with DCP therapy and noted 100% remission in their study. Azathioprine is an alternative adjuvant treatment option in patients who have not completed their family. A study from Yemen reported remission in 8 out of 11 pemphigus patients treated with DAP therapy. Results of the present study apparently indicate that DCP therapy is efficacious as compared to DAP therapy in inducing remission in pemphigus patients. However, statistical analysis between two groups could not be done which is the major limitation of the study.
Thirty-two patients (51.6%) who were on DCP therapy achieved remission after 6–9 pulses, whereas nine patients (42.8%) on DAP therapy achieved remission after 9–12 pulses. The shortest duration of Phase I in our study was 4 months and longest was 24 months. In a study by Rao et al, 54% of the patients completed Phase I in 6 pulses and 75% in 9 pulses. In a study by Pasricha et al. with minor modifications, i.e., thorough cleaning of skin and scalp, addition of oral betamethasone in Phase I, and use of systemic antibiotics and anti-Candida drugs where required, the duration of Phase I was reduced in most of the cases to 3–4 months.
Relapse in pemphigus is defined as the appearance of 3 or more new lesions that do not heal spontaneously within 1 week, or by the extension of established lesions, in a patient who has achieved disease control. Five patients on DCP therapy and two patients on DAP therapy relapsed, of which 4 were irregular in taking the pulses. Recently, Pasricha et al. reported a low-relapse rate of 7.7%, where majority of the patients completed the regimen strictly according to the prescribed schedule. Hassan et al. reported relapse in 9 (75%) of 12 pemphigus patients treated with DAP therapy. Treatment administered during Phase II and III is necessary for long-term clinical remission. Most of the relapses in the pemphigus patients treated with DCP therapy are known to occur during the first 2 years of post-treatment follow-up period. Without any maintenance treatment if the patient does not get any relapse in 5 years, it is reasonable to presume that the patient has been cured. On this basis, ten pemphigus patients in our study were declared to have been cured of the disease.
The lengthy duration of pulse therapy is associated with poor compliance and higher dropout rates. In our study, the dropout rate was 27%. This finding is slightly higher than the findings of Kandan et al. study  and Rao et al, who had reported dropout rates of 21.5% and 17%, respectively. Mahajan et al. in their study reported a high dropout rate (58%). The probable reasons for dropouts in our study were a long duration of treatment, repeated hospitalization, and negligence in continuation of treatment once remission was achieved.
The pulse dose of steroids has been associated with fatal outcomes although very rare. In our study, four (4.5%) patients had died (3 on DCP and 1 on DAP), while on pulse therapy. The causes of death were septicemic shock in three patients and acute respiratory distress syndrome in one patient. Pasricha had reported 19 deaths in 500 pemphigus patients treated with DCP therapy, of which 12 deaths were not related to DCP therapy. Roy et al. reported 4 deaths among 37 patients of pemphigus treated with DCP therapy, of which two patients died of septicemia, one each from peripheral circulatory failure and cardiac arrest. A thorough investigation of the patient before and after each pulse, appropriate management of underlying infections before initiation of pulse therapy, barrier nursing of the pemphigus erosions, and proper education of the patient regarding personal hygiene would help in further reducing the mortality risks.
According to Pasricha et al., side effects of pulse therapy are lesser compared to conventional method of administering systemic corticosteroids and other immunosuppressive drugs. Most of the side effects in the present study were observed in Phase I of pulse therapy. Generalized weakness was the most common side effect noted during infusion of pulse therapy which lasted for 4–7 days. Long-term side effects such as Cushingoid facies, osteoporosis, and cataract were seen in patients who were given intermittent doses of oral steroid for prolonged periods.
Gonadal toxicity is a well-known side effect of cyclophosphamide. Infertility due to ovarian failure is probably the most common and serious side effect of cyclophosphamide. High incidence of amenorrhea and oligomenorrhea was noted in the present study. A similar observation was made in other studies by Kandan et al. and Mahajan et al., Pasricha noted amenorrhea in about 50% of the female patients who received DCP therapy for pemphigus. No specific side effects related to azathioprine were observed in our patients.
Other immunosuppressants such as mycophenolate mofetil, cyclosporine, and methotrexate are tried in the treatment of pemphigus with variable efficacy. Currently, in India, novel-targeted therapeutic agents such as rituximab and intravenous immunoglobulins are increasingly used. Emerging therapies include plasmapheresis, immunoadsorption, and extracorporeal photopheresis. Rituximab is being used as the first-line therapy in the management of pemphigus at various centers due to early remission, fewer relapses, and better prognosis.,, However, cost, availability, lack of expertise, and limited clinical experience are the major drawbacks with rituximab.
Pulse therapy in the management of pemphigus is being considered as the first-line treatment option in many dermatology centers in India, and the results are quite encouraging. Prevention of relapses requires strict adherence to the treatment schedule.
A number of patients receiving DAP therapy were less in our study due to which comparative analysis between DCP and DAP could not be done.
| Conclusion|| |
Salient features of the study include:
- Pulse therapy has been shown to have good remission rates in the treatment of pemphigus
- Outcome of DCP was found to be better as compared to DAP therapy; however, randomized control trials with large sample size are required to confirm this observation
- Considering high rates of amenorrhea and oligomenorrhea in females on DCP therapy and gonadal toxicity due to cyclophosphamide, DAP seems to be a good alternative in patients of reproductive age group
- Emphasizing on continuation of the treatment during Phase II and III and also on taking the pulses regularly is absolutely essential for preventing further relapses.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]