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ORIGINAL ARTICLE
Year : 2014  |  Volume : 59  |  Issue : 1  |  Page : 30-34
Non comparative study on various pulse regimens (DCP, DAP and DMP) in pemphigus: Our experience


1 Department of Dermatology, STD and Leprosy, Government Medical College Srinagar, Kashmir, India
2 JLNM Hospital, Directorate Health Services Rainawari, Kashmir, India

Date of Web Publication23-Dec-2013

Correspondence Address:
Farah Sameem
J Faculty Quarters GMC Boys Hostel, Bemina Srinagar, Jammu and Kashmir
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-5154.123487

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   Abstract 

Background: Pemphigus has been treated with Dexamethasone Cyclophosphamide Pulse (DCP) Therapy since 1981.Various modifications have been suggested in the original regimen. These include Dexamethasone Azathioprine Pulse (DAP) and Dexamethasone Methotrexate Pulse (DMP) therapies. Aims: To report our experience on the noncomparative study of various Pulse regimens DCP, DAP AND DMP therapies in patients with Pemphigus. Materials and Methods: The patients were put on three regimens depending upon the situation-Conventional DCP, DAP in the reproductive age group, DMP in patients who showed prolonged Phase I more than 12 months while on DCP. Results: 30 patients were put on DCP therapy. The duration of phase I was on an average six months. Relapse was seen in 3 patients in phase IV. 12 patients on DAP therapy were considered. In Phase III 5 patients relapsed in phase IV four patients relapsed. Five patients were put on the DMP. Disease activity was poorly controlled and in three DMP was discontinued. Conclusion: DCP remains the most effective regimen with quickest onset of remission and continuance of remission. In DAP therapy fixation of dose of azathioprine at 50 mgs daily may be counterproductive. DMP does not fulfil the promise of a viable treatment option in recalcitrant pemphigus and this lacunae needs to be plugged.


Keywords: Pemphigus, pulse therapy, relapse


How to cite this article:
Hassan I, Sameem F, Masood QM, Majid I, Abdullah Z, Ahmad QM. Non comparative study on various pulse regimens (DCP, DAP and DMP) in pemphigus: Our experience. Indian J Dermatol 2014;59:30-4

How to cite this URL:
Hassan I, Sameem F, Masood QM, Majid I, Abdullah Z, Ahmad QM. Non comparative study on various pulse regimens (DCP, DAP and DMP) in pemphigus: Our experience. Indian J Dermatol [serial online] 2014 [cited 2019 Jun 18];59:30-4. Available from: http://www.e-ijd.org/text.asp?2014/59/1/30/123487

What was known?
DCP is an effective treatment optiom for pemphigus. DAP and DMP are modifications in the original regimens.



   Introduction Top


Pemphigus has been treated with Dexamethasone Cyclophosphamide Pulse (DCP) Therapy since 1981 with several studies having reported its efficacy. [1],[2],[3],[4],[5],[6] Various modifications have been suggested in the original regimen from time to time. [5],[6],[7],[8] The occurrence of premature ovarian failure (POF)/amenorrhoea/azoospermia leading to sterility with the administration of Pulse cyclophosphamide dose led to the search for a safer regimen to circumvent this side effect. [9] One recommendation was to withhold the monthly Cyclophosphamide pulse while allowing the daily oral cyclophosphamide 50 mg to be continued for the Phases I, II and III. Alternatively Dexamethasone Azathioprine (DAP) therapy consisting of Conventional Dexamethasone pulses in Phases I, II and daily oral azathioprine 50 mg in Phases I, II and III was recommended for patients in the reproductive age group and those who had not completed their families as azathioprine has no effect on gonads. [8] Some patients showed a poor response to conventional DCP and had a prolonged Phase I. In these patients an alternative immunosuppressant was given.Methotrexate 7.5 mg orally weekly was given for the first three phases along with Dexamethasone pulses in first two phases (DMP). [8]

DCP therapy has been used in our centre from1998. [3] However prior to 2004 DCP regimen used was the basic one in which the duration of Phase II was 6 months and that of Phase III was 12 months. Also no Additional Dexamethasone pulses were used in Phase I.


