Combination of Intravenous Methylprednisolone and

Cyclophosphamide Pulse Therapy Weekly in Severe Autoimmune

Bullous Disease: A Preliminary Report

Jesslyn Amelia

, Prasta Bayu Putra

, Yohanes Widodo Wirohadidjojo

, Sunardi Radiono

Department of Dermatology and Venereology Faculty of Medicine, Gadjah Mada University / Dr. Sardjito General

Hospital, Yogyakarta, Indonesia

Keywords: pemphigus, bullous pemphigoid, cyclophosphamide, methylprednisolone, pulse therapy.

Abstract: Pemphigus vulgaris (PV), pemphigus foliaceus (PF), and bullous pemphigoid (BP) are amongst autoimmune

bullous skin diseases that are characterized by bullae formation at different levels of the skin. The mainstay

treatment is still by systemic corticosteroids, but the outcome is not satisfying with many side effects and

frequent relapse. One of the drugs that can be used as steroid-sparing agent is cyclophosphamide. In this

report, we evaluate the therapy outcome of intravenous methylprednisolone and cyclophosphamide pulsed

therapy (MCP) weekly in 6 patients with severe PV, PF, and BP who have completed six MCP. The severity

of the disease was measured using Pemphigus Disease Area Index (PDAI) for pemphigus and Bullous

Pemphigoid Disease Area Index (PBDAI) for bullous pemphigoid. The aim of this report is to evaluate the

therapy response and the side effects of this regimen therapy. After being given six MCP, four patients showed

excellent response therapy, one patient showed a good response therapy, while one patient showed a poor

response therapy. MCP might be an effective treatment for severe pemphigus and BP but the side effects

should be closely monitored. Further long follow up is needed to see the possibilities of relapse and the safety

of this regimen therapy to be used in larger sample population.

1 INTRODUCTION

Pemphigus is a rare autoimmune bullous skin

disease involving the skin and mucosa that is

characterized with intraepidermal bullae formation.

Pemphigus vulgaris (PV) is the most frequent type of

pemphigus, accounting for about 70% of cases, while

pemphigus foliaceus accounts for about 20%-30% of

cases (Joly, 2011). Bullous pemphigoid is an

autoimmune subepidermal blistering disease with

incidence is estimated to be between 6 and 20 new

cases per million people (Bernard, 2017). There were

27 cases of pemphigus vulgaris, 8 cases of pemphigus

foliaceus, and 9 cases of bullous pemphigoid

hospitalized in Dr. Sardjito General Hospital from

January 2015 to December 2017.

The mainstay therapy of PV, PF, and BP have

been systemic corticosteroids, which has reduced the

mortality rate from 75% to less than 10% since their

introduction in the 1950s. However, because of the

chronicity of the disease, prolonged therapy is

necessary, leading to the development of a wide

spectrum of corticosteroid related side effects. Thus,

mortality today are caused by treatment complication

of corticosteroids (Atzmony et al, 2015). Because of

the side effects associated with long-term systemic

corticosteroids, a lot of recent research has been

directed at finding the optimal steroid-sparing agent

(Daniel, 2014).

One of the drugs that can be used as a steroid-

sparing agent is cyclophosphamide. There was an

evidence of a steroid-sparing benefit for

cyclophosphamide compared with glucocorticoid

alone (Atzmony et al, 2015). In 1984, Parischa and

Ramji introduced intravenous corticosteroid and

cyclophosphamide pulse therapy monthly with 50 mg

cyclophosphamide orally given daily that is known to

have less side effects compared to corticosteroid

group alone and have longer remission period (Gupta,

2015),(Saha, 2010). Because cyclophosphamide oral

regimen was unavailable widely in Indonesia, we

modified this regimen into intravenous

methylprednisolone and cyclophosphamide pulse

therapy weekly with oral corticosteroid between the

514

Amelia, J., Putra, P., Wirohadidjojo, Y. and Radiono, S.

Combination of Intravenous Methylprednisolone and Cyclophosphamide Pulse Therapy Weekly in Severe Autoimmune Bullous Disease: A Preliminary Report.

DOI: 10.5220/0008161005140518

In Proceedings of the 23rd Regional Conference of Dermatology (RCD 2018), pages 514-518

ISBN: 978-989-758-494-7

pulse given twice per week. In this report, we evaluate

the therapy outcome of MCP weekly in 6 patients

with severe PV, PF, and BP who have completed six

pulsed therapy. The severity of the disease was

measured using Pemphigus Disease Area Index

(PDAI) for pemphigus and Bullous Pemphigoid

Disease Area Index (PBDAI) for bullous pemphigoid

(Rahbar, 2014), (Daniel, 2012), (Fuertes, 2014). The

aim of this report is to evaluate the therapy response

and the side effects of this regimen therapy.

2 CASE

Six patients were included in this report. It

consisted of one case of PF, one case of BP, and four

cases of PV. All patients had already undergone

various therapies previously. The baseline

characteristics of each patient are described in table

All patients had undergone biopsy and direct

immunofluorescent before starting MCP to ensure the

diagnosis of PV, PF, and BP. An informed consent

about the benefit, risk, and possible complication that

might happen was explained to the patient and their

family, and they were asked to sign an informed

consent form. Before starting MCP, evaluation of

electrocardiogram and laboratory test that consisted

of complete blood test, electrolytes, blood glucose,

albumin, renal and liver function test were done for

these patients. Contraindications include

hypersensitivity to this regimen, pregnancy and

lactation, altered renal and hepar function, leucopenia

(leucocyte < 3000/L), thrombocytopenia

(thrombocyte < 100000/L), and urine erythrocyte

sediment > 10/L. Methylprednisolone 250 mg

intravenous injection was given in the morning.

Premedication of cyclophosphamide that consisted of

10 mg diphenhidramine intravenous injection, 8 mg

ondansetron intravenous injection, and 100 mg of 2-

mercaptoethanesulfonate natrium (mesna) in 50 ml

NaCl 0.9% were given within 15 minutes. Then 500

mg of cyclophosphamide in 250 ml NaCl 0.9% was

given within 1-2 hours. After infusion of

cyclophosphamide was finished, 100 mg mesna in 50

ml NaCl 0.9% was given three times with interval of

three hours. Vital signs were assessed during and after

cyclophosphamide infusion. Evaluation of

electrocardiogram and urinalysis were done after the

MCP. This MCP regimen was repeated once weekly

for six consecutive weeks with methylprednisolone

varying from 32 mg to 64 mg given orally, twice a

week.

The severity of the disease was measured at

every visit using PDAI for patients with PV/PF, and

BPDAI for patient with BP. The score can be seen in

table 2 below.

Side effects were found in 2 patients. One patient

developed furuncles after the fourth injection of MCP

and was later healed with tetracycline 500 mg, four

times orally. One patient had nausea and vomiting

after three injection of MCP. Because of the severe

nausea and vomiting, one patient had the MCP given

every two weeks to minimize the side effects. Neither

of these patients developed severe hematologic

deprivation nor renal and liver failure.

Table 1. Baseline Characteristics of Patients Before Treatment with MCP.

Combination of Intravenous Methylprednisolone and Cyclophosphamide Pulse Therapy Weekly in Severe Autoimmune Bullous Disease: A

Preliminary Report

515

Table 2. PDAI and BPDAI Score

Figure 1. A 40 year old bullous pemphigoid patient. A-C: Pictures before starting MCP therapy; D-F: Pictures after given six

MCP therapy.

3 DISCUSSION

Cyclophosphamide is a nitrogen mustard

compound. After hepatic metabolization, it acts as an

actively alkylating agent, thus causing cross-linking

of DNA. While the half-life of the unmetabolized

substances is only short (4-6.5 hours), its metabolites

have a longer half-life. Cyclophosphamide

suppresses B and T lymphocyte responses. The

lymphocyte nadir (maximum reduction) after pulse

therapy is reached after 8-15 days. A return to

previous levels should be reached after 28 days. The

active metabolites are eliminated via the kidneys.

They are bladder toxic and may cause hemorrhagic

cystitis if hydration is insufficient. A fluid intake >

1.5 liters should be observed. The simultaneous

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administration of 2-mercaptoethansulfonat-natrium

(mesna) dose adapted is definitely to be considered

for high-dose and pulse therapy. Evaluation of

complete blood count, renal and liver function test,

electrolytes, as well as urinalysis should be performed

to closely monitor the side effects that might

happened (Eming, 2015), (Shimizu, 2014).

The side effects that were happened in this report

are furuncles in one patient after the fourth MCP that

was healed after administration of systemic

antibiotics, and nausea/vomiting in one patient after

the third MCP. These side effects are common as

reported before in the previous study. Patients with

MCP therapy are more susceptible to infections,

especially when the skin and/or mucosa are eroded.

Nausea and vomiting are the most common

gastrointestinal side effects that occurred in MCP

patients (Gupta, 2015),(Saha, 2010). Any other side

effects like hematological abnormalities

(thrombocytopenia, leucopenia), electrolyte

imbalance, and signs of bladder toxicities were not

found in these patients receiving MCP.

Figure 2. The Average of PDAI and BPDAI Score.

We used PDAI and BPDAI score as the disease

severity measurement of this report because it had the

highest validity (Rahbar, 2014), (Fuertes, 2014). The

PDAI score can be classified as mild (score 0-8),

moderate (score 9-24), and severe (score > 25)

(Shimizu, 2014). At the beginning of this study all

patients had severe disease. After being given six

MCP, four patients showed excellent response

therapy with PDAI/BPDAI score < 8, one patient

showed a good response with PDAI score classified

as moderate, while one patient showed a poor

response therapy. The patient with poor response to

the therapy might be caused by uncontrolled diabetes

mellitus. Although the patient had already been given

subcutaneous insulin daily, the glycemic control was

still poor because of unhealthy diet of this patient.

4 CONCLUSIONS

After being given six MCP, four patients showed

excellent response therapy, one patient showed a

good response therapy, while one patient showed a

poor response therapy. MCP might be an effective

treatment for severe pemphigus and BP but the side

effects should be closely monitored. Further long

follow up is needed to see the possibilities of relapse

and the safety of this regimen therapy to be used in

larger sample population.

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