   Materials and Methods Top


This retrospective and prospective study was carried out on Native Kashmiri patients of Pemphigus from October 2004 to October 2010. The diagnosis of pemphigus was made on clinical grounds with confirmation being done by submitting the skin or mucosal biopsy for Histopathology and Direct Immunoflourescence. Due to non availability of facilities, Indirect immunoflourescence of serum for antibody levels could not be done. The approval of the Ethics committee of Government Medical College Srinagar was sought for the study. A complete demographic profile of the patients was taken including age, sex, occupation, marital status (especially if family has been completed) as also family history of pemphigus, menstrual history (in case of females) and any co morbid illness. The variant of pemphigus diagnosed in each case was noted and the duration of disease prior to diagnosis was recorded. The extent of skin involvement, presence and extent of mucosal involvement, presence of Nikolsky ' s sign was noted in each case. Exclusion criteria for pulse therapy were pregnancy, lactation, and age less than 18 years, uncontrolled diabetes, hypertension or any severe systemic disease where large dose steroids are contra indicated. All patients were admitted in the inpatient wing of the department. After taking informed consent, baseline investigations were done. These included a complete haemogram, renal and liver function tests, Blood sugar estimation, Skiagram chest, electrocardiogram, Mantoux test and Serum amylase. Baseline body weight and blood pressure recording was done. Depending upon the individual patient situation bacterial culture sensitivity from infected cutaneous lesions was taken. All patients were put on daily Condys baths, Rexidin gargles and sterile Vaseline gauze dressings. Antibiotics and antifungal were given in individual cases depending upon the presence of cutaneous or mucosal infection. Then the patients were put on three regimens depending upon the situation: Conventional DCP, DAP for patients in the reproductive age group and DMP in those in whom Phase I on DCP was more than 12 months. For this study only those patients with pemphigus who had completed Phases I, II and III on DCP, Phases I and II on DAP and all those put on DMP were included to simplify the results. All diabetics were administered 10U of insulin in the Dextrose 5% along with the pulse. Depending upon individual response ADP or daily steroids were given in phase I. The monitoring included monthly hemogram, Urine analysis, renal and liver function tests and six monthly skiagram chest for DCP, Weekly hemogram for first two weeks for Methotrexate, then monthly and monthly renal and liver function monitoring, weekly hemogram and liver function for Azathioprine for first month and then monthly. The presence of side effects was noted.

All patients were routinely administered daily calcium vitamin D supplements and weekly bisfosfonates. The number of treatment dropouts and mortality if any was noted. After completion of phase III, the patients were put on monthly follow-up.


   Results Top


Of the 50 consecutive patients, the total number of patients included in the present study were 47. One patient with a clinical (hypopyon sign positive) and histopathological diagnosis of Ig A pemphigus was not put on pulse therapy. Two other female patients who were married and had one offspring each were put on DP plus daily cyclophosphamide therapy in view of the very severe disease in them. Incidentally one of these developed secondary amenorrhoea which on investigation was secondary to premature ovarian failure. These three patients were excluded.

There were 11 males and 36 females patients included in the present study (M:F ratio being approximately 1:3). The age ranged from 18 to 70 years with an average age at presentation of disease being 40 years in males [Table 1]. A significant number of female patients were in early twenties to late teens indicating an earlier onset in females in our cohort of patients. No case of childhood onset pemphigus was seen.
Table 1: The age distribution of all patients


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The patients in the reproductive age group and those yet to complete their families were nine females and three males. Family history was positive in none. Majority were housewives. Socio economic conditions ranged from affluent in four, middleclass in 25 and poor in 18. Co morbid conditions included diabetes in six and hypertension in ten. The variants of pemphigus seen were vulgaris (41), Vegetans (4), foliaceous (2). No case of erythematosus, drug-induced or paraneoplastic pemphigus were seen in the present study. The extent of skin involvement by blistering and denudation at the time of presentation ranged from 0% to more than 90% body surface area. The duration from eruption till the time of seeking medical attention was ranging from three days to seven months with mucosal lesions being referred and diagnosed later than skin lesions. Mucosal involvement was seen in 45 patients. (45 oral, 4 genital, 1 conjunctiva). Cerebriform tongue (Premalathas sign) was seen in our female patients with P vegetans. Palmoplantar and nail involvement was seen in one young female patient with a severe disease who subsequently succumbed to the disease. One elderly male patient with prolonged Phase I on DCP therapy presented with dyshidrosiform lesions of pemphigus. One patients male aged 35 years presented with acral lesions predominantly and he showed a prolonged phase I. Eight patients had a positive bacterial swab needing antibiotics and five had mucosal candidiasis (oral in 5, vaginal in 3, esophageal in 2) needing antifungal at the time of admission.

30 patients were put on DCP, 12 on DAP therapy and 5 on DMP therapy [Table 2].
Table 2: The number of patients on each therapy


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30 patients were put on DCP. These included eight males and 22 females. Duration of disease prior to diagnosis was one day to seven months. Patients with disease presenting in or localised to oral mucosae were more likely to have a longer duration of disease prior to diagnosis due to lack of referral or misdiagnosis. Age range was 27-75 years majority being in their 40s. All these patients had completed their families.

P vegetans was present in two females, P foliaceous in two males while all others had p. vulgaris and the extent of involvement varied [Table 3] and [Table 4].

Mucosal involvement was seen in all except two with foliaceous. The duration of phase I was as short as one month in one patient [Table 5].
Table 3: The variants of pemphigus on DCP therapy

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Table 4: The extent of involvement in patients on DCP therapy

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Table 5: The duration of phase 1 on DCP

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On an average six months would suffice, It was as prolonged as 20 months in one patient (a young male with P.foliaceous who was not coming at fixed 28 day periods) but as the diseases activity remained mild therapy was continued.

One of the patients died in Phase I due to pulmonary embolism. All the patients completed phase II and III successfully. Relapse was seen in three patients. One of these was not regular in taking treatment and relapsed in Phase IV (male with severe mucosal involvement).The second patient relapsed after four years of completion of phase IV. These patients were again restarted on DCP therapy. ADP was needed in six patients for 3-4 months. Daily steroid therapy was given in 10 patients for 4-7 months. 1 patient developed haemorrhagic cystitis while on DCP while RBCs in urine were seen in 5 patients. 2 patients developed avascular necrosis head of femur while on DCP therapy. Both were young patients with a severe disease who had also taken daily oral steroids in their Phase II. Further treatment in these patients was challenging as disease and treatment side effects had to be weighed. One patient developed nail pigmentation on DCP.

12 patients with pemphigus who had completed phase I and II of DAP therapy were considered for the present discussion. These included 3 males and 9 females. Age range of patients was from 19-40 years. Seven patients were unmarried. 11 patients had p.vulgaris and 1 had p. vegetans. Mucosal involvement was seen in all patients. Majority had mild oral mucosal involvement only. One female had extensive orogenital lesions.

1 Patient had concomitant diabetes and none had hypertension. 9 patients had 10-30% involvement of BSA and 3 had 30-70% involvement.

Duration of phase I was less than 6 months in 1,6-12 months in 4 and greater than 12 months in 7 patients [Table 6].
Table 6: Duration of phase I on DAP


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Five patients needed ADP (for 3-6 months) and these five needed Daily steroids also (4-6 months). In phase II, one patient developed disease activity in the third month itself. This patient subsequently died in spite of ADP and daily steroids due to a very active disease leading to septicaemia. A significant relapse rate was seen [Table 7].
Table 7: The number of relapses on DAP

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In Phase III five patients relapsed at 5-9 months. In phase IV one patient relapsed just 15 days after discontinuing azathioprine. Three further patients relapsed in 4 th , 7 th and 12 th month. No case of leucopenia or hypersensitivity was seen.

Five patients one male and five females were put on the Dexamethasone Methotrexate therapy. Four patients had pemphigus vulgaris and one (female, 45yrs old) had pemphigus vegetans.

Age of the patients ranged from 40-60 yrs. None of the patients in this category had diabetes while two had hypertension and were on calcium channel blockers for the same. No coexistent cutaneous disease was present in any. One patient had been on DCP since the last thirteen months while all others had been on DCP since 9-12 months. ADP had been administered in two patients and daily steroids were given to all five while on DCP.

All five patients had mucosal involvement but severe orogenital and conjunctival lesions were seen in one female patient only (variant vegetans). Severity of disease on the basis of BSA was 10-30% in 1 and 30-70% in four. All patients had completed their families. Only one patient of these completed the first three phases of DMP therapy [Table 8]. Of the others disease activity was poorly controlled and hence one patient defaulted and in three others DMP was discontinued as patient response was poor.
Table 8: The course of disease on DMP


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Poor healing of lesions and an increased requirement for concomitant antibiotic and anti fungal therapy was felt in all five patients.


   Discussion Top


The criteria for confirmation of diagnosis did not include IIF as facilities for same are not available. The levels of Anti desmoglein 1 antibodies by ELISA and Anti Desmoglein 3 antibodies by ELISA have been found to corelate with the severity of cutaneous and mucosal involvement respectively. [10] This led to a grey area as regards the definition of severity of disease at the time of diagnosis by a reproducible and non biased criteria with no possibility of inter observer error. This criteria however remains controversial as a few other studies have shown that correlation of severity with antibody levels is not foolproof. Recently a clinical set of criteria for disease severity on the basis of mucosal involvement and body surface area denuded was suggested. [10] The same was however not available to us in the study. Individualised treatment on the basis of severity was not given. Hence whether the disease was mild or severe same megadoses of steroids and immunosuppressants were given. Even the daily steroid dose in Phase I was not individualised. A paradoxical worsening of disease seen after first few pulses in patients with mild disease at presentation was seen and had a bearing on patient compliance.

In contrast to studies from North India, a greater female preponderance was seen. The second most common type of Pemphigus seen was Pemphigus vegetans. [11] The younger age of patients and an increased female proportion of patients were similar as in studies from Iran. [12] In view of these two factors marital status and whether family was completed assumed greater importance in our cohort of patients. DAP would be recommended as a safer regimen as cases of POF was seen even with DP plus Daily cyclophosphamide regimen. [13],[14],[15] This corroborates the apprehensions raised in previous study that even daily cyclophosphamide 50 mg during three phases gives a high cumulative dose in grams which can have a disastrous effect on gonads even if monthly megadose has been withheld. Shortest duration of Phase I, quickest onset of response even in more extensive disease and lowest relapse rates were seen with conventional DCP regimen. Hence remission could be induced by DCP therapy. However noteworthy side effects were seen here These included Premature ovarian failure (seen prior to 2005 when DAP was not used), haemorrhagic cystitis and avascular necrosis head of femur. Pertinently only one case of unmasking of tuberculosis is in contrast to the increased incidence of tuberculosis seen in a parallel study on systemic sclerosis patients who were on dexamethasone pulsed therapy. [16]

Even though dexamethasone methotrexate pulse was given in poor responders it was seen that Phase I was still the longest in this group. This may be indicative of the more severe disease per se but poor healing of lesions with methotrexate may also contribute. One way of circumventing this problem would be to give a higher dose of Methotrexate in poor responders and to administer daily steroids on the basis of body weight.

Routine antibiotic and antifungal administration during Phase I was not given. [13],[14],[15]

Hence only if situation so demanded was antibiotic (quinolones for 7-10 days) or anti candidial treatment (fluconazole daily for 7-21 days) given.

Duration of Phase I and Relapses were seen more with azathioprine regimen as compared to DCP regimen suggesting that perhaps the present DAP regimen needs modification-Individualise the azathioprine dose rather than sticking to 50 mg daily in all cases.

A major grey area is the duration of Phase II and III being fixed at 9months.The decision should ideally include the elicitation of Dry, wet or microscopic Nikolskys sign, DIF findings and antibody levels by IIF at the end of phase I, II and III. [17],[18],[19]

Limitations of the study: Indirect immunoflourescence of the patients' serum for anti desmoglein antibodies was not done due to non availability of facilities for same. The major limitation of this study was that a randomised controlled trial was not done as the disease is a serious one and immediate treatment is needed. [9],[12]

 
   References Top

1.Pasricha JS, Gupta R. Pulse therapy with dexamethasone Cyclophosphamide Pulse in pemphigus, Indian J Dermatol Venereol Leprol 1984;50:199-203.  Back to cited text no. 1
    
2.Pasricha JS, Thanzama J, Khan UK. Intermittent high dose Dexamethasone Cyclophosphamide Pulse therapy for pemphigus. Br J Dermatol 1988;119:73-7.  Back to cited text no. 2
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3.Masood Q, Hassan I, Majid I, Khan D, Manzooi S, Qayoom S, et al. Dexamethasone Cyclophosphamide Pulse therapy in pemphigus: Experience in Kashmir valley. Indian J Dermatol Venereol Leprol 2003;69:97-9.  Back to cited text no. 3
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4.Dogra A, Gupta S, Khurana S. Dexamethasone Cyclophosphamide pulse therapy in Pemphigus a five year retrospective study. Indian J Dermatol 2003;48:18-21.  Back to cited text no. 4
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5.Pasricha JS. Pulse Therapy in Pemphigus and other diseases. 3 rd ed. Pulse Therapy and Pemphigus Foundation. New Delhi: [Available from: http://www.ijdvl.com/article.asp?issn=0378-6323;year=2008;volume=74;issue=3;spage=217;epage=221;aulast=Pasricha] 2006.  Back to cited text no. 5
    
6.Kandan S, Thappa DM. Outcome of Dexamethasone cyclophosphamide therapy in Pemphigus: A case series. Indian J Dermatol Venereol Leprol 2009;75:373-8.  Back to cited text no. 6
[PUBMED]  Medknow Journal  
7.Pasricha JS, Poonam. Current regimen of pulse therapy for pemphigus: Minor modifications, improved results. Indian J Dermatol Venereol Leprol 2008;74:217-21.  Back to cited text no. 7
[PUBMED]  Medknow Journal  
8.PN Rao, TS Lakshmi. Pulse therapy and its modifications in pemphigus. A six year study. Indian J Dermatol Venereol Leprol 2003;69:329-33.  Back to cited text no. 8
    
9.Saoji VA. Premature ovarian failure due to cyclophosphamide: A report of 4 cases in dermatology practice. Indian J Dermatol Venereol Leprol 2008;74:128-32.  Back to cited text no. 9
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10.Kumar B, Arora S, Sendhil M. Study of desmoglein 1 and 3 antibody levels in relation to disease severity in Indian patients with pemphigus. Indian J Dermatol Venereol Leprol 2006;72:203-6.  Back to cited text no. 10
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11.Kanwar AJ, Dipankar De. Pemphigus in North India. Indian J Dermatol Venereol Leprol 2011;77:39-49.  Back to cited text no. 11
    
12.Javidi Z, Meibidi NT, Nahidi M. Epidemiology of Pemphigus in north east Iran: A 10 year retrosspective study. Indian J Dermatol 2007;52:188-91.  Back to cited text no. 12
  Medknow Journal  
13.Singh S, Chaudhary R. Pulse therapy for Pemphigus: The burden of proof. Indian J Dermatol Venereol Leprol 2009;75:83-4.  Back to cited text no. 13
    
14.Raman M. Prolonged antimicrobial and oral cyclophosphamide therapy in pemphigus-need for caution. Indian J Dermatol Venereol Leprol 2009;75:85.  Back to cited text no. 14
    
15.Singh S. Pulse therapy. Evidence versus faith and unconditional other acceptance. Indian J Dermatol Venereol Leprol 2010;16:183-4.  Back to cited text no. 15
    
16.Masood Q, Hassan I, Nuaman Q, Sameem F, Sultan SJ. Increase incidence of tuberculosis in patients of systemic sclerosis on Dexamethasone Pulse therapy. Indian J Dermatol 2008;53:24-5.  Back to cited text no. 16
    
17.Vaishnavi JB, Basariya SS. Pemphigus: Active or inactive? Ind J Dermatol 2009;54:186-8.  Back to cited text no. 17
    
18.Hameed A, Khan AA. Microscopic Nikolskys sign. Clin Exp Dermatol 1999;24:312-4.  Back to cited text no. 18
[PUBMED]    
19.Salopeck TG. Nikolskys sign: Dry or wet. Br J Dermatol 1997;36:762-7.  Back to cited text no. 19
    

What is new?
DAP and DMP in pemphigus need further scrutiny.



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]



 

